Sampson's Textbook of Radiopharmacy

Title_Page Dated: 16/11/2010 At Time: 18:12:8

Sampson's Textbook of Radiopharmacy

Sampson's Textbook of Radiopharmacy
Title_Page Dated: 16/11/2010 At Time: 18:12:8
Sampson's Textbook of Radiopharmacy
Title_Page Dated: 16/11/2010 At Time: 18:12:8

Sampson's Textbook
of Radiopharmacy
FOURTH EDITION

Edited by
Tony Theobald
Formerly at the Department of Pharmacy,
King's College, London

On behalf of the UK Radiopharmacy Group

Sampson's Textbook of Radiopharmacy
Copyright Dated: 16/11/2010 At Time: 21:20:26

Published by Pharmaceutical Press

1 Lambeth High Street, London SE1 7JN, UK

1559 St. Paul Avenue, Gurnee, IL 60031, USA

Ó Ms Frances Paris

is a trade mark of Pharmaceutical Press

Pharmaceutical Press is the publishing division of the

Royal Pharmaceutical Society of Great Britain

First, second and third editions published by

Gordon & Breach Science Publishers Ltd 1990, 1994, 1999
Fourth edition published by Pharmaceutical Press 2011

Typeset by Thomson Digital, Noida, India

Printed in Great Britain by TJ International, Padstow, Cornwall

ISBN 978 0 85369 789 3

All rights reserved. No part of this publication may be reproduced,

stored in a retrieval system, or transmitted in any form or by any means,
without the prior written permission of the copyright holder.
The publisher makes no representation, express or implied, with regard
to the accuracy of the information contained in this book and cannot accept
any legal responsibility or liability for any errors or omissions that may be made.
The right of Tony Theobald to be identified as the author of this work
has been asserted by him in accordance with the Copyright, Designs and
Patents Act, 1988.

A catalogue record for this book is available from the British Library.
Sampson's Textbook of Radiopharmacy
Contents Dated: 16/11/2010 At Time: 17:20:54

Contents

Preface ix
About the editor xi
Contributors xiii
Abbreviations xv

1 What is radiopharmacy? 1
Tony Theobald

Section A Physics applied to radiopharmacy 9

2 Nuclear structure and radioactivity 11
Richard Fernandez
3 Radiation protection 23
Stanley Batchelor
4 Detection of radiation 47
Alan C Perkins and John E Lees
5 Physics applied to radiopharmacy: imaging instruments for nuclear medicine 61
Brian F Hutton
6 Production of radionuclides 73
Steve McQuarrie

Section B Radiopharmaceutical chemistry 85

7 Radiopharmaceutical chemistry: basic concepts 87
Philip J Blower
8 Fundamentals of technetium and rhenium chemistry 101
Adriano Duatti
9 Trivalent metals and thallium 125
Adrian D Hall
10 Radiohalogenation 141
Maggie Cooper
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vi | Contents

11 Radiolabelling approaches with fluorine-18 157

Julie L Sutcliffe and Henry F VanBrocklin
12 Carbon-11 181
Tony Gee
13 Other radioelements 189
Philip J Blower
14 Radiolabelling of biomolecules 201
Stephen J Mather

Section C Radiopharmacokinetics 217

15 Radiopharmacokinetics 219
Roger D Pickett, with the collaboration of colleagues at GE Healthcare
16 Receptors and transporters 251

James M Stone and Erik A rstad
17 Radiation dosimetry for targeted radionuclide therapy 263
Glenn Flux

Section D Radiopharmaceutics 275

18 Survey of current diagnostic radiopharmaceuticals 277
Paul Maltby, Tony Theobald and members of the UK Radiopharmacy Group
19 Survey of current therapeutic radiopharmaceuticals 303
Pei-San Chan and Jilly Croasdale
20 Formulation of radiopharmaceuticals 325
James R Ballinger
21 Principles and operation of radionuclide generators 339
Joao Osso and Russ Knapp
22 Quality assurance requirements 365
Alison Beaney
23 Quality control methods for radiopharmaceuticals 371
Tony Theobald and Paul Maltby
24 Radiolabelling of blood cells: theory and practice 421
Beverley Ellis
25 Particulate radiopharmaceuticals 447
Peter Williamson, Pei-San Chan and Richard Southworth

Section E Radiopharmacy practice 465

26 Design and operation of radiopharmacy facilities 467
Tom Murray and David Graham
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Contents | vii

27 Regulation of radiopharmacy practice in Europe 483

Clemens Decristoforo
28 Regulation of radiopharmacy practice in the United Kingdom 495
Neil G Hartman
29 Regulation of nuclear pharmacy practice in the United States 501
Joseph C Hung
30 Packaging and transport of radiopharmaceuticals 525
Alistair M Millar
31 Patient safety and dispensing of radiopharmaceuticals 531
James Thom
32 The effect of patient medication and other factors on the
biodistribution of radiopharmaceuticals 541
Sue Ackrill
33 Use of drugs to enhance nuclear medicine studies 555
Helen Whiteside

Section F Techniques in research and development 575

34 Molecular biology techniques in radiopharmaceutical development 577
Jane Sosabowski
35 Chemical characterisation of radiopharmaceuticals 589
Philip J Blower
36 Evaluation of radiopharmaceuticals using cell culture models 605
Daniel Lloyd
37 Animal models: preclinical molecular imaging, why and how? 617
Richard Southworth

Appendix 633
Glossary 639
Index 685
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Contents Dated: 16/11/2010 At Time: 17:20:54
Sampson's Textbook of Radiopharmacy
Preface Dated: 16/11/2010 At Time: 17:20:3

Preface

Some ten years have passed since the last edition of the Americas, thus giving a wide view of the state of
‘Sampson’ was published and the science and art of radiopharmacy. The book is intended for advanced
radiopharmacy have changed considerably over the students and radiopharmacy practitioners and covers
decade. The need for a new edition of this textbook the various aspects of radiopharmacy, from physical
was long felt by radiopharmacists and the current edi- principles through radiopharmaceutical chemistry,
tor was invited to oversee the compilation of this edi- radiopharmacology, radiopharmaceutics and radio-
tion by the United Kingdom Radiopharmacy Group. pharmacy practice, to new material on techniques in
Many changes have occurred in practice since the radiopharmaceutical research and development.
last edition. The emergence of positron emission tomo- Thanks are due to many people who have made
graphy (PET) and short-lived radiopharmaceuticals, this book possible, including members of the United
new imaging modalities, new types of radiopharma- Kingdom Radiopharmacy Group. My thanks go par-
ceuticals, changes in practice and regulation, and mer- ticularly to a small group comprising Dr J Ballinger,
gers of commercial suppliers have all influenced the Professor P Blower. Mr Guinness and Professor S
way in which radiopharmacy is practised throughout Mather who were instrumental in advising on the con-
Europe and other parts of the world, coupled with the tent and choice of authors. My thanks go to the pub-
recent global shortage of molybdenum-99 which has lishers for their understanding and support during the
affected the supply of that most popular and versatile prolonged gestation of this volume. Lastly, thanks to
radionuclide, technetium-99m, for imaging studies. my wife Patricia whose immeasurable patience and
This edition has been completely revised and re- understanding enabled this work to reach the press.
written with many new chapters covering topics gain-
ing importance since the last edition. The contributors Tony Theobald
have been drawn from many parts of Europe and Bishop’s Castle, Shropshire, UK
Sampson's Textbook of Radiopharmacy
Preface Dated: 16/11/2010 At Time: 17:20:3
Sampson's Textbook of Radiopharmacy
About the editor Dated: 16/11/2010 At Time: 17:18:55

About the editor

Tony Theobald is a Fellow of the Royal Pharma- as Dean of the School of Health and Life Sciences at
ceutical Society, whose career was in academic phar- King’s College in 2005, only to be asked to come back
macy at Chelsea and King’s Colleges, University of part-time to design and run a new Masters programme
London. in Radiopharmaceutics and PET Radiochemistry in
After completing his PhD on medicinal chemistry the School of Medicine.
in the 1960s, his main teaching and research interests Now fully retired, he took on the editorship of this
were the study of the quality and purity of medicines, volume at the request of the United Kingdom
and the design and formulation of radiopharmaceu- Radiopharmacists Group. His other interest is pharmacy
ticals. He was instrumental in devising and running history; he is a member of the British Society for the
numerous courses in radiopharmacy for practising History of Pharmacy and has been studying the history
radiopharmacists over a thirty-year period. He retired of pharmacy in Shropshire for a number of years.
Sampson's Textbook of Radiopharmacy
About the editor Dated: 16/11/2010 At Time: 17:18:55
Sampson's Textbook of Radiopharmacy
Contributors Dated: 16/11/2010 At Time: 17:48:28

Contributors

Sue Ackrill BSc, MSc, MRPharmS, Radiopharmacist, Nuclear Medicine Centre, Central Manchester
Queen Elizabeth Hospital, Birmingham, UK University Hospitals, Manchester, UK

Erik A rstad BSc, MSc, MRSC, PhD, Senior Lecturer Richard Fernandez BSc, Clinical Scientist, Guy’s and
in Radiochemistry, Institute of Nuclear Medicine, St Thomas’ NHS Trust, London, UK
University College London, London, UK Glenn Flux PhD, Physics Department, Royal Marsden
James R Ballinger PhD, Chief Radiopharmaceutical Hospital, Sutton, Surrey, UK
Scientist, Guy’s and St Thomas’ NHS Foundation Tony Gee PhD, Director PET and Radiotracer
Trust, London, UK Development, GlaxoSmithKline plc, UK
Stan Batchelor BSc, MSc, CPhys, CRadP, MInstP, David Graham BPharm MRPharmS, Chief Radio-
MIPEM, MSRP, Head of Radiation Safety, Medical pharmacist, Aberdeen Royal Infirmary, Aberdeen,
Physics Department, Guy’s and St Thomas’ NHS Scotland, UK
Foundation Trust, London, UK
Adrian D Hall BSc, PhD, Physics Department, Royal
Alison M Beaney DProf, MSc, MRPharmS, Regional Marsden Hospital, Sutton, Surrey, UK
Quality Assurance Specialist, North-East Region
Dr Neil G Hartman BPharm, MSc, PhD, Head of
NHS, Newcastle, UK
Radiopharmacy, Barts and The London NHS Trust,
Philip J Blower BA, DPhil, CChem, MRSC, Professor London, UK
of Imaging Chemistry, King’s College London,
Joseph C Hung PhD, BCNP, FASHP, FAPhA,
Division of Imaging Sciences, Rayne Institute, St
Professor of Pharmacy, Professor of Radiology,
Thomas’ Hospital, London, UK
Mayo Clinic College of Medicine; Director of
Pei-San Chan BSc, MSc, MRPharmS, Principal Nuclear Pharmacy Laboratories, Director of PET
Radiopharmacist, Nuclear Medicine Department, Radiochemistry Facility, Mayo Clinic, Rochester,
Royal Free Hampstead NHS Trust, London, UK Minnesota, USA
Maggie Cooper PhD, Department of Nuclear Brian F Hutton BSc, MSc, PhD FACPSEM, Professor of
Medicine, St Bartholomew’s Hospital, London, UK Medical Physics in Nuclear Medicine, and Molecular
Jilly Croasdale BPharm, MRPharmS, Head of Imaging Science, Institute of Nuclear Medicine, UCL
Radiopharmacy for Sandwell and West Birmingham and UCLH NHS Foundation Trust, London, UK
NHS Trust, West Midlands, UK Russ Knapp Jr PhD, Manager, Nuclear Medicine
Clemens Decristoforo MSc, PhD, Radiopharmacist, Program, Nuclear Science and Technology Divi-
Clinical Department of Nuclear Medicine, Medical sion, Corporate Fellow, ORNL, Oak Ridge National
University Innsbruck, Innsbruck, Austria Laboratory (ORNL), Oak Ridge, Tennessee, USA
Adriano Duatti PhD, Professor, Laboratory of John E Lees BSc (Hons), PhD, CPhys, MInstP,
Nuclear Medicine, Department of Radiological Reader in Space Physics, Department of Physics and
Sciences, University of Ferrara, Italy Astronomy, University of Leicester, Leicester, UK
Beverley Ellis BPharm, PhD, MRPharmS, CSci, Daniel R Lloyd PhD, Senior Lecturer, School of
CChem, MRSC, Consultant Radiopharmacist, Biosciences, University of Kent, Canterbury, UK
Sampson's Textbook of Radiopharmacy
Contributors Dated: 16/11/2010 At Time: 17:48:28

xiv | Contributors

Paul Maltby CSci MIPEM MRPharmS, Chief Jane Sosabowski, Department of Nuclear Medicine,
Radiopharmacist, Radiopharmacy Department, St Bartholomew’s Hospital London, London, UK
Royal Liverpool University Hospital, Liverpool, Richard Southworth BSc, PhD, Lecturer, Division
UK of Imaging Sciences, King’s College London,
Stephen J Mather PhD, FRPharmS, Professor, Centre London, UK
for Molecular Oncology and Imaging, Institute of James M Stone MBBS, MRCPsych, PhD, Clinical
Cancer, Barts and The London School of Medicine Senior Lecturer in Biological Psychiatry, Imperial
and Dentistry, London, UK College London, London, UK
Steve McQuarrie PhD, Professor, Faculty of Medicine Julie L Sutcliffe BSc, MSc, PhD, Associate Professor,
and Dentistry, University of Alberta, Edmonton, Department of Biomedical Engineering, Division of
Alberta, Canada Hematology-Oncology Director, Cyclotron and
Alistair M Millar PhD, FRPharmS, Principal Radio- Radiochemistry Facility, Center for Molecular and
pharmacist, The Royal Infirmary of Edinburgh, Genomic Imaging, University of California, Davis,
Edinburgh, Scotland, UK California, USA
Tom Murray MSc, PhD, MRPharmS, West of Tony Theobald BPharm, PhD, FRPharmS, Bishop’s
Scotland Regional Radiopharmacist, Radionuclide Castle, Shropshire, UK
Dispensary, Western Infirmary, Glasgow, Scotland, James Thom DipRadSci, BPharm, MRPharmS,
UK Principal Radiopharmacist, Nuclear Medicine,
Joao Osso PhD, Head of Research and Development, Southampton University Hospitals NHS Trust,
Radiopharmacy Center, IPEN-CNEN-SP, S~ao Paulo, Southampton, UK
SP, Brazil Henry F VanBrocklin PhD, Director of Radio-
Alan C Perkins BSc, MSc, PhD, CSci, FIPEM, ARCP, pharmaceutical Research, Professor, Department of
FRCR, Professor of Medical Physics and Honorary Radiology and Biomedical Imaging, University of
Consultant Clinical Scientist, University of California San Francisco, San Francisco, USA
Nottingham and Nottingham University Hospitals Helen Whiteside BPharm, MRPharmS, Specialist
NHS Trust, Medical School, Queen’s Medical Clinical Pharmacist – Radiopharmacy, Leeds
Centre, Nottingham, UK Teaching Hospitals NHS Trust, Leeds, UK
Roger D Pickett BPharm, PhD, MRPharmS, Specialist Peter Williamson PhD, Division of Imaging Sciences,
Scientist, GE Healthcare, Medical Diagnostics, Hemel The Rayne Institute, St Thomas’ Hospital, London,
Hempstead, UK UK
Sampson's Textbook of Radiopharmacy
Abbreviations Dated: 16/11/2010 At Time: 17:14:26

Abbreviations

2D-DIGE two-dimensional difference gel BSC biological safety cabinet

electrophoresis BUD beyond-use date
2D-PAGE two-dimensional polyacrylamide gel CCD charge coupled device
electrophoresis CCK cholecystokinin
2-FDG 2-fluorodeoxyglucose CCK2 cholecystokinin
2-FDM 2-fluorodeoxymannose CDR complementarity determining
a-MSH alpha-melanocyte-stimulating region
hormone cfu colony-forming units
ACE angiotensin-converting enzyme CGE capillary gel electrophoresis
ACPH appropriate number of air changes cGRPP Current Good Radiopharmaceutical
per hour Practice
ACTH adrenocorticotrophic hormone CHM Commission on Human Medicines
ADD automated dose dispenser CHMP Committee for Medicinal Products
ADME absorption, distribution, metabolism for Human Use
and excretion CHO cells Chinese hamster ovary
ALARA as low as reasonably practical CIEF capillary isoelectric focusing
ALI annual limit of intake CIT b-carbomethoxy-3b-(4-
AMS accelerator mass spectrometry iodophenyltropane)
ANP authorised nuclear pharmacist CLDR continuous low dose-rate
AO atomic orbital COPD chronic obstructive pulmonary
APCI atmospheric pressure chemical disease
ionisation COREC Central Office for Research Ethics
APF 4-azidophenacyl-fluoride Committees
APIs active pharmaceutical ingredients CPR cardiopulmonary resuscitation
ARSAC Administration of Radioactive cps counts per second
Substances Advisory Committee CSF colony-stimulating factor
ATP adenosine triphosphate CSP compounded sterile preparation
ATSM diacetyl-bis(N4- CTC Clinical Trial Certificate
methylthiosemicarbazone) CTD Common Technical Document
AUC area under the curve CTX Clinical Trials Exemption
BBB blood–brain barrier CZE/FSCE capillary zone electrophoresis/free-
BED biologically equivalent dose solution CE
BER base excision repair CZT cadmium zinc telluride
bmim 1-butyl-3-methylimidazolium Da Dalton
BNMS British Nuclear Medicine Society DEDC N,N-diethyldithiocarbamate
Boc t-butoxycarbonyl DG Directorate General
BrudR bromodeoxyuridine DIPEA N,N-diisopropylethylamine
Sampson's Textbook of Radiopharmacy
Abbreviations Dated: 16/11/2010 At Time: 17:14:26

xvi | Abbreviations

DMARD disease-modifying antirheumatic FETNIM fluoroerythronitroimidazole

drug FHMA hydroxide macroaggregates
DMRC Defective Medicines Report Centre FHPG 9-[(1-fluoro-3-hydroxy-2-propoxy)
DMSO dimethyl sulfoxide methyl]guanine
dopa 3,4-dihyroxyphenylalanine FLT 30 -deoxy-30 -fluorothymidine
DOTA 1,4,7,10-tetraazacyclododecane- FMISO fluoromisonidazole
1,4,7,10-tetraacetic acid Fmoc fluorenylmethoxycarbonyl
DOTMP 1,4,7,10-tetraazacyclododecane- FPA 2-fluoropropionic acid
1,4,7,10-tetramethylene-phosphonic FP-CIT N-3-fluoropropyl-2b-
acid carboxymethoxy-3b-(4-iodophenyl)
dps disintegrations per second nortropane
DSB double-strand break FPyME 1-[3-(2-fluoropyridin-3-yloxy)
DTPA diethylenetriamine pentaacetic acid propyl]pyrrole-2,5-dione
EA Environment Agency FSD full scale deflection
EANM European Association of Nuclear FWHM full width at half maximum height
Medicine GCP Good Clinical Practice
EBRT external beam radiotherapy GDP Good Distribution Practice
EC electron capture GE gel electrophoresis
EDE effective dose equivalent GEP gastroenterohepatic
EDQM European Directorate of Quality of GFR glomerular filtration rate
Medicines GIST gastrointestinal stromal tumour
EDTA ethylenediaminetetraacetic acid GLP Good Laboratory Practice
EDTMP ethylenediaminetetramethylene GLP glucagon-like peptide
phosphonic acid GM Geiger–M€ uller
EGF epidermal growth factor GMP Good Manufacturing Practice
EHT electrical high tension GPvP Good Pharmacovigilance Practice
ELISA enzyme-linked immunosorbent assay GRP bombesin/gastrin releasing peptide
EM Electromagnetic HAMA human anti-mouse-antibodies
EPC European Pharmacopoeia HAS human serum albumin
Commission HASS High Activity Sealed Radioactive
EPR enhanced permeability and retention Source
ESI electrospray ionisation HATU O-(7-azabenzotriazol-l-yl)-1,1,3,3-
EU endotoxin unit tetramethyluronium
EU European Union hexafluorophosphate
EUD equivalent uniform dose HBsAg hepatitis B surface antigen
eV electronvolt HCC hepatocellular carcinoma
EXAFS extended X-ray absorption fine HED meta-hydroxyephedrine
structure HEHA 1,4,7,10,13,16-
F-50 -FDA 50 -fluoro-50 -deoxyadenosine hexaazacyclohexadecane-N,N0 ,N0 ,
FB N-succinimidyl 4-fluorobenzoate N00 ,N000,N-hexaacetic acid
FBA 4-fluorobenzaldehyde HEPA high-efficiency particulate air
FBA 4-fluorobenzoic acid HIDA scan hepatobiliary iminodiacetic acid scan
FBAU 5-bromo-20 -fluoro-20 -deoxyuridine HIPDM N,N,N0 -trimethyl-[2-hydroxy-3-
FBEM N-[2-(4-fluorobenzamido)ethyl] methyl-5-iodobenzyl]-1,3-
maleimide propanediamine
FBP filtered back projection HMPAO hexamethylpropyleneamine oxime
FDAMA FDA Modernization Act HOMO highest occupied molecular orbital
FDG-MHO FDGmaleiimidehexyloxime HPGe high-purity germanium
Sampson's Textbook of Radiopharmacy
Abbreviations Dated: 16/11/2010 At Time: 17:14:26

Abbreviations | xvii

HPLC high performance liquid MDR multidrug resistance/resistant

chromatrography mIBG meta-iodobenzylguanidine
HR homologous recombination MIRD Medical Internal Radiation
HSAB hard/soft acid base Dosimetry [Committee of the Society
classification of Nuclear Medicine]
HSE Health and Safety Executive MMP matrix metalloproteinase
HVCZE high-voltage capillary zone MO molecular orbital
electrophoresis MPE medical physics expert
HYNIC hydrazinonicotinic acid; 6- MS mass spectrometry
hydrazinopyridine-3-carboxylic acid MTC medullary thyroid cancer
HYNIC hydrazinonicotinic acid MTT 1-(4,5-demethylthiazoyl-2-yl)-3,5-
IAEA International Atomic Energy Agency diphenylformazan
IBZM (S)-3-iodo-N-[(1-ethyl-2- MUGA multigated radionuclide angiography
pyrrolidinyl)]methyl-2-hydroxy-6- n.c.a. no-carrier-added
methoxybenzamide NACWO Named Animal Care and Welfare
ICH International Conference on Officer
Harmonisation NaI(Tl) thallium-activated sodium iodide
ICRP International Commission on NBS N-bromosuccinimide
Radiological Protection NET neuroendocrine tumour
IDA iminodiacetic acid NF nitrogen-fluorinated
IEF isoelectric focusing NHEJ non-homologous end joining
IMBA N-(2-diethylaminoethyl)-3-iodo-4- NIMP Non Investigational Medicinal
methoxybenzamide Product
IMP Investigational Medicinal Product NIOSH National Institute for Occupational
IMPD Investigational Medicinal Product Safety and Health
Dossier NIS sodium iodide symporter
IRMER Ionising Radiation (Medical NOTA 1,4,7-triazacyclononane-N,N0 ,N00 -
Exposure) Regulations triacetic acid
IPD interstitial pulmonary disease NPSA National Patient Safety Agency
ISFET ion-selective field-effect transistor NPY neuropeptide Y
IudR iododeoxyuridine NTCP normal tissue complication
LA Licensing Authority probability
LAL Limulus amoebocyte lysate OMCL Official Medicines Control
LAN lanreotide Laboratories
LC Liquid chromatography PANDA PET and NMR dual acquisition
LCM laser capture microdissection PBBS peripheral benzodiazepine binding
LET linear energy transfer sites
LQ [model] Linear-quadratic PCR polymerase chain reaction
LRPRP leukocyte-rich platelet-rich plasma PEC primary engineering control
LUMO lowest unoccupied molecular orbital PEG poly(ethylene glycol)
LUV large unilamellar vesicle PEO poly(ethylene oxide)
MAA macroaggregated albumin PET positron emission tomography
MABG 1-(m-astatobenzyl)guanidine PHA pulse-height analysis
MAG3 mercaptoacetyltriglycine PHYP particulate hydroxypatite
MALDI matrix assisted laser desorption PIC/S Pharmaceutical Inspection Co-
ionisation operation Scheme
MCA Medicines Control Agency PPARg peroxisome proliferator activated-
MDA Medical Devices Agency receptor gamma
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Abbreviations Dated: 16/11/2010 At Time: 17:14:27

xviii | Abbreviations

PPP platelet-poor plasma SOP standard operating procedure

PRP platelet-rich plasma SPC Summary of Product Characteristics
PRRT peptide receptor radiation therapy SPE solid-phase extraction
QA quality assurance SPECT single-photon emission computed
QC quality control tomography
QWBA quantitative whole body SSB single-strand break
autoradiography SST somatostatin
RBE relative biological effectiveness/ SSTR somatostatin receptor
efficacy SUV unilamellar vesicle
rCBF regional cerebral blood flow SV40 Simian virus-40
RCY radiochemical yield TATE Tyr3-Thr3-octreotide
rhTSH recombinant human thyroid- TCEP tris(2-carboxyethyl) phosphine
stimulating hormone TCP Tumour control probability
RIT radioimmunotherapy TETA 1,4,8,11-tetraazacyclotetradecane-
RNAi RNA interference N,N0 ,N00 ,N00 -tetraacetic acid
RPA Radiation Protection Adviser TFA trifluoroacetic acid
RT-PCR reverse transcriptase polymerase THF Tetrahydrofuran
chain reaction TI Transport Index
SAB N-succinimidyl TIA ischaemia/ischaemic attack
[211At]astatobenzoate TIC total ion current
SAPS N-succinimidyl N-(4- TLC thin-layer chromatography
astatophenethyl) succinamate TLD thermoluminescent dosemeter
SCA segregated compounding area TOC Tyr3-octreotide
ScFv single-chain variable fragments Toc a-tocopheryl/a-tocopherol
SCK shell cross-linked knedel-like TOF time-of-flight
(nanoparticles) TPN total parenteral nutrition
SDS sodium dodecyl sulfate TRT targeted radionuclide therapy
SGMAB N-succinimidyl 3-astato-4- TSTU O-(N-succinimidyl-N,N,N0 ,N0 -
guanidinomethylbenzoate tetramethyluronium tetrafluoroborate
SI Statutory Instrument VEGF vascular endothelial growth factor
siRNA short interfering RNA VIP vasoactive intestinal peptide
SLN sentinel lymph node VLLW very low-level waste
Sampson's Textbook of Radiopharmacy
Chapter No. 1 Dated: 16/11/2010 At Time: 15:30:19

1
What is radiopharmacy?
Tony Theobold

The radionuclide 2 Dispensing and supply 4

Ionising radiations 2 The radiopharmacy 4

Radiotracer and imaging fundamentals 2 Radiopharmaceuticals in the clinic 6
Molecular imaging 3 Conclusion 7
Design and synthesis of radiopharmaceuticals 3

Radiopharmacy, the subject of this book, is the discipline, both scientific and regulatory, so radio-
science and art (for there is still much of the craft pharmaceutical scientists must be aware of advances
about it) of the design, preparation, quality assur- and changes as part of their continuing professional
ance and clinical pharmacy of radioactive medi- development.
cines, called radiopharmaceuticals. The British and Radiopharmacy is unusual in being governed by
European Pharmacopoeias define a radiopharmaceu- two distinct sets of legislation and regulation: as radio-
tical as ‘any medicinal product which, when ready for active substances on one hand, and as medicines on the
use, contains one or more radionuclides (radioactive other. The two sets of legislation may be in conflict,
isotopes) included for a medicinal purpose.’ and a reasoned and justified compromise is sometimes
Radiopharmacy draws on all the physical and necessary in practice.
biological sciences and is a truly interdisciplinary The physical basis for using radiopharmaceu-
subject, ranging from the production and properties ticals is twofold. For diagnostic applications
of the radionuclide, through its incorporation into a employing imaging techniques, the radiopharmaceu-
carrier, formulation and quality control, to adverse tical must act as a ‘signal generator’ by emitting
effects and drug interactions. It is a recognised health radiation that is easily detected outside the body
science specialty, employing pharmacists, chemists, and that causes minimum damage or harm to the
physicists and life scientists, with all practitioners patient, and this implies the use of tracer quantities
required to demonstrate adequate knowledge and of the agent. By contrast, in therapeutic applications
practical competence through a number of accredi- the radiations emitted from the radiopharmaceutical
tation schemes. must act like a ‘magic bullet’ and be absorbed
Some, but not all, of the knowledge required for locally, imparting maximum damage to its target
good radiopharmacy practice will be found within organ or tissue, and minimum damage elsewhere in
the covers of this volume; it is a rapidly evolving the body.
Sampson's Textbook of Radiopharmacy
Chapter No. 1 Dated: 16/11/2010 At Time: 15:30:19

2 | Sampson's Textbook of Radiopharmacy

A radiopharmaceutical, then, is a radioactive medi- tomography) from its current leading position. These
cine and has two essential components; a radionuclide very short-lived radionuclides (with half-lives rang-
that emits an appropriate ionising radiation when it ing from about 2 hours down to 2 minutes) must be
disintegrates, and a pharmaceutical ligand that binds produced, formulated as radiopharmaceuticals and
the radionuclide and transports it to the target organ or administered to the patient as rapidly as possible for
tissue. Both components are necessary: a simple radio- imaging, otherwise the radioactivity will have
nuclide itself will rarely be concentrated in the desired decayed to a low and almost undetectable level.
target; and the ligand by itself will not provide diag-
nostic information, nor will it have a therapeutic effect
since the ‘signal generator’ or ‘magic bullet’ is absent. Ionising radiations
Some radiopharmaceuticals combine both components
in a single molecule, such as 11C-labelled raclopride, a Ionising radiations can be harmful to living organisms
dopamine receptor-binding molecule where the ‘signal – indeed, large radiation doses are used to sterilise
generator’ is a radioisotope replacing the naturally standard pharmaceuticals and medical devices. Strict
occurring carbon at a specific position in the molecule. control is necessary in the production of radionuclides
and radiopharmaceuticals to minimise the exposure
of operators and medical staff to these radiations.
The radionuclide Likewise to ensure the patient receives the minimum
radiation dose commensurate with the value of the
As mentioned above, a fundamental component of the investigation. Much of the content of later chapters
radiopharmaceutical is the radionuclide (radioactive in this volume will deal with the properties of these
isotope) and the choice is governed by a number of radiations together with practical, regulatory, and leg-
factors: islative measures taken to protect operators, patients,
and the general public from exposure.
* Suitable half-life (the time taken for the
radioactivity to decay to one-half its initial value)
* Appropriate radiation (gamma photons for
Radiotracer and imaging
diagnostic imaging, alpha or beta particles for
therapy) fundamentals
* Ease of production and availability (by extraction
Diagnostic nuclear medicine employs radiopharma-
from nuclear waste, or by bombardment with
ceuticals as tracers of biochemical processes, both
neutrons or charged particles)
*
normal and abnormal. As described above, imaging
Suitable chemistry for bonding to the
enables the clinician to view the distribution of the
pharmaceutical ligand.
radiotracer within the patient’s body and, through
Medicinal radionuclides are characterised by multiple time-lapse images, to follow the kinetics of
their short half-lives (measured in hours or days), the distribution and target uptake process.
ease of production and ready availability. There
are numerous chemical techniques for attaching the
Radiotracers
radionuclide to the ligand, some simple and others
ingenious but complex. The radiations emitted are A tracer is a labelled molecule used to trace the prog-
generally low-energy gamma photons (100 keV) ress of a process, in vitro or in vivo. A simple analogy
for imaging, or higher-energy particles (1 MeV) would be for a plumber to throw a small amount of
for therapy. Very short-lived cyclotron-produced dye down a drain and look at the possible outfalls to
positron-emitting radionuclides are used in the tech- see which one has a coloured outflow – not an environ-
nique of positron emission tomography (PET), which mentally friendly action but perhaps the only possible
is now developing rapidly and is likely to become the technique when the drains disappear underground and
major imaging modality in the future, replacing con- which illustrates the basic principle: add an easily
ventional SPECT (single-photon emission computed detectable substance to a system and search for it after
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What is radiopharmacy? | 3

administration to see where, when, and how much is * Easy and complete mixing with indigenous
detectable in a specified place. chemicals – the mixing must be faster than the
Coloured tracers have long been used in biology process being studied.
and physiology and some of the earliest studies on the * Signal strength (radioactivity) must be
metabolism of fatty acids were made with phenyl- proportional to concentration.
substituted fatty acids, these being easily detectable
A radiotracer having these properties can be used with
through their ultraviolet absorption in spectropho-
confidence to determine both the location and quan-
tometry. But many other natural substances contain
tity of the substance being traced.
aromatic rings and the detection of the phenyl-fatty
Many radiochemicals can be used as tracers, as
acid among all the others may be difficult. Also, it is
can radiopharmaceuticals, but radiochemicals are not
possible that the fatty acid is metabolised and the
radiopharmaceuticals; they are sold expressly for
aromatic phenyl group is transferred to other mole-
experimental purposes and cannot be administered
cules so that its final location is not the same as the
to humans. Radiopharmaceuticals, on the other hand,
unlabelled fatty acid. This example suffers from
are licensed for administration to humans and comply
several deficiencies: the label is not unique, the labelled
with stringent standards for purity and sterility, among
molecule is different from the natural one, and meta-
other properties. Most diagnostic radiopharmaceuti-
bolic processes may remove the label. Hence the char-
cals can be regarded as radiotracers for human disease,
acteristics of an ideal tracer may be summarised as
indicating either normal or abnormal distribution and
follows:
kinetics. Therapeutic radiopharmaceuticals can be
* A unique label regarded as selectively toxic agents, designed to kill
* The labelled molecule is identical in all physical off unwanted or cancerous cells in the body.
and chemical properties to the natural one
* The label is firmly fixed and does not come adrift
during the investigation or experiment. Molecular imaging
Isotopic labels fulfil all these criteria: they are This term has come into use to describe the process
easily detected and only the labelled molecules are so of imaging an organ or receptor with a radiolabelled
detected; there are no differences in properties (except molecule, often formulated as a radiopharmaceuti-
for some small molecules labelled with deuterium, cal. Many radiopharmaceuticals are molecular imag-
2
H); and the covalent bonds fix the isotope firmly in ing agents. In essence, the labelled molecule is
the molecule. There is now a choice between stable localised on specific receptors in the organ imaged,
and radioactive isotopes. For preliminary metabolic and the radiolabelled molecule is designed to have a
studies of new drugs in humans, the stable isotopic high binding affinity for the target. There are many
label (2H or 13C) is preferred to avoid radiation dosage examples of molecular imaging agents, ranging from
to the volunteer, although this is changing with the technetium-99m (99mTc) complexes for studying the
introduction of 11C-labelled drugs that can be studied condition of the brain, to 11C-labelled agonists hav-
by PET. ing exquisite sensitivity for disease states. Examples
Radioisotopic tracers, or radiochemicals, are of molecular imaging agents will be found through-
widely used in biology and medicine because their out this book.
radioactivity is easily detected by fairly simple equip-
ment and is not affected by other properties of the
sample. The ideal characteristics of a radiotracer are:
Design and synthesis of
* Chemical or biological properties are not radiopharmaceuticals
changed.
* The signal (radioactivity) is easily detected. The design and synthesis of radiopharmaceuticals is
* Minute amounts are employed that do not upset an important aspect of radiopharmaceutical chemistry
the kinetics of the system. and radiopharmacology. The pharmaceutical ligand,
Sampson's Textbook of Radiopharmacy
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4 | Sampson's Textbook of Radiopharmacy

carrying the ‘signal generator’ radionuclide must pos- by International Atomic Energy Agency (IAEA). The
sess a number of essential and desirable properties: VirRad website (www.virrad.eu.org) is an invaluable
source of information and interactive learning about
* Accumulation, when radiolabelled, in the target
radiopharmacy and is recommended to all readers of
organ or tissue
this book; registration is free and gives access to a
* Little or no accumulation in surrounding tissues,
large number of discussion forums and learning aids.
thereby giving a high target-to-background ratio
* Easy and quick radiolabelling
* Physical stability before and after radiolabelling.
The radiopharmacy
In the case of radiopharmaceutical kits (in which
the radionuclide is added to a sterile vial containing the Another distinct characteristic of the radiopharmacy
pharmaceutical ligands, reagents and other ancillary is its location, generally within or close to a nuclear
substances), a great deal of formulation chemistry and medicine department and often not associated with
art is required to produce a reliable system that will the conventional hospital pharmacy. The staff, too,
always produce the desired radiopharmaceutical, and is often independent of the pharmacy organisation
these aspects are described in the radiopharmaceutical and is not restricted in the UK to registered pharma-
chemistry section of this book. Quality control meth- cists or pharmacy technicians.
ods for determining identity, purity, etc., are another
important application of radiopharmaceutical and Operations
radioanalytical chemistry.
The operations in a radiopharmacy fall in two distinct
categories: procurement and production of radio-
Dispensing and supply pharmaceuticals, and maintenance of quality (materi-
als, environment, facilities and people).
Dispensing and supply of radiopharmaceuticals is Nearly all radiopharmaceuticals are administered
restricted to hospital and licensed commercial radio- by injection, usually intravenously, as this route offers
pharmacies; there is no call for these articles in com- the most immediate access to the target organs or
munity or retail pharmacy and they are used only in tissues, avoiding reflux and vomiting and incomplete
the hospital setting within nuclear medicine or radio- absorption from the gastrointestinal tract (also, the
therapy departments under the supervision of licensed radioactive material is then safely contained within
clinicians. All aspects of procurement, dispensing and the body).
supply are strictly controlled in all countries, with Parenteral administration requires a sterile inject-
regulation in the UK and USA being probably the most able formulation, and all pharmacopoeial injections
prescriptive and stringent, although all European are required to be sterile. Most radiopharmaceuticals
Community nations are bound by the relevant must be treated differently from conventional paren-
Community legislation. Inspection of premises and teral preparations for a number of reasons. Firstly, the
facilities is undertaken, but curiously, there are at pres- limited half-life of the radionuclide effectively pre-
ent no national or internationally recognised quali- cludes manufacture and quarantine until a satisfactory
fications in the UK and most practitioners are self- sterility test result is obtained, a process that can take
taught or have learnt their craft under the supervision from 7 to 14 days. Secondly, many of the ingredients
of a senior colleague. In the USA, radiopharmacy is are not stable to heating and the preparation cannot be
recognised as a special discipline and practitioners can sterilised by heating in an autoclave. These limitations
undertake examination for certification by the Board mean that a rapid aseptic assembly or dispensing pro-
of Pharmaceutical Specialities, an independent orga- cedure must be used and the finished product released
nisation. There are numerous other unofficial quali- without the ‘seal’ of a sterility test. In these circum-
fications: the European Postgraduate Specialisation stances the quality of the manufacturing or dispensing
Certificate in Radiopharmacy, and many national unit environment is paramount: the design and oper-
short courses and other specialist courses sponsored ation of the facility must conform to strict standards
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What is radiopharmacy? | 5

specified by regulation and good manufacturing Protection (ICRP), now based in Canada, an inde-
practice. All operators must be fully trained and dem- pendent organisation that offers advice to regulatory
onstrate their competence at working in an aseptic bodies. The over-riding principle is public (and oper-
environment through competency tests at regular ator) protection through keeping radiation expo-
intervals. sure as low as reasonably achievable – the ALARA
But this is only half of the picture: these mater- principle.
ials are radioactive and constitute a health hazard.
Precautions must be taken and procedures developed
Standards for radiopharmaceuticals
to reduce the radiation exposure to operators, to pre-
vent ingestion of radioactive material, and to prevent Like all medicinal substances, there are standards for
contamination of the working area and the general the quality of radiopharmaceuticals. These may be
environment enjoyed by the public at large. It turns published in the pharmacopoeias, and comprise part
out that conditions normally employed to keep micro- of a marketing authorisation specification in the case
bial organisms out of the aseptic dispensing area will of licensed products. In the case of ‘specials’ and
effectively aid the spread of radioactive contamination research materials, standards are set in the scientific
and increase the likelihood of ingestion of radioactive journals, research papers or monographs. The radio-
material. A compromise is often necessary here, usu- pharmacy has a duty to ensure that all its products
ally by design of special cabinets or enclosures which comply with the recognised standards, and must have
provide containment of adventitious radioactive mate- appropriate testing equipment and procedures to
rial (through spills, formation of aerosols, etc.). Thus ensure compliance.
the two objectives of patient safety and operator and
public protection must be satisfied and demonstrated
Technetium radiopharmaceuticals
through numerous environmental monitoring (micro-
biological and radiation) schemes and records – a The majority of diagnostic radiopharmaceuticals con-
system of parametric release for the final radiophar- tain technetium-99m as the radionuclide, and this
maceutical. A full account of current rules, practice, is obtained daily by ‘milking’ of a generator system
and recommended procedures appears in the section (see Chapter 21 for details). (At the time of writing there
on the Practice of Pharmacy. is a world shortage of the parent radionuclide molyb-
denum-99, and supplies of the daughter technetium-
99m (99mTc) are somewhat limited.) This radionuclide
The daily routine
is bound to the pharmaceutical ligand by injection of
The daily routine will be similar in most medium to a sterile solution of the radionuclide into a sterile
large radiopharmacies. Since the radiopharmaceu- ‘kit’ vial containing all the ligands, reagents and other
ticals will be required in the clinics in the first part ingredients necessary to produce the final radiopharma-
of the morning, production and dispensing will com- ceutical. These manipulations constitute a ‘closed’ pro-
mence much earlier. In some commercial radiophar- cedure in which none of the ingredients or components
macies and cyclotron units production may start in is exposed to microbial contamination, but the process
the middle of the night to ensure that materials are is still carried out in an aseptic environment (an iso-
despatched and transported to their site of use in time lator, or laminar flow cabinet). Once reconstituted,
for administration. according to the daily dispensing schedule, the radio-
activity is measured and the vial and its protective lead
shielding ‘pot’ are labelled; a small sample may be taken
Radiation hygiene
for some simple quality control tests and the completed
The principles and practice of radiation hygiene radiopharmaceuticals are delivered to (or collected by)
are described in several chapters of this book as this the receiving department. Strict controls are operated
is a topic that affects all operations and the busi- on the type of packaging and mode of transport, espe-
ness of the radiopharmacy, The central body here cially if the radioactive material is to be delivered to a
is the International Commission on Radiological remote site along a public highway.
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6 | Sampson's Textbook of Radiopharmacy

Other radiopharmaceuticals of very short-lived positron-emitting radionuclides (18F,

11
C, 13N, 15O) incorporated into radiopharmaceuticals
Non-technetium radiopharmaceuticals may be pre-
for PET studies. The main difference lies in the higher
pared at the same time, or shortly after. These range
degree of automation in production and quality con-
from simple dispensing of aliquots from a sterile stock
trol necessary to reduce the radiation exposure of
solution into sterile vials, essentially under the same
staff from the highly energetic 0.51 MeV annihilation
conditions as for technetium agents, to complex chem-
photons from these radionuclides and the very large
ical manipulation and radiolabelling of biological
quantities of radionuclide that have to be produced to
molecules such as peptides and proteins or polysac-
compensate for the rapid decay of radioactivity. The
charides and oligosaccharides. These agents require
production process must obviously be a rapid one in
special equipment, operator expertise, and a strict
view of the short half-lives of these radionuclides (e.g.
aseptic manipulation regime because many stages of
that of 11C is 20 minutes). The same pattern of work
their preparation cannot be regarded as ‘closed’ pro-
is undertaken as in a conventional radiopharmacy
cedures; for example, the purification of radiolabelled
with the same attention to aseptic manipulations, the
peptide by high performance liquid chromatography
environment and quality assurance. Automation of syn-
(HPLC). Sometimes the quality control tests are very
thesis and formulation is very common in these units.
time consuming, and the manufacture must start early
in the day to ensure that the product is passed fit for
use in the afternoon clinic.
Radiopharmaceuticals in the clinic
Blood labelling Radiopharmacy involvement does not stop at the point
Another complex and time-consuming operation is the of delivery of the product to the clinic; radioactive
labelling of a patient’s (autologous) blood and other residues are returned for disposal and any abnormal
cells, ready to be re-injected later that day. Such cell biodistributions or adverse reactions are reported in
labellings are carried out in a separate aseptic enclo- case the radiopharmaceutical itself is at fault. These
sure and extra precautions are necessary to prevent reports are collated at national centres and anonymised
infection of operators – and other patients – by bacte- summaries are circulated to all contributors for infor-
ria and viruses that may be present in the blood sam- mation and checking. Annual summaries are often pub-
ples of the previous patient. lished in the European Journal of Nuclear Medicine.
The majority of radiopharmaceuticals are used as
diagnostic agents in nuclear medicine. After injection
Procurement, storage and disposal and a period of waiting until the biodistribution is
Materials, both radioactive and ‘cold’, are received in complete, an image is taken of the distribution of radio-
the radiopharmacy each day and each one has to be activity in the appropriate region of the body. Some
checked for identity, leakage and radioactive contami- clinical procedures require the administration of a drug
nation. A record or log is maintained of all goods to modify the normal response and others may be
received, which are then stored under appropriate con- affected by the medicines currently taken by the
ditions: lead-shielded enclosure, cupboard or refrigera- patient; many examples of these are described in
tor for radioactive materials; ambient or cold storage Chapter 31. The radiopharmaceutical is acting as a
for reagents and kit vials. Waste radioactive materials radioactive tracer of a normal or abnormal biochemical
(used syringes, vials, tissues, etc.) must be stored sepa- process and its location is measured or detected exter-
rately and disposed of by an authorised route as spec- nally by some form of camera system. There are two
ified in the licence to hold and use radioactive materials. main types of imaging system used: SPECT and PET.

Cyclotron units SPECT

The processes and procedures just described will be very SPECT stands for single-photon emission computed
similar in a cyclotron unit dedicated to the production tomography and is a technique whereby an image of
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What is radiopharmacy? | 7

the distribution of radioactivity (more properly, the practice and the basic principles underlying the
emitted radiation) is made with a gamma camera. use of radiopharmaceuticals as tracers. Much more
This consists of a collimator (a thick sheet of lead detail will be found in the following chapters.
having many parallel holes) placed in front of a large The book also contains a glossary of technical terms
scintillation crystal of sodium iodide that is backed which, it is hoped, will aid the reader in under-
by an array of photomultipliers to convert the scintil- standing the sometimes jargon-laden world of
lations into electrical pulses for further processing. radiopharmacy.
The collimator allows gamma photons to reach the
detector only if they travel normally to the scintillation
crystal; otherwise they are absorbed by the lead. This The Literature of radiopharmacy
is the only practical way of ‘focusing’ high-energy As befits a multidisciplinary subject, there are few
photons – mirrors and lenses are not effective as the journals devoted exclusively to radiopharmacy, the
photons just pass through. Electronic processing of material being published in a variety of clinical and
the pulses from the photomultipliers produces a two- scientific journals. The following list includes the
dimensional image of the distribution of radioactivity journals most frequently consulted by radiophar-
throughout the depth of the field of view. Images are macists. Most are available on-line to recognised
taken at a number of angles to give an approximate subscribers, either through professional bodies or
representation of the three-dimensional distribution. universities.
By use of more complex collimators and software
processing of the information, a more complete * American Journal of Hospital Pharmacy
three-dimensional image may be obtained, and this * Applied Radiation and Isotopes
can be viewed as a series of ‘slices’ or as a rotating * Bioconjugate Chemistry
object, thus enabling better visualisation of the radio- * Bioorganic & Medicinal Chemistry Letters
activity distribution. * Bioorganic Chemistry
* Clinical Nuclear Medicine
* European Journal of Nuclear Medicine and
PET
Molecular Imaging
By contrast, the PET camera produces three-dimen- * European Journal of Pharmaceutical Sciences
sional images routinely. PET stands for positron emis- * Journal of Labelled Compounds and
sion tomography and employs short-lived positron- Radiopharmaceuticals
emitting radionuclides – 11C, 13N, 15O, 18F being the * Journal of Nuclear Cardiology
most usual. They emit positrons (positively charged * Journal of Nuclear Medicine
anti-particles of the electron) which are annihilated * Journal of Nuclear Medicine Technology
by combining with an ordinary electron and converted * Journal of Organic Chemistry
to two gamma photons of energy 0.511 MeV emitted * Journal of Organometallic Chemistry
in opposite directions. The camera is a circular array of * Journal of Pharmaceutical Sciences
detectors which register both gamma photons, and * Journal of Radioanalytical and Nuclear
electronic processing results in a complete distribution Chemistry
of radioactivity within the subject. * Nuclear Medicine and Biology
* Nuclear Medicine Communications
* Nuklearmedizin
Conclusion * Quarterly Journal of Nuclear Medicine and
Molecular Imaging
This short introduction has attempted to describe * Radiochimica Acta
the main features of radiopharmacy science and * Seminars in Nuclear Medicine
Sampson's Textbook of Radiopharmacy
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Sampson's Textbook of Radiopharmacy
Section A Dated: 16/11/2010 At Time: 16:44:28

SECTION A
Physics applied to
radiopharmacy
Sampson's Textbook of Radiopharmacy
Section A Dated: 16/11/2010 At Time: 16:44:28
Sampson's Textbook of Radiopharmacy
Chapter No. 2 Dated: 16/11/2010 At Time: 15:25:47

2
Nuclear structure and radioactivity
Richard Fernandez

Nuclear structure 11 Decay processes 16

Kinetics 13 Interaction of radiation with matter 19

Radiation 15

Nuclear structure Electronic structure of the atom

In the simplest model of the atom, first proposed by
Elementary particles and atoms
Bohr in 1913, electrons orbit the nucleus, analogous to
All matter, whether living or inert, is composed of the planets orbiting the sun, but occupying discrete
molecules. Molecules are themselves formed from energy states or ‘shells’ around the nucleus.
combinations of elements. The smallest constituent Each shell is referred to as the K shell, the L shell,
of an element exhibiting identical chemical properties the M shell and so on, with the electrons in the K
is the atom, and for this reason atoms are often termed shell closest to the nucleus. According to quantum
the ‘building blocks’ of matter. theory each individual shell is designated by a unique
The atom consists of three types of elementary quantum number. This is an integer value and is
particles: protons, neutrons and electrons. Classi- referred to as the principal quantum number, n.
cally, the atom of any given element consists of a For the innermost shell, the K shell, n ¼ 1, for the
positively charged nucleus, comprising positively L shell n ¼ 2, and for the M shell n ¼ 3. From quan-
charged protons and electrically neutral neutrons tum theory the maximum number of electrons per-
(collectively termed nucleons) surrounded by nega- mitted in each shell is 2n2. Therefore the K, L and M
tively charged electrons. Properties of the elemen- shells contain a maximum of 2, 8 and 18 electrons,
tary particles are detailed in Table 2.1. respectively.
The physical size of the atom is of the order of Within each shell, electrons can exist in various
tenths of a nanometre (10
10 m) and that of the subshells depending on their spin states (each subshell
nucleus is of the order of a femtometre (10
15 m). has its own set of subsidiary quantum numbers related
The electron configuration of the atom determines to spin) – quantum theory necessitates that no two
the chemical properties of the element, whereas the electrons in a given subshell can occupy the same spin
nuclear composition determines the stability of the state, i.e. no two electrons can have all quantum num-
nucleus and the radioactive decay process. bers identical.
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12 | Physics applied to radiopharmacy

Table 2.1 Properties of elementary particles when two opposing magnetic poles are placed close
together – the closer they are brought to each other, the
Particle Symbol Charge (e)a Mass (u)b greater the amount of energy required to pull them
apart.
Proton P þ1 1.00726
Electrons may be transferred or shared between
Neutron n 0 1.00867 atoms to form molecules. Examples of these chemical
Electron e
1 0.00055
bonds are ionic (or electrovalent) bonds when elec-
trons are transferred and covalent bonds when elec-

19
a
1e ¼ 1.6  10 coulombs. trons are shared; the typical energy is of the order of a
b
1u ¼ 1 universal mass unit ¼ 1.66  10
27 kg.
few electronvolts.

Figure 2.1 is a schematic representation of a neu-

Nuclear structure
tral atom with 6 protons in the nucleus and 6 orbiting
electrons occupying the K and L shells. Neutral atoms have no overall charge as the number of
When the atom is in its most stable, i.e. lowest, electrons is equal to the number of protons. The num-
energy state (also termed the ground state) electrons ber of protons in the nucleus is termed the atomic
occupy the lowest possible shells, closest to the number, Z. The number of neutrons in the nucleus is
nucleus. denoted by N. The summation of Z and N gives the
The attractive electrostatic force binds the elec- total number of nucleons in the nucleus and is referred
trons to the nucleus. Energy is therefore required to to as the mass number, A. A particular element with
excite electrons from lower to higher, unoccupied chemical symbol X is typically represented by the
energy levels. This energy may be supplied, for exam- notation A Z X. In this notation N is usually omitted
ple, by incident radiation interacting with the atom. If since it can be simply calculated from A
Z. In the
sufficient energy is transferred to the electrons, they literature, the atomic number is often also omitted,
can be removed completely from the atom – termed since for a particular element Z is the same for all
ionisation. The energy required to ionise electrons is atoms of that element and the simple notation AX is
referred to as the binding energy and is measured used.
in electronvolts (eV). An electronvolt is equivalent Nucleons are bound together by the strong nuclear
to 1.6  10
19 J. force, which acts to overcome the repulsive electro-
Electrons in different shells have different binding static force between the protons in the nucleus. The
energies. Electrons closest to the nucleus have the grea- nuclear force is a short-range force, the extent of its
test binding energy (in the keV range) and electrons influence being limited to the nucleus itself, resulting
in higher shells, farther from the nucleus have lower in the very small size and very high density of the
binding energy (in the eV range). This is analogous to nucleus.
Nucleons can be thought of as existing in discrete
energy shells, similar to electrons in the Bohr atomic
model. In the same way that electrons orbiting the
nucleus have an associated binding energy, nucleons
proton in the nucleus also have a binding energy. However,
unlike electrons, which have binding energy of up to a
neutron few keV, the energy required to separate an individual
nucleon from a stable nucleus is much higher, of the
electron order of a few MeV.
K
L shell vacancy
Nuclear stability and radioactivity
The stability of a nucleus is determined by its compo-
Figure 2.1 Structure of a neutral atom. sition of neutrons and protons. The term nuclide is
Sampson's Textbook of Radiopharmacy
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Nuclear structure and radioactivity | 13

used to describe a particular nuclear composition. For emission of radiation. Radioactive nuclides, also
stable, low-atomic-number nuclides, the ratio of neu- termed radionuclides, can occur naturally (e.g. 14C)
trons to protons (N/Z) is approximately 1. Examples or they can be produced artificially in a nuclear reactor
include 42 He , 126 C and 168 O . With increasing atomic or cyclotron.
number, N/Z increases to approximately 1.5, i.e. more
neutrons than protons are required to ensure nuclear
stability. In heavy nuclei an excess of neutrons is Kinetics
required as they provide only (attractive) nuclear
force, unlike protons which provide both nuclear force Radioactive decay
and (repulsive) electrostatic force. Examples of stable, Radioactive decay is the spontaneous transformation
high-atomic-number nuclides include 197 208
79 Au and 82 Pb. of an unstable nucleus into a nucleus in a more stable
Figure 2.2 is a diagram showing the relationship state. The process of radioactive decay is governed by
between proton and neutron number and nuclear the laws of probability and the number of unstable
stability for known nuclides. nuclei decaying within a fixed time interval follows a
Nuclides with an excess or deficiency of protons/ Poisson distribution. The unstable, radioactive nuclide
neutrons relative to the stable element are energetically is termed the parent nuclide and, following the decay
unstable. This is because there is insufficient binding process, the resulting nuclide is termed the daughter
energy to hold the constituent nucleons together. nuclide. The daughter nuclide itself may be radioactive
These unstable nuclides lie above or below the line of and therefore may subsequently undergo further
stability. They are termed radioactive as they trans- nuclear transformation until a more stable state is
form to a more stable nuclide (and approach the line eventually reached. An example of this is the molyb-
of stability) through the emission of radiation. The denum–technetium decay process. Parent nuclide
various modes of radioactive decay and types of emit- molybdenum-99 (99Mo) decays to daughter nucleus
ted radiation are discussed subsequently. technetium-99m (99mTc) with the emission of beta
Most elements have a mixture of stable and un- radiation. Technetium-99m exists in a metastable
stable isotopes. Isotopes are nuclides which have the state, denoted by the ‘m’, and subsequently decays to
99
same atomic number, and therefore identical chemical Tc with the emission of gamma radiation.
properties, but which have different numbers of neu- The unit of radioactivity is the becquerel (Bq),
trons. For example 11C, 12C and 14C are all isotopes of named after Henri Becquerel who first discovered
carbon. In this example, 11C and 14C (among others) radioactivity in 1896. The becquerel is defined as
are termed radioisotopes as these nuclei are radioac- one nuclear disintegration per second and therefore
tive and convert to more stable states through the has units of s
1.

100
90
80 Neutron deficient
Atomic number (Z )

70
60
50
40
30
20 Proton deficient
10
0
0 10 20 30 40 50 60 70 80 90 100 110 120
Neutron number (N )
N = Z, Line of nuclear stability.

Figure 2.2 Diagram of Z versus N and nuclear stability.

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14 | Physics applied to radiopharmacy

Decay rate and half-life to substitute for N and N0 in equation (2.2) gives

Radioactive decay is a random process and conse- A ¼ A0 expð
l tÞ

quently for a particular radioactive sample containing
where A0 is the initial activity of the sample at time
identical radioactive nuclei, at any instant of time we
t ¼ 0.
are unable to specify exactly which nuclei will undergo
The radioactive half-life (T1/2) is defined as the
transformation. Rather, there is a probability asso-
time taken for half the number of radioactive nuclei to
ciated with the number of nuclei decaying at any time.
decay. This can be obtained by substituting N ¼ N0/2
For N identical radioactive nuclei, the probability of a
into equation (2.2) above and rearranging to give
particular nucleus decaying in unit time is given by l.
The activity A of the sample, i.e. the number of nuclei lne ð2Þ
T 1=2 ¼ ð2:3Þ
decaying per unit time, is given by Nl. This is a fun- l
damental property of radioactive decay – the number For a particular radionuclide, half-life is constant
of nuclei decaying per unit time is proportional to the and characteristic of that radionuclide. Half-life varies
number of nuclei present at that instant in time. This greatly between different radionuclides – some have
can be written as extremely short half-lives measured in fractions of a
dN second, while others have half-lives of millions of
A¼ ¼
Nl ð2:1Þ years. Half-lives for radionuclides commonly used in
dt
clinical practice are listed in Table 2.2.
The negative sign is inserted to indicate that N Specific activity is defined as the radioactivity
decreases with time. l is termed the decay constant per unit mass of the element or compound and typi-
or decay rate; it is specific to the radionuclide and cally has units of Bq/gram or MBq/mole (or multiples
has units of s
1. Equation (2.1) may be rearranged to of these). The maximum possible specific activity,
give termed the ‘carrier-free’ specific activity, is when all
the atoms present in sample are radioactive, i.e. there
dN
¼
l dt are no stable atoms present. For a given mass of radio-
N
active sample the carrier-free specific activity can be
Since it is assumed that the probability of a nucleus calculated for a particular radionuclide by obtaining
decaying is independent of its age, i.e. that l is inde-
pendent of time and is therefore a constant, we can
write Table 2.2 Half-life of radionuclides used in clinical
Z Z practice (Pearce 2008)
dN
¼
l dt
N Radionuclide Half-life Radionuclide Half-life

At time t ¼ 0 the number of radioactive nuclei is Carbon-11 20 min Oxygen-15 122

N0 and at some subsequent time t the number is N. seconds
Solving the above equation yields
Chromium-51 27.7 days Phosphorus-32 14.3 days
 
N
lne ¼
lt Fluorine-18 110 min Rhenium-186 3.7 days
N0
Gallium-67 78.3 hours Rhenium-188 17 hours
or
Iodine-123 13.2 hours Samarium-153 1.9 days
N ¼ N 0 expð
l tÞ ð2:2Þ
Iodine-125 59.4 days Strontium-89 50.6 days
Equation (2.2) eloquently shows the exponential
Iodine-131 8.02 days Technetium-99m 6.01 hours
nature of the radioactive decay process.
The activity of a radioactive sample (measured Indium-111 67.3 hours Thallium-201 3.04 days
in becquerels) is a more useful quantity than the
Krypton-81m 13 seconds Yttrium-90 64 hours
number of radioactive nuclei. Using equation (2.1)
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Nuclear structure and radioactivity | 15

the tabulated half-life and substituting for l using 210 being a relevant example, can have lethal
equations (2.1) and (2.3). It is important that specific consequences.
activity is not confused with radioactive concentration
which is simply the radioactivity per unit volume. Beta particles
Beta particles (b
) are high-energy electrons and are
emitted from an unstable nucleus when a neutron
Radiation converts to a proton. Since b-particles have only a
single charge and are much lighter than a-particles,
The term radiation refers to the process of emission of they have a much lower LET and can therefore pen-
energy and includes both particulate and electro- etrate further before absorption. Beta particles can
magnetic forms. Particulate radiation carries energy be emitted with a range of energies up to a finite
in the form of kinetic energy and examples include, maximum.
among others, alpha particles and beta particles.
Electromagnetic radiation on the other hand carries X-rays and gamma rays
energy by oscillating electrical/magnetic fields. X-rays Both X-rays and gamma (g-) radiation are part of the
and gamma rays are examples of electromagnetic electromagnetic spectrum and therefore have an asso-
(EM) radiation and are emitted with discrete energy, ciated energy and wavelength. However the origin of
specific to the atom or radionuclide. their production differs as X-rays arise from electronic
transitions whereas g-rays result from nuclear
Alpha particles transitions.
An alpha (a-) particle is essentially a helium-4 (4He) Incident radiation can cause ionisation or excita-
nucleus as it consists of two protons and two neu- tion of electrons in the atom and this creates vacancies
trons tightly bound together. The binding energy of in the inner shells. Electrons in outer, higher-energy
these nucleons is high enough to ensure that the shells promptly fill the vacancy, with the difference in
a-particle behaves as if it were a fundamental parti- binding energy between the two shells released as X-
cle. The a-particle has a charge of þ2e, mass number radiation. These X-rays are termed characteristic X-
of 4 and atomic number of 2. Due to its charge and rays as they are specific to each element as different
mass the a-particle has a high linear energy transfer nuclides have different electron binding energies. As
(LET) compared with other forms of radiation. an alternative to characteristic X-ray emission, the
LET is defined as the amount of energy deposited energy released when an outer-shell electron fills a
per unit length of the path traversed by the radiation; vacancy in a lower shell can be transferred to another
it is expressed in units of keV/mm and relates to the outer electron. This ionised electron (or Auger elec-
biological damage caused. Owing to the high LET of tron) results in a second vacancy in the outer
a-particles, ingestion of an alpha emitter, polonium- shell. Figure 2.3 shows schematically the processes of

Auger
electron
X-ray

Nucleus Nucleus

(a) (b)

Figure 2.3 Characteristic X-ray emission (a) and Auger electron emission (b) for a K-shell vacancy.
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16 | Physics applied to radiopharmacy

characteristic X-ray and Auger electron emission for An example of this decay process is the decay of
an inner-shell vacancy. uranium-238 (238U) by a-particle emission to tho-
When the nucleus converts from an energetically rium-234 (234U):
unstable state to a more stable, lower-energy state, the
difference in energy is released as a g-ray. The excited
238
92 U ! 234
90 Thþ2 a
4

energy states of the nucleus are referred to as isomeric Other examples of radionuclides that emit a-particles
states and are unique to the particular radionuclide. are 235U and 210Po.
Consequently the energy of the g-radiation emitted An alternative to alpha decay for heavy nuclides is
from the de-excitation process (termed isomeric tran- fission, whereby the unstable nucleus breaks down
sition) is specific to the radionuclide. For example, the into two roughly equal fragments. Fission can occur
g-ray emitted when 99mTc reverts to its ground state spontaneously, but is more usually induced by bom-
has energy 140 keV, whereas for 81mKr the associated bardment of the target nucleus by charged particles in
g-ray has energy 191 keV. a nuclear reactor.

Decay processes Beta decay

b
emission
There are a number of different modes of radio-
This mode of radioactive decay occurs when a nucleus
active decay, some of which have been alluded to
has an excess of neutrons relative to more stable
above. These modes include alpha and beta decay,
neighbouring nuclides. A more stable state is achieved
electron capture, isomeric transition and internal
by a neutron in the unstable nucleus converting to
conversion and spontaneous fission. All of these
a proton. This is accompanied by the emission of a
various decay processes are bound by the fundamen-
b-particle, necessary for the conservation of charge.
tal physical laws of conservation of charge, mass
The process of b
decay may be represented as:
and energy.
A A
ZX ! Zþ1 Y þ
01 b þ n

Alpha decay The anti-neutrino (n) also emitted in the process is

the ‘anti-particle’ to a neutrino. Both neutrino and
Emission of an a-particle occurs in unstable nuclei
anti-neutrino have neither mass nor charge and are
with a high atomic number (Z > 80). The a-particle
not discussed further as they have no relevance in
ejected from the nucleus carries away energy released
nuclear medicine. The excess energy resulting from
in the process as kinetic energy. The decay process can
the nuclear transition is characteristic of the radionu-
be written as:
clide, and is shared between the b-particle and the anti-
A
ZX !A
4
Z
2Y þ 2a
4 neutrino. Beta particles can therefore be emitted with a
range of energies from zero up to a finite maximum
Note that total mass number and total atomic num- depending on the particular nuclide.
ber on the right-hand side of the expression are Following b-particle emission, as for alpha decay,
equal to the corresponding mass and atomic num- the daughter nucleus may be in an excited energy state
ber on the left side of the expression, satisfying the and may convert to a more stable state by the imme-
requirement for conservation of both mass and diate emission of one or more g-rays. An example of
charge. The daughter product is a different element beta decay is the molybdenum-technetium decay pro-
from the parent (transmutation) as atomic number cess where molybdenum-99 (99Mo) decays to techne-
has decreased by 2. Following a-particle emission, tium-99m (99mTc) with a 66 hour half-life and the
the daughter nucleus (often termed the recoil emission of a b-particle followed immediately by an
nucleus) may still be energetically unstable and additional g-ray of typical energy 740 keV:
undergo subsequent transitions with further emis-


sion of radiation.
99
42 Mo ! 99m
43 Tc þ b þ g
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Nuclear structure and radioactivity | 17

bþ or positron emission decay by electron capture are utilised in nuclear medi-

The converse of b decay occurs in positron emission. cine including 51Cr, 67Ga, 111In and 123I.
An unstable nucleus with a higher proton-to-neutron
ratio than more stable neighbouring nuclides converts Isomeric transition
to a more stable energy state through the conversion of
This decay process occurs where a daughter nuclide
a proton to a neutron with the emission of a positron
(arising from previous radioactive decay) in an excited
(and neutrino). This process may be written as:
energy state decays to a more stable state through the
A
ZX ! Z
A1 Y þ þ10 b þ  emission of a g-ray. Unlike all the aforementioned
decay processes, there is no change in mass number
The positron bþ is the anti-particle of the electron,
or atomic number during isomeric transition. The
having identical mass but opposite charge of þe. As
reversion to a lower-energy state by isomeric transi-
for b-particles, the excess energy arising from the
tion is not necessarily instantaneous and the nucleus
nuclear transition is shared between the positron and
can exist in the excited state for a measurable length of
the neutrino and consequently positrons are emitted
time. This prolonged state is referred to as a metastable
with a range of energies up to a finite maximum.
state and is usually denoted by the letter m following
The positron loses its kinetic energy through
the mass number in the notation AmX. This is an
interactions in a medium and subsequently annihi-
extremely useful process for nuclear medicine imaging
lates with a free electron, yielding two g-ray photons.
as the metastable daughter nucleus decaying by iso-
These two photons are emitted at 180 to each other,
meric transition emits only gamma radiation, thus
each with initial energy 511 keV (equivalent to the
reducing the radiation dose to the patient. The most
rest mass of an electron from Einstein’s famous equa-
widely utilised radionuclide in nuclear medicine imag-
tion E ¼ mc2). The coincident detection of these two
ing is technetium-99m (99mTc) which has a half-life of
511 keV g-rays is the objective of positron emission
6.01 hours and decays by emission of a g-ray with
tomography (PET) imaging.
energy 140 keV. This decay process is represented as:
The most widely utilised positron emission process
in PET is the decay of fluorine-18 (18F) to oxygen-18 99m
! 99
43 Tc 43 Tc þ g
(18O) with the release of a positron:
Technetium-99 decays via b
emission with a half-
18
9F ! 188 O þ bþ
life of 2.1  105 years and so can essentially be treated
as stable.
Electron capture
An alternative to the emission of a g-ray by the
When a neutron-deficient nuclide has insufficient isomer is the process of internal conversion in which
energy for positron emission, the excess of protons the excited nucleus transfers its excess energy directly
may be reduced by the ‘capture’ of an orbital electron. to an orbital electron. The electron is ejected if the
A proton in the nucleus combines with an electron, excitation energy is greater than the binding energy
typically from an inner shell due to its proximity to of that particular shell. Although b-particles and con-
the nucleus, and converts to a neutron with the emission version electrons are essentially the same fundamental
of a neutrino. Since the latter is without charge and particle, both their origin and their emitted energy
mass and therefore virtually undetectable, the process differ. Beta particles originate from the nucleus and
of electron capture would be undetectable externally. are emitted with a continuous distribution of energies
However the vacancy created by the captured electron up to a finite maximum, whereas conversion electrons
results in rearrangement of atomic electrons and sub- are orbital, atomic electrons emitted with discrete
sequent characteristic X-ray or Auger electron emission energy characteristic of the binding energy levels of
from the daughter nucleus. In some cases g-ray emission the particular nuclide.
can also accompany characteristic X-ray/Auger emis- As for the electron capture process, subsequent
sion if the daughter nucleus is left in an excited energy rearrangement of atomic electrons, to fill the vacancy
state. This consequence is useful for nuclear medicine created by the ejected conversion electron, results in
applications and accordingly many radionuclides that characteristic X-ray or Auger electron emission.
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18 | Physics applied to radiopharmacy

The ratio of the number of conversion electrons Z values are represented from left to right. The
to observed g-rays is termed the conversion coeffi- vertical distance between the lines is
cient. Internal conversion is undesirable in imaging proportional to the energy released in the
applications as the electron emission adds to the process.
effective dose of the patient without imparting any * b
decay is identified by a left-to-right diagonal
diagnostic information. For this reason, a low con- arrow, i.e. Z r Z þ 1.
version coefficient is desirable for radionuclides * bþ, electron capture (EC) and alpha decay
intended for use in diagnostic imaging. are identified by right-to-left diagonal
arrows, i.e. Z t Z
1 or Z t Z
2,
respectively.
Decay schemes * Excited energy states are represented by
A decay scheme diagram is a useful way of illustrating horizontal lines directly above the daughter
the decay process for radionuclides. The following ground state.
conventions are followed for representing decay * Vertical arrows between energy levels indicate
scheme diagrams: g-ray emissions.

* Parent and daughter nuclei are identified by Figure 2.4 shows simplified decay scheme diagrams
bold, adjacent horizontal lines. Increasing for a number of clinically used radionuclides.

Molybdenum–
99
Mo (66 h) Technetium–99m
42
Fluorine–18

99m 18
Tc (6.01 h)
β– 43 9
F (110 m)
140 keV

γ EC, β+

99
43
Tc (2.12 × 105 y)
18
8
O (Stable)

Indium-111
131 Iodine–131
111 53
I (8.02 d)
49
In (67.3 h)

EC
β– 637 keV
417 keV
γ1
245 keV
364 keV

γ2
80 keV
51
24
Cr (27.7 d)
111
Cd (Stable) 6% 81% 7%
48
90 131
EC 39 Y (64.0 h) Xe (Stable)
54
320 keV

γ β–

51 90
V (Stable) Chromium–51 40Zr (Stable)
23

Yttrium–90

Figure 2.4 Simplified decay schemes for some clinically useful radionuclides.
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Nuclear structure and radioactivity | 19

Interaction of radiation with matter Excitation is the less prevalent mechanism for
particulate radiation and occurs when incident radia-
The interaction of radiation with matter is impor- tion has insufficient energy for ionisation. Instead of
tant as it has implications both for radiation pro- being ejected, orbital electrons are excited to higher
tection, since it determines how energy is deposited energy states.
in the medium (whether shielding material or tis- Electrons liberated through particulate ionisation
sue), and instrumentation design, since it deter- may themselves have sufficient energy to cause further
mines how the radiation is detected and measured. excitation and ionisation of other atomic electrons –
Particulate and EM radiation interact with matter termed secondary ionisation.
via different mechanisms and are therefore consid-
Bremsstrahlung
ered separately.
Charged particles whose path is in close proximity
to the nucleus can interact directly with the nucleus.
Particulate radiation Due to the strong electrostatic force exerted by the
nucleus, the incident charged particle is deflected.
Particulate radiation loses kinetic energy through This interaction causes rapid deceleration of the par-
electrostatic interactions with atoms in the absorbing ticle and as a consequence it loses kinetic energy. This
material. The primary mechanisms for this are energy is released as EM radiation, termed brems-
through ionisation and excitation of atomic electrons strahlung or ‘braking’ radiation, and is emitted as a
and the production of bremsstrahlung radiation. continuous spectrum of X-rays. The energy of the
bremsstrahlung radiation ranges from almost zero
Ionisation (where the charged particle is only slightly deflected)
Ionisation is the process of stripping of electrons up to a maximum equal to the initial energy of the
from the atom. This occurs where particulate radia- incident particle (where the charged particle is virtu-
tion transfers sufficient energy to orbital electrons to ally stopped).
completely remove them from the atom, resulting in The intensity of bremsstrahlung radiation emitted
the formation of ion pairs. The number of ion pairs in a particular medium with atomic number Z is pro-
formed per millimetre is termed the specific ionisa- portional to Z2. For this reason in X-ray tubes, in
tion. Owing to their higher mass and charge, a-par- which electrons are accelerated across high voltages
ticles have a specific ionisation of the order of 100 to bombard a target, the target material is chosen to
times greater than that of b-particles. Ionisation is have a high Z. Conversely, in clinical applications
the most prevalent mechanism of interaction for where shielding of beta radiation is required, materials
a-particles. with low Z (such as glass and Perspex) are typically
The high specific ionisation of a-particles means chosen to minimise the secondary bremsstrahlung
that they have an extremely short range in an absorb- radiation produced.
ing material – a sheet of paper is sufficient to absorb Figure 2.5 is a schematic diagram showing
a-particles. Beta radiation, being more penetrating the processes of ionisation and bremsstrahlung
due to its lighter mass and single charge, requires radiation.
a few millimetres of aluminium for complete
absorption.
Electromagnetic radiation
Positrons cause ionisation in a similar way to beta
radiation as they have almost identical physical prop- Particulate and electromagnetic radiation differ not
erties. However, when the positron has expended all of only in their form but also in the way in which they
its kinetic energy through ionisation, combination interact with matter. The former causes primary ioni-
with a free electron results in two 511 keV annihilation sation whereas the latter causes secondary or indirect
photons. Shielding of the high-energy gamma radia- ionisation. It is the resulting secondary electrons that
tion associated with positron annihilation requires a are responsible for the radiobiological effects caused
few centimetres of lead. by g-ray, X-ray and bremsstrahlung radiation.
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20 | Physics applied to radiopharmacy

Incident particle Incident particle

Secondary electron
Bremsstrahlung

Nucleus Nucleus

(a) (b)

Figure 2.5 Ionisation (a) and production of bremsstrahlung radiation (b) when particulate radiation interacts with matter.

Gamma radiation interacts with matter via three transferred is independent of Z or the density of the
mechanisms: the photoelectric effect, Compton scat- absorbing material – that is, Compton scattering is
tering and pair production. The prevalence of each of strictly a photon–electron interaction.
these interactions is dependent on the energy of the The maximum recoil electron energy occurs when
incident gamma radiation. the g-ray is scattered at 180 to its incident direction (i.e.
back-scattered). As the g-ray loses only a small fraction
Photoelectric effect
of its initial energy when undergoing Compton scatter-
In this interaction all of the energy of the incident g-ray ing, it may subsequently undergo multiple Compton
is completely absorbed by the atom and transferred to scattering events as it traverses the absorbing medium
an inner-shell electron, which is subsequently ejected. until its energy is sufficiently reduced for it to be
The energy imparted to the electron, called a photo- completely absorbed via the photoelectric effect.
electron, is the difference between the g-ray energy, Eg ,
and the binding energy of the particular electron shell. Pair production
The number of photoelectrons produced is propor- An incident g-ray photon with sufficiently high energy
tional to Z3 and inversely proportional to Eg 3. This passing close to the electrostatic field of the nucleus
latter property means that radionuclides emitting low can create an electron–positron pair. The incident
energy g-rays are not suitable for diagnostic imaging as g-ray photon, which disappears in this process, must
the g-rays will be stopped in tissue by the photoelectric have energy greater than 1.022 MeV (twice the rest
effect, causing unnecessary patient dose and providing mass energy of the electron/positron) in order for elec-
no diagnostic benefit. tron–positron pair creation to be possible.
The ejected photoelectron subsequently causes Any energy that the incident g-ray has in excess of
ionisation, excitation and bremsstrahlung radiation 1.022 MeV is shared between the electron and posi-
as described in the previous section. Rearrangement tron as kinetic energy. The electron and positron sub-
of atomic electrons to fill the vacancy created by the sequently lose their kinetic energy through ionisation
photoelectron can additionally result in subsequent and excitation of atoms. The positron finally combines
characteristic X-ray or Auger electron emission. with a free electron, resulting in the creation of two
511 keV annihilation g-ray photons.
Compton scattering
For a particular absorbing material, Compton scatter-
Attenuation of electromagnetic radiation
ing dominates at higher g-ray energies. Compton scat-
tering occurs where a g-ray imparts only a fraction of When a beam of X-ray or gamma radiation traverses an
its energy to an outer-shell electron, termed the recoil absorbing medium, photon energy is transferred to mat-
electron, and continues onwards but scattered at a ter via the various mechanisms detailed above. For each
particular angle to its incident direction. The energy individual X-ray or g-ray photon a series of interactions
Sampson's Textbook of Radiopharmacy
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Nuclear structure and radioactivity | 21

occurs involving secondary electrons and resulting sec- Table 2.3 Half-value thickness for radionuclides
ondary photons (e.g. characteristic X-rays, scattered or used in nuclear medicine (Short 1999; Cherry et al.
annihilation photons) of progressively less energy. 2003)
The probability of a particular interaction depends
on the energy of the incident radiation and on the Radionuclide Half-value thickness (cm)
composition and thickness of the absorbing medium.
Water Lead
For the latter, as would be expected, the thicker the
absorber the greater the probability that an inter- Gallium-67 4.7 0.07
action will occur. The actual type of interaction that
Krypton-81m 5.0 0.06
occurs depends on the energy of the radiation and
absorber composition (density, atomic number) in a Technetium-99m 4.5 0.03
more complex way, as alluded to above.
Indium-111 5.1 0.07
At photon energies typically found in nuclear med-
icine, the prevalent interactions in tissue are photoelec- Iodine-123 4.6 0.04
tric absorption and Compton scattering. In the former,
Iodine-131 6.3 0.25
the photons are absorbed and completely eliminated;
in the latter, the photons are deflected from the direc- Thallium-201 4.3 0.03
tion of the incident radiation. Both interactions have
Fluorine-18 (511 keV g-rays) 7.1 0.41
the same effect of reducing the intensity of the beam
traversing the absorbing medium.
For an incident narrow beam of mono-energetic value thicknesses ([1/2]7 ¼ 0.008). Table 2.3 shows
radiation with initial intensity I0, the residual intensity that for 99mTc, 0.2 cm of lead is required for 99%
I after travelling through material of thickness d is reduction in radiation intensity. For 131I, which has
given by a higher energy g-ray (364 keV compared with
I ¼ I0 expð
m dÞ 140 keV), 1.8 cm of lead is required for the same
reduction in radiation intensity. The 511 keV anni-
where m is termed the linear attenuation coefficient hilation photons resulting from the positron emis-
and has units of cm
1. Note that this equation show- sion by 18F require 2.8 cm of lead for an equivalent
ing that EM radiation is attenuated exponentially is absorption of the gamma radiation.
similar in form to that for radioactive decay, given in
equation (2.2). The linear attenuation coefficient
includes the effect of all the interactions detailed pre-
References
viously (photoelectric, Compton scattering and pair
Cherry SR et al. (2003). Physics in Nuclear Medicine,
production) and is characteristic of the photon energy 3rd edn. Philadelphia: Elsevier Science, Philadelphia.
and the composition of the absorber. Pearce A (2008). Recommended Nuclear Decay Data. NPL
The half-value thickness D1/2, analogous to half- Report IR6. Teddington: National Physical Laboratory.
ISSN 1754-2952
life, is defined as the thickness of absorbing material
Short MD (1999). Basic Principles of Radionuclide Physics.
that reduces the intensity of a beam of radiation to half In: Samson C, ed. Textbook of Radiopharmacy, 3rd edn.
its initial value and can be written as New York: Gordon and Breach Science Publishers, 1–17.
lne ð2Þ
D1=2 ¼
m Further reading
It follows that the half-value thickness also depends on
Martin A, Harbinson S (2006). An Introduction to Radiation
both the absorbing material and the energy of the radi- Protection, 5th edn. London: Hodder Arnold.
ation. Table 2.3 gives the half-value thickness for water Saha GB (2004). Fundamentals of Nuclear Pharmacy, 5th
(equivalent to soft-tissue density) and lead for a number edn. New York: Springer-Verlag.
Walker B, Jarritt P (1995). Basic Physics of Nuclear
of radionuclides used commonly in nuclear medicine.
Medicine. In: Murray IPC, Ell PJ, eds. Nuclear Medicine
A reduction in the incident radiation intensity in Clinical Diagnosis and Treatment. Edinburgh: Churchill
by 99% is effected by approximately seven half- Livingstone, 1279–1289.
Sampson's Textbook of Radiopharmacy
Chapter No. 2 Dated: 16/11/2010 At Time: 15:25:49
Sampson's Textbook of Radiopharmacy
Chapter No. 3 Dated: 24/11/2010 At Time: 11:8:50

3
Radiation protection
Stanley Batchelor

Introduction 23 Specific hazards 35

General methods of reducing Security of radioactive sources 36

radiation dose 23
Personnel monitoring 36
ICRP guidance on radiation protection
and general radiation protection measures Pregnancy and working with radiation 39
required 24 Monitoring for contamination 40
Concise overview of legislation for Management of radioactive waste 44
protection of worker 30

Introduction is that of keeping radiation exposure to as low as

reasonably achievable (ALARA) or as low as reason-
This chapter gives an overview of the basic radiation ably practical (ALARP), and this is a common theme
protection measures needed to work safely with through all European legislation.
radioactive materials with a description of what the
International Commission on Radiological Protection
(ICRP) recommends in different grades of radionu- General methods of reducing
clide laboratories. It also explains the requirements radiation dose
of United Kingdom law that exists to protect the
patient, worker, members of the public and the en- Radiation dose is received by direct irradiation from a
vironment from risks of radiation exposure. Finally, source external to the body or from radioactive mate-
subjects such as personnel monitoring, decontamina- rial absorbed into the body. The former is reduced by
tion and radioactive waste disposal are covered. correct optimisation of the three well-known dose
Most legislation stems from world governments saving factors:
taking due notice of the ICRP recommendations and * Time
so, although there will be some variation to that * Distance
described in this chapter, the differences in developed * Shielding.
countries should not be too marked. Certainly in the
European Community the legislation of member states The first factor, time, is pretty obvious: the shorter the
will be very similar as they will be in accordance with exposure to a radiation source the less dose is received.
European Directives. An underlying principle of ICRP This means that all radioactive sources should be
Sampson's Textbook of Radiopharmacy
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24 | Physics applied to radiopharmacy

returned to their shielded containers as soon as possi- those as in positron emission tomography (511 keV
ble; bins full of hot waste should be removed and annihilation photons) or 22/24Na may need several
placed away from workers whenever possible; work- if not tens of millimetres just to reduce the dose by
ers should proceed with their work as quickly as they a factor of 2. Refer to Table 3.1 on the radiation and
are able but without adding an undue risk of error or shielding properties for commonly encountered
spill. ‘Cold runs’ can also be carried out where a pro- radionuclides.
cedure using high activities is being performed for the
first time.
The second factor, distance, is often not appre- ICRP guidance on radiation
ciated fully. The intensity of, and hence the absorbed
dose from, a radioactive source varies inversely as
protection and general radiation
the square of the distance from the source (the inverse protection measures required
square law). So on doubling the distance, the dose
rate drops to one-quarter. However the effect is even No new facilities or significant modification of exist-
more dramatic at short distances. If the fingers, for ing facilities should be designed and brought into use
example, are touching the external surface of a glass without expert advice from the employer’s Radiation
vial containing a gamma emitter, the dose may be one Protection Adviser (RPA). This is one of the roles of
hundred times higher than that experienced by using the RPA detailed in the Ionising Radiation Regulations
tongs of reasonable length. Making a 10-fold in- 1999 (HMSO 2000b). The facilities required will
crease in distance between source and finger means a depend on the nature of the hazard involved.
100-fold reduction in absorbed dose. (It must also The ICRP (ICRP 1989) classifies laboratories
be remembered that the inverse square law is quite in which radioactive materials are used as being of
approximate once distances become comparable to low, medium or high hazard. This designation takes
the dimensions of the source.) Some people criticise account of the risks of contamination for the various
the use of tongs, saying that they are able to handle procedures. In order to determine which hazard
items more quickly without them, thereby gaining in category a given procedure comes into, a ‘weighted
the time factor what they lose in the distance factor. activity’ is calculated. This is the activity actually
There are two flaws in this argument: the first is that encountered multiplied by two modification factors
the gain does not compensate, and the second that – one for the radionuclide (Table 3.2) and one for the
if they persevere with tongs (and other dose-saving type of operation to be carried out (Table 3.3). The
devices) they will find they quickly get used to them ‘weighted activity’ is then compared with the values
and perform the operations no slower than before. given in Table 3.4, from which the hazard category of
The third factor, shielding, may appear obvious to the laboratory is determined.
many but there are many small points that make this
subject quite complex at times. The electrons from
Requirements for the different
beta emitters can be completely absorbed with a centi-
laboratories
metre or so of Perspex (beta energy does not go up and
up but has a finite maximum for any radionuclide). The standards required in low-, medium- and high-
Gamma emitters show an exponential absorption with hazard laboratories are summarised below.
any absorber but this absorption depends on the A low-hazard laboratory requires: no structural
energy of the gamma radiation and the atomic number shielding, cleanable floor and bench surfaces, no fume
and density of absorber. For low gamma energies the cupboard for radiation work activities, standard ven-
absorption varies as the cube of the atomic number, tilation and plumbing, and simple hand wash facilities.
whereas for higher energies it is independent of atomic Upgrading this to a medium-hazard laboratory
number. This means that for low-energy gamma/ requires in addition: continuous, cleanable flooring,
X-ray emitters such as 125I only a very small thickness good room ventilation, fume cupboard and some
of lead will reduce the intensity of radiation by a factor decontamination facilities. This room is likely to be a
of 10, whereas for the higher-energy emitters such supervised or may possibly be a controlled area.
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Table 3.1 Radiological data for radionuclides encountered in nuclear medicine and positron emission
tomography centres

Radionuclide Decay mode Principal emission energy (MeV) (beta Half-lifea First tenth value Annual limit of
energies are maximum energies) layer (mm Pb)b intakec (MBq)

Radionuclides encountered in nuclear medicine

57
Co EC Eg 0.122, 0.136 271 d 0.7 21

58
Co bþ Eb 0.475; Eg 0.811 70.8 d 28 10

67
Ga EC Eg 0.093, 0.185, 0.300 78.3 h 5.3 71

89
Sr b Eb 1.463 50.5 d 5000 (estimate) 3.6

99
Mo b Eb 1.232; Eg 0.740, 0.141 66.0 h 20 17

99m
Tc IT Eg 0.141 6.02 h 0.9 690

111
In EC Eg 0.171, 0.245 2.83 d 2.5 65

123
I EC Eg 0.027, 0.159 13.2 h 1.2 95

131
I b Eb 0.606; Eg 0.364 8.04 d 11 1.8

127
Xe EC Eg 0.172, 0.203, 0.375 36.4 d — —

133
Xe b Eb 0.346; Eg 0.081,0.033 5.25 d 0.7 —

201
Tl EC EX/g 0.075 ave.; Eg 0.167 73.1 h <0.9 211

32
P b Eb 1.71 14.3 d range 6000 air 6

51
Cr EC Eg 0.320; EX 0.005 27.7 d 7 526

125
I EC Eg 0.035; EX/g 0.030 ave. 60.1 d 0.06 1.3

Radionuclides encountered in positron emission tomography

11
C bþ, EC Ebþ 0.960; Eg 0.511 20.4 min 13.5 880

13
N bþ, EC Ebþ 1.198 Eg 0.511 10 min 13.5 not listed

15
O bþ, EC Ebþ 1.732 Eg , 0.511 2.03 min 13.5 not listed

18
F bþ, EC Ebþ 0.633 Eg 0.511 110 min 13.5 215

a
min, minutes; h, hours; d, days; y, years.
b
These data are taken from tables published from multiple sources; they may not take account of low-energy (20 keV) X- or gamma emissions.
Where a radionuclide is a pure beta emitter the range in air is given.
c
Mostly taken from ICRP Publication 68 (ICRP 1994) Dose Coefficients for Intakes of Radionuclides by Workers and ICRP Publication 72 (ICRP 1996)
Age dependent Doses to members of the Public from Intake of Radionuclides: Part 5 Compilation of Ingestion and Inhalation Dose Coefficients.
These values are minimum values giving the most pessimistic case. Radionuclides in certain forms, or taken in through a different route, may have
a higher ALI than that shown.
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26 | Physics applied to radiopharmacy

16 (1) in the Ionising Radiations Regulations 1999

Table 3.2 Weighting factors for different
if more detail of this definition is required).
radionuclides
A radiopharmacy hot room with a 99Mo/99mTc
Radionuclide Weighting factor generator will be a high-hazard area laboratory. A
89
low-level assay room preparing, for example, glo-
Sr, 125I, 131I 100
merular filtration rate (GFR) samples would be a
11
C, 13N, 15O, 18F, 32P, 51Cr, 57Co, 58Co, 59Fe, 1.0 low-hazard laboratory. A cell labelling room could
67
Ga, 99Mo, 99mTc, 123I, 111In, 201Tl be either a medium-hazard or possibly a high-hazard
3
H, 14C, 81mKr, 127Xe, 133Xe 0.01
area (although some of the higher specification fea-
tures of the high-hazard laboratory may still be present
due to the need for higher standards of cleanliness,
etc., required).
Table 3.3 Weighting factors for different activities

Operation performed Weighting factor

General design requirements of rooms for
Simple storage area 0.01
using unsealed radioactive sources
Radioactive waste: decay storage or 0.01–0.1 Security
storage prior to consignment
It is a legal requirement that radioactive sources are
Diagnostic procedures (scans, sample 0.1 kept locked away. This means fridges and other stores
counting), radioactive patients (diagnosis) that contain radioactive materials must be lockable.
in a waiting room or on wards See later in this chapter for more about security.
Dispensing and administering 1
radionuclides, ward therapy patients, Ventilation
normal chemical operations Ventilation systems should function so that they do
not extract radioactive material from one room and
Complex operations, radiopharmaceutical 10
expel it into another room. This can occur either by
preparation
design (i.e. using part of the extracted air to mix with
external air) or by the location of the exhaust duct
A high-hazard laboratory may require structural outlet position. This should be checked at commis-
shielding, floor surface as before but welded to walls, sioning. In some cases, such as dispensing for iodine
special plumbing, forced ventilation, and enhanced therapy, a fume hood operating at a negative pressure
fume cupboard facility – depending on the nature of is needed for protection of the worker. In other cases,
the hazard. This room is likely to be a ‘Controlled such as sterile production, it is appropriate to have a
Radiation’ area. A controlled radiation area is defined fully exhausted laminar vertical flow system under
within UK legislation (HMSO 2000a) as an area where positive pressure.
special protection procedures must be followed in
order to restrict exposure such that 3/10 of any rele- Space
vant dose limit is not exceeded (refer to Regulation It is essential that there is adequate space in work areas
in rooms where radionuclides are handled. Workers
must be able to safely perform their tasks without risk
Table 3.4 Hazard category depending on
of collision and subsequent spills. Low-activity assay
weighted activity
work areas must be separated from areas involving
Weighted activity (MBq) Category higher-activity work. Sensitive beta or gamma count-
ing or imaging equipment (or whole body counters)
Less than 50 Low hazard
should not be sited physically close to high-energy
50–50 000 Medium hazard sources such as molybdenum/technetium generators
or stock amounts of positron-emitting radionuclides.
Greater than 50 000 High hazard
The interference between such high- and low-activity
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Radiation protection | 27

work can invalidate results or significantly restrict the and/or the amounts of radioactivity so dictate, or it
use of the facility for either purpose. may be a cupboard within a room used for another
purpose. This waste will be stored for a given length of
Washing facilities time prior to being despatched off site either as radio-
It is important that workers have convenient access active waste or possibly (for short-half-life material
to hand-washing facilities; these may usefully be sited such as technetium-99m) as non-active waste (clinical
close to the exit of the room. Taps should be able to be or black bag, etc.) The store may need shielding unless
operated without using the hands (e.g. elbow or foot the waste is very low level. Even if radiation levels are
controls). Disposable towels for drying are preferred only moderately low, the exposure of staff or public is
and a mains-operated monitor should be located rea- not acceptable nor is it within the ‘ALARP’ principle,
sonably close to the sink. The monitor should be left so it is necessary to reduce this with shielding and/or
turned on so that staff are able and encouraged to use it by removal as soon as possible after production.
without touching the controls and also the monitor
will not have flat batteries – a common finding in Benching
audits. In addition, a personnel monitoring logbook Medium- and high-hazard category laboratories
should be kept with the monitor, preferably mounted should have a bench design with a raised lip at the
on a dedicated, small inclined shelf under the monitor front and coved at the back onto the wall to contain
with a pen attached so that record keeping is made as spills. There should be no gaps in joining of parts of the
easy as possible. bench top as these would allow absorption of radio-
active contamination into the joins. It is important that
Designated sinks these features are still employed even if the worker
In situations where large amounts of radioactivity are employs a spill tray covered with disposable liner.
used, the designated sink for aqueous waste disposal The benching should be resistant to corrosion by chem-
should be connected as directly as possible to a main icals and also be easily decontaminated. The bench
sewer. Although this is not always possible, one should must also be able to support the loading of lead shields.
still trace back the route of such drainpipes to deter-
mine whether there are any problems that can be fore-
seen as a consequence of the disposal. Examples that Area designation
have been encountered (not infrequently) include:
Controlled areas are required in the technetium gen-
* Lengths of pipe that do not empty due to erator suite of the radiopharmacy. Other rooms such
insufficient downward gradient on the pipe as the blood labelling room, aseptic dispensing room
* Hand wash basins situated further down the pipe and quality control laboratory may or may not be
run which are lower than the designated sink, so controlled areas depending on the nature of work
that if a blockage did occur waste would come undertaken, the activities handled and the local deci-
into the hand wash basin before appearing in the sions made between the RPA and staff involved. These
bottom of the designated sink rooms will almost certainly be supervised areas if they
* Large-volume ‘traps’ on the waste outlet that are are not controlled areas. The radionuclide store is
designed for holding materials to encourage likely to be a controlled area unless the amounts of
dilution. These result in a delay in complete radioactive material stored are low and well shielded.
discharge of radioactive materials and therefore Sometimes it is more practical to control the entire
cause unnecessary irradiation to staff in the suite or the entire suite past an entry/collection point
laboratory. Such traps on sinks designated for where local deliveries may be made. The status of such
aqueous radioactive waste disposal are not rooms must be clearly signed and they should be fully
generally acceptable to the regulator. described in local rules. It is customary to control an
entire room rather than declare only part of it to be
Solid waste controlled, although this latter option is always avail-
Some form of solid radioactive waste store is neces- able. An example of this would be the area behind a
sary. This may be a dedicated room where the volume shield or in a fume cupboard, where only the hands can
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28 | Physics applied to radiopharmacy

enter. In this case that area alone may be controlled on appropriate (except in SPECT, where they would be
the basis of the dose limit for an extremity being likely needed for X-ray attenuation).
to be exceeded. Rooms that are controlled radiation
areas because of their potential for contamination, as
Local shielding
well as direct radiation exposure, such as the radio-
pharmacy, will require the entrance to be via a ‘step By ‘local shielding’ is meant a shield placed over a
over’ barrier. This not only serves to act as a conve- radiation-emitting area so that control of dose rate at
nient point at which to put on disposable overshoes its source is effected, thereby making the rest of the
and use monitoring facilities, but also draws attention room safer for work (as opposed to shielding a large
to the special nature of the area being entered. It also area such as an entire wall). Local shielding should be
demonstrates to a regulator that control of potential applied wherever a significant reduction in dose may
contamination is being appropriately managed. be possible. Obvious examples of sources for which
local shielding is appropriate are 99Mo/99mTc genera-
tors (both primary shields in which they are shipped
Liquid waste disposal – delay tanks
and additional secondary shields in which the assem-
and storage
bly is placed on delivery to the suite), multidose vials
‘Delay’ tanks may be used in some hospitals for the for patient administrations, individual diagnostic
reduction of environmental impact of the discharged and therapeutic patient doses and flood sources for
iodine from cancer patients treated with radioiodine. gamma camera quality control. Multidose vials con-
This is unlikely to be required purely as a result of radio- taining 99mTc-labelled products are easily shielded
pharmacy activities. There currently appears to be fur- using 2–4 mm thickness of lead pot. Iodine-131
ther controversy between regulators as to whether delay therapy doses need much more protection (the tenth
tanks are justified in many situations in healthcare. value thickness is 11 mm) and additional shielding
It is important to be aware of the local licensing to the pot used for transit may be deemed necessary
conditions under which the site has to operate (see the when the sources are locked away in a shielded/
later part of this chapter). If the hospital does not have isolated store. This is because what can be deemed
the ability to store aqueous radioactive waste then it is acceptable for a short exposure duration may not be
important that the way such unwanted liquid waste is so acceptable during a longer-term exposure situation
handled be agreed with the RPA and local Environ- (see ‘Shielding of the generator’ below). Distance can
ment Agency inspector at the outset. In cases like this also be usefully employed to reduce the dose rate, as
the waste must be disposed of at the moment it is well as time by storing the source in a room that has
declared as aqueous liquid waste. close to zero occupancy (see later).
Other shielding solutions are employed for opera-
tional procedures. Manipulation of radioactive mate-
Wall shielding
rials must take place behind a body and eye shield,
On safety grounds, it is rarely justified to shield rooms often termed an ‘L shield’ (Figure 3.1) Note that there
containing the radionuclides used in nuclear medicine is a bottom to the shield to protect the workers’ lower
imaging. However, it is possible for imaging to suffer body and to make the shield more stable. It is essential
if there are high radioactivities in rooms adjoining that the benching is able to safely accommodate the
the imaging room. Such interference can result from weight of the shielding. Commercial benching can
patients being imaged in adjoining imaging areas, be specified to take various loads. The shield acts
from an injected patient waiting in an adjoining room both to attenuate radiation and as a guard to stop
or from a radiopharmacy situated too close to imaging the operator becoming contaminated. Radioactive
facilities. Hence wall shielding is sometimes found to waste (whether solid or liquid) will also require local
be required. The amount of shielding needed is gener- shielding. Distance may be used for bulky items
ally up to 2 mm thickness of lead, which should reduce such as sacks of clinical radioactive waste. When this
any such effects by more than 100-fold. The use of is considered appropriate, it can be accomplished
leaded doors in nuclear medicine is not usually through the use of an entire dedicated room or by
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Radiation protection | 29

Lead glass window

Lead shield

Benching with upstand at front and coved to wall at rear.

Figure 3.1 Typical shield for operational shielding of sources.

promptly depositing the waste in the institution’s cen- necessarily equate to its application during storage
tral radioactive waste store. Sometimes both shielding and use. For example, upon delivery the generator
and distance (using a locked room) are required – e.g. needs to be moved without lifting equipment and
for the waste from an iodine therapy in-patient. hence the weight of the primary shield has to take
Ventilation of such areas must not be overlooked. this into account. The primary shield may be depleted
uranium as this offers more attenuation than lead
Radionuclide manipulation and administration (thickness for thickness) due to its higher atomic num-
It is important that protective devices are used when ber and density. However, once placed within its
vials and syringes containing radioactive materials are secondary shield, the assembly (i.e. both the primary
handled. For gamma emitters, tungsten is generally shielded generator and the secondary shield around
used in commercial protective products as it has a it) is not required to be moved until the generator is
higher atomic number and density than lead, thereby removed. So what satisfies ALARP during transit
providing more attenuation for the same thickness. (hours of personnel exposure at a significant distance)
Some lead-glass shields can provide better visibility. is different from what is needed during use (days of
Perspex syringe shields are generally used for shielding exposure at potentially closer personnel distance).
beta emitters as they not only absorb the b-particles Dose rates around the secondary shield should be
but also minimise the Bremsstrahlung X-radiation pro- measured for dosimetry validation. Adjoining rooms
duced, which occurs when a shielding material of high should not be overlooked if the generator is placed in
atomic number is used. However, with sufficient proximity to a dividing wall and further shielding has
thickness of lead the attenuation can be great enough to be added if required and environmental dosemeters
to absorb all the beta radiation and most of the used to integrate the dose at wall surfaces over a long
Bremsstrahlung. It is important that the operator does period of use. Typically, total shielding of the order of
not become too complacent when using syringe shields. 80–100 mm lead may be needed. All shielding within
The radiation emitted from the ends of the shield the radiopharmacy must be easily cleanable – this
results in a far lower overall protection than might be generally means that exposed lead surfaces are coated
expected from the thickness of lead in the shield. with paint or some other material.

Shielding of the generator Robotic systems

Radiation protection has to follow the ‘as low as rea- There has been some development of robotic systems
sonably practical’ principle (‘ALARP’) The applica- so that automated formulation may be achieved,
tion of this principle to the shielding requirements thereby reducing the hand doses of radiopharmaceu-
for the transport of a new generator does not tical staff. These systems need to overcome the
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30 | Physics applied to radiopharmacy

the nature of the bin’s contents and that it must not be

inadvertently removed by cleaning staff. Unintended
radioactive waste leaving the premises as ordinary or
clinical waste can result in legal action being taken
against the employer by the Environment Agency
due to the failure to keep waste secure and dispose of
it via an appropriate waste stream.

Concise overview of legislation

for protection of worker
In the UK the main items of legislation that will be
relevant to workers using radioactive materials in a
radiopharmacy are:

1 The Ionising Radiation Regulations 1999

2 The Ionising Radiation (Medical Exposure)
Regulations 2000 (IRMER)
3 The Radioactive Substances Act 1993
4 The Environmental Permitting Regulations 2010
5 The High Activity Sealed Radioactive Source and
Orphan Sources Regulations 2005 (HASS)
6 Carriage of Dangerous Goods and Use of
Transportable Pressure Equipment Regulations
Figure 3.2 Remote fill station for use in PET. (Photograph
2007 (HMSO 2007)
courtesy of Amercare Ltd.)
7 The Medicines (Administration of Radioactive
Substances) Act 1978 (and amendments in 1995
potential contamination problems that seem to occur and 2006)
in the early generations of this equipment. Simplified,
automated syringe filling stations are being developed
to aid in manual manipulations. An example of such a The Ionising Radiation Regulations
device, an automated dispenser for PET, is shown 1999 (HMSO 2000b)
in Figure 3.2. This, at least, may reduce the significant
These regulations come under the umbrella of the
radiation dose that is received from the unshielded end
Health and Safety at Work Act 1973. They are princi-
of syringe shields, etc.
pally there to protect the worker from exposure to
ionising radiation in the workplace. They are enforced
General procedures by the Health and Safety Executive (HSE), which may
issue Improvement and/or Prohibition Notices if it
The access allowed to the radiopharmacy for cleaning
feels that working practices are a significant threat to
staff and other service personnel must take into
workers or the public.
account the hazards to which such staff may be
The main features of these regulations are:
exposed. If the area remains controlled or supervised
when they need access, such workers must follow local 1. Employers must notify the HSE 28 days
rules. There must be clear marking, with an appropri- prior to working with radiation of their
ate radiation trefoil warning symbol, of bins that are intention to start such work. They must also
used for the accumulation of solid radioactive waste. It do this if they are significantly changing the
is also required that there be a clear written sign stating way they are working with radiation (e.g.
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Radiation protection | 31

starting work with radioactive substances subject to these dose limits although they need to be
after working with X-ray generators, such as optimised and justified under the IRMER.
going to PET from CT).
2. The employer must have access to the services of 5. The employer must ensure that they have
a suitably qualified and trained Radiation suitable contingency plans to cover cases where
Protection Adviser (RPA) unless the work falls a reasonably foreseeable accident with radiation
under the category of this not being necessary. occurs.
For radiopharmacy situations an RPA would be 6. The employer must also ensure that all the
required. The RPA must be accredited by a body employees working with radiation are
that has been accepted by the HSE as fit to suitably trained. The degree of training will vary
perform this accreditation (e.g. RPA 2000; this is with the nature of the work performed. For
currently the only body accepted by the HSE). workers formulating and dispensing in
3. The employer must have performed a suitable the radiopharmacy this may be a one-day
and sufficient written radiation risk assessment radiation protection course, whereas
for all work they are undertaking. This risk for supervisory staff this may last several days.
assessment is pivotal in determining whether 7. Areas where work with radiation takes place
the area needs to be given special status have to be assessed as to whether they should
(see controlled areas below) and also whether be controlled or supervised. A supervised area
environmental or personal monitoring needs to is any area where a public dose limit may be
be undertaken. exceeded and a controlled area is any area
4. All doses must be ‘as low as reasonably where 3/10 of the dose limits may be exceeded.
practical’ – the ALARP principle. This means These areas are required to have clear
that where it is reasonable and practical to reduce demarcation and work in them must follow
a significant dose and it is cost-effective to do so, local rules and/or systems of work (depending
then this must happen. Employees’ and public whether they have a controlled area within
doses must, in any event, be within the specified them). If local rules exist then a suitably trained
dose limits. Prosecution can occur for employers Radiation Protection Supervisor needs to
not keeping radiation doses ALARP – even if ensure radiation workers understand and
they are within dose limits. These limits are follow the local rules.
absolute – exceeding them is illegal and 8. The employer has a duty to monitor the
prosecution is then a high probability. Limits workplace and workers for radiation exposure,
are: 20 mSv for whole body* (effective dose); unless prior assessment has shown that the
500 mSv for extremities, skin,* etc.; 1 mSv for workers’ radiation dose does not justify this.
the fetus and public; 13 mSv for the abdomen of For workers in a radiopharmacy this monitoring
a woman of reproductive capacity during a will be necessary (see later in this chapter) and
3-month interval; 5 mSv per 5 years for a person this may be both whole body and extremity.
who may be exposed to ionising radiation as a Records of such monitoring must be kept for
result of the exposure of someone else. (The statutory periods, which vary depending on the
limits marked * apply only to what are termed nature of the record. The time for which
‘classified radiation workers’, who are persons contamination records should be kept is not
who have been formally assessed as being fit specified in the Radioactive Substances Act but
to work with radiation and are likely to exceed there is detailed guidance for the retention of
3/10 of the limits above.) other records in the Medical and Dental
Guidance Notes, Appendix 9 (IPEM 2002).
Other staff, the majority (>95%) of healthcare work- 9. There are many other requirements such as leak
ers, are just ordinary radiation workers and have limits testing of sealed sources (e.g. those that are
of 3/10 of these (i.e. 6 mSv for body, 150 mSv for used to test the isotope calibrator); the need to
extremities, etc.). Also, medical exposures are not account for the radioactive materials held and
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32 | Physics applied to radiopharmacy

to keep them secure; the need to notify HSE * Quality assurance and audit procedures
if there are uncontrolled dispersals or losses * Procedures for recording target doses (diagnostic
of material; and the need to move materials reference levels)
around premises in a secure and safe manner. * Procedures for overexposure of patients
There is also a duty on the installer of * Other considerations such as the need for clinical
equipment that exposes patients to radiation audit, medical legal procedures, etc.
to ensure that a critical examination is
There must also be protocols that describe how the
performed (to verify that safety devices and
procedures are to be performed.
warning devices are functioning) and for
The training requirements for the operator and
employers to ensure that quality assurance is
practitioner are set out in a schedule attached to the
performed. Overexposures due to equipment
regulations.
failure must be reported to the HSE if they
Radiology, nuclear medicine and radiotherapy
exceed specified levels.
activities are required to have an appropriately expe-
Failure to conform to these regulations can rienced medical physics expert (MPE) whose role is
result in the issue of an Improvement Notice by to advise on the patient radiation dosimetry and radi-
the HSE. If improvement fails to be implemented ation physics aspects of the procedures – these are
then a prohibition notice may be issued that re- separate from the role of the Radiation Protection
quires the activity to cease immediately (these Adviser (RPA).
may be issued straight away if the non-compliance These regulations chiefly apply to routine diag-
is deemed serious enough). If the issue escalates to nostic procedures, therapy procedures (both unsealed
prosecution (or such a major breach dictates this source therapy, e.g. iodine-131 for Ca thyroid and
to occur after an incident has occurred) then sub- hyperthyroidism and for external beam radiotherapy/
stantial fines and custodial sentences are also likely. brachytherapy) and also research procedures.
The associated Approved Code of Practice is also An inventory for equipment that controls radia-
useful (HSC 2000). tion exposure must be kept – this must include all of
the following:
The Ionising Radiation * Make and type of equipment
(Medical Exposure) Regulations 2000 * The year of manufacturer and of installation
(and Amendment Regulations 2006) * Serial number and name/model of equipment.
(HMSO 2000a, 2006)
For a radiopharmacy this would include the isotope
In England these regulations are now enforced through calibrator as this directly affects the activity and
the Care Standards Commission and they require the hence radiation dose delivered to the patient. It could
employer to have in place measures to ensure that also include any other hardware or software that
patients’ radiation exposures are controlled through could affect the dispensed radiopharmaceutical dose
sound procedures, referred with adequate clinical infor- delivery procedure.
mation, performed by adequately trained, approved
and identified practitioners and operators using equip-
ment that is sound and fit for use. The Radioactive Substances
Employers must have written procedures that Act 1993 (HMSO 1993) and the
cover: Environmental Permitting Regulations
*
2010 (HMSO 2010)
Identifying the patient
* Ascertaining the status of pregnancy There is a legal obligation for UK users of radioactive
* A framework for naming who is a practitioner materials to comply with the Radioactive Substances
(justifies the procedure) and Act 1993 (RSA93) unless working under an exemption
 who is an operator (performs the practical order (but this is very unlikely to apply to a hospital
aspect of the exposure) with a radiopharmacy). The purpose of this act is to
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Radiation protection | 33

ensure control over radioactive material and resulting no radioactivity, less activity or a less damaging
radioactive waste. Because this waste is potentially radionuclide.
harmful, it is important that it is stored, used and * Evidence that there is management control of
disposed of safely, and that it is not produced in un- the use of radionuclides and that there are
necessary quantities. Control is therefore necessary adequate written procedures in place that relate
over the use and storage of radioactive materials as to the licence conditions of use.
well as over the waste produced.
This application process is usually undertaken by
the Radiation Protection Adviser or his support team
Environmental Permitting requirements although the act does not specifically mention the term
under RSA93 and EPR 2010 ‘RPA’.
The Environment Agency (EA) provides a regulatory
system of registration and authorisation for the use, Disposal of radioactive waste
accumulation and disposal of radioactive materials.
Record keeping
The act is policed by the EA whose inspectors have
Record keeping is an important part of complying
the right of access to premises to determine whether
with permits, and requires very explicit records of
a user is complying with the act. For a user such as
stock and waste (e.g. activity levels, volumes and the
a hospital to obtain permits they must submit an
time waste has been stored).
application to the EA, which assesses it, and if satis-
fied, issues the appropriate permits. Applying for, Solid waste
keeping or changing these site/employer specific docu- Radioactive waste from the radiopharmacy is char-
ments generally involves the payment of a significant acterised according to activity and is treated as
fee unless the variation requested is very minor in follows:
nature.
* Solid waste less than 0.4 Bq/g is exempt under
Applications must include:
the act, so this can go out as non-radioactive
* Details of organisation and premises and waste. It may still be toxic waste and be bound
radioactive materials to be held. by other requirements.
* Justification case – why do you need to use * Low level: 400 kBq in 0.1 m3 and 40 kBq per
radioactive material and what steps will you article (or for 14C and tritium, 4000 kBq in
take to minimise the production of radioactive 0.1 m3 and 400 kBq per article) may be disposed
waste? of as normal refuse. (A volume of 0.1 m3 is
* Form of waste you are requesting to store or specified as it is considered equivalent to ‘one
dispose of, i.e. solid, liquid, gas, organic dustbin’; this is commonly termed dustbin level
scintillant. waste.) Again, if the waste is toxic for other
* Maximum amounts, storage times and volumes of reasons (such as clinical waste) then it may not
each waste requested. be possible for it to be disposed of as dustbin
* Accumulation of waste – use of decay storage to type waste.
reduce the waste discharged into the * Incineration: transfer to external
environment by taking advantage of natural contractor under certain conditions.
radioactive decay. The activity here must be within that
* Assessment – calculation of the maximum allowed on the permit.
radiation dose to a critical group from the * Transfer to an authorised company/body may
requested disposal. occur. This route is generally used by hospitals
* Demonstration that the organisation will be for the disposal of sealed sources (including
working to Best Practical Means and Best spent gamma camera flood sources and sample
Available Technology. The EA will want to see counter checking standards). The waste may
that a review has been done that shows the work then be processed or sent to secure storage for
cannot be done in an equivalent way using either decay.
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34 | Physics applied to radiopharmacy

Liquid waste Carriage of Dangerous Goods

Drains may be used, but the disposal route must be and Use of Transportable Pressure
known and designated and records must be kept of all Equipment Regulations 2009
disposals; monthly totals again must comply with site
These regulations are enforced through the Depart-
limits.
ment for Transport and define the requirements for
the transport of radioactive materials in the UK.
Organic solvents
They define many roles (carrier, driver, consigner,
Transfer off-site may occur, but the amounts trans-
packer, etc.) and detail the responsibilities that these
ferred have to be within the limits of the permit.
roles carry. They also define radionuclide specific
activity levels for exemption and excepted packages
Inspection process
(i.e. excepted gives partial exemption from some of
Inspectors can visit whenever they wish, although
the regulations) and further classify packages into
prior notice is normally given. If an inspector
Type A, Type B, etc. The need for the correct docu-
feels that the conditions of the authorisation or
mentation to accompany such packages is also
registration are not being met, he or she is empow-
strictly defined. Quality assurance programmes that
ered to issue an Enforcement Notice which details
show that the whole transport process is being con-
how the employer is not fulfilling the conditions of
trolled have to be in place and emergency procedures
the site licence. The employer is given a date by
have to be rehearsed so that, should an accident
which improvements must be made; if it is not met,
happen whereby the integrity of the containment
prosecution is likely. Penalties can range from size-
or shielding is threatened or breached, the staff
able fines to imprisonment of relevant corporate
involved are well versed in the emergency procedure.
person.
Placarding of vehicles and signage on packages
is also defined. In recent years the regulations have
changed several times in the UK with promises that
The High Activity Sealed further changes will occur every few years. The
Radioactive Source and Orphan Department for Transport is also inspecting hospi-
Sources Regulations 2005 (HASS) tals performing such activities with increasing
(HMSO 2005) frequency.
The transport of radioactive materials may
These regulations place duties on the owners of
also require a Dangerous Goods Safety Adviser
radioactive sealed sources so that they are kept and
(see Chapter 30 on packaging and transport of
used in a secure manner. These regulations require
radiopharmaceuticals).
an increasing raft of security measures to be in place
depending on the activity of the radioactive sealed
source. Different activity values apply to different
Medicines (Administration
radionuclides due to their differing radiotoxicity.
of Radioactive Substances)
The measures in place include physical measures
Regulations 1978 (HMSO 1978)
(e.g. door locks and door frames to a specified stan-
dard), security checks on staff who have access to Clinicians (doctors and dentists) require a licence
the sources, information and site security plans from the Department of Health if they intend to
about the sources, evidence of adequate financial administer a radioactive material to a patient for
arrangements in place for eventual disposal of the the purposes of diagnosis, therapy or research. The
source at the end of its working life or if the orga- licences are specific for a purpose, for a site and for
nisation ceases to exist for any reason, and so on. a doctor, and run for a finite period of time (5 years).
Although these regulations do not apply to unsealed Hence, if a doctor wishes to practise on a new site
sources, the Environment Agency expects the advice they must apply for a new licence. If they wish to
of the police to be followed where the hazard is perform a specific research project they must apply
similar. for a specific licence and this has to be renewed if the
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Radiation protection | 35

time expires or if the number of patients originally slight possibility of volatility. Such a state can acciden-
asked for has been reached. tally be created by deviations from recommended pro-
The application for the licence has to have the cedures, such as unintended pH changes. An exception
signature of the applicant as well as the supporting to this could be the manipulation of the very small
scientist, the radiopharmacist and the RPA who are amounts of radioiodine in, for example, radioimmu-
testifying that they feel able to support the applicant in noassay procedures. It is suggested that the wearing
their application. of two pairs of gloves, possibly of different materials,
These regulations are enforced though the when working with radioiodine is good practice as
Department of Health. there is evidence that some iodine-labelled materials
do penetrate some gloves (Connor, McLintock 1997).
It is also suggested that if liquid radioactive iodine
Specific hazards waste is being stored, this should be done by preparing
a solution of 25 g sodium thiosulfate and 2 g sodium
Hazards from contamination and specific
iodide in 1 litre of 1 mol/l sodium hydroxide and
hazards from iodine ingestion
then adding the waste to this solution as it arises.
The very low annual limit of intake (ALI) for 131I Spills of radioiodine can be made safer by adding a
(see Table 3.1) reflects the danger of ingestion of this solution of 5% sodium thiosulfate before carrying out
radionuclide. Part of the reason for this very low ALI the decontamination.
is that the thyroid gland is avid for iodine – ingestion The thyroid glands of workers handling mega-
of a small amount results in a very high percentage becquerel quantities of radioiodine materials should
being taken up by the gland. Iodine is also found in regularly be checked; good practice would be at
the salivary and pituitary glands, ovaries, muscle and least weekly or preferably a few hours after a pro-
bile (Underwood 1977). Approximately, the commit- cedure. Although this can be done very accurately
ted dose equivalent from thyroidal ingestion of either using a dedicated thyroid uptake probe system, a
125
I or 131I is 1 mSv/kBq. Uptake of iodine in the contamination monitor with a sodium iodine scin-
thyroid gland before or after contamination can be tillation crystal a few millimetres thick with a rate-
blocked using stable iodine. There are a number of meter display will suffice. Data on the fraction of
125
possible methods for achieving this, but one must I remaining for up to 60 days after ingestion with
beware of potential side-effects and it is recommended normal thyroid function are given in Appendix 3 of
that a medical adviser be consulted. Administration of Health Physics Aspects of the Use of Radioiodines.
potassium iodate is often thought to be the simplest (Prime 1985).
method and the suggested daily dose has been reported
to range from ‘>5 mg per day’ (Prime 1985) to 100 mg
Hazards from contamination and specific
(Bolton 1985). The delay in administration after
hazards from phosphorus-32 ingestion
ingestion affects the effectiveness of this treatment.
A 100 mg dose given within 3–4 hours after ingestion As Table 3.1 shows, 32P has the third lowest annual
is reported to reduce uptake by more than 50% limit of intake (ALI) in the listing. In the form of
(NCRP 1977). This ionic blocking works by the mech- sodium phosphate it can irradiate important cells
anism of the ‘Wolff–Chaikoff block’. This involves the related to the blood – indeed it is used in this form
blocking of the organic binding of iodine and its incor- to treat polycythaemia vera (a potential side-effect
poration into hormones caused by large doses of of this radionuclide therapy is the induction of leukae-
iodine; it is usually a transient effect, but in large doses mia; therapeutic amounts are in the region of only
and in susceptible individuals it can be prolonged and 200 MBq, so the ingestion of any amount is of signi-
cause iodine myxoedema. Note that workers should ficant concern).
not routinely take excess stable iodine prior to per- For dosimetry purposes phosphorus is assumed
forming iodination procedures. to be deposited in the endo-osteal cells of the skele-
It is strongly recommended that iodine be mani- ton and retained on the bone surfaces; hence there is
pulated inside fume cupboards when there is even a also a risk of bone cancer after irradiation. Jackson,
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36 | Physics applied to radiopharmacy

Dolphin (1966) give details of a model used to Security of radioactive sources

describe the whole body retention of phosphorus.
Airborne ingestion via droplets is a hazard in pro- These regulations are to some extent described in
cesses such as centrifuging, blending or transfer of the section concerning the HASS (High Activity
liquids using syringes. It is wise to perform a simple Sealed Radioactive Source) regulations above. It is
wipe test when a shipping container is opened. This worth emphasising, however, that it is not only the
enables contamination to be detected at source from HASS regulations that make it mandatory to use and
a previous, perhaps undetected, incident. Such an keep radioactive material securely. The Ionising
incident could leave a dried residue on the surface Radiation Regulations 1999 and the Radioactive
of the vial, creating an invisible, insidious hazard. Substances Act 1993 (and Exemption Orders under
Staff should also be aware that Eppendorf the Act) as well as the Carriage of Dangerous Goods
tubes have an attenuation for the a-particles from and Use of Transportable Pressure Equipment Regu-
32
P of only 30–50 % that for average glass vials. lations 2009 all require radioactive sources (sealed
Indeed, the surface dose rate from such tubes con- or unsealed) to be kept, used and transported in a
taining tens of megabecquerels of 32P can be several secure manner.
millisieverts per minute. An operator handling a few These regulations require:
tens of these tubes a day, each for less than a minute,
* Locking sources away in a suitable store
could receive more than the dose limit to the skin of
the fingers (500 mSv per year). Additional shielding (it is seldom acceptable to justify to Regulators
should be used by placing the Eppendorf tubes for a source not being in a locked store by saying
behind a 10 mm thick Perspex shield or in Perspex that the door to the room is locked).
* Having records readily available so that any
sample blocks, which are obtainable commercially.
A 1 MBq spot of 32P contamination, spread over suspected loss is readily ascertained.
* Reporting any loss, theft or uncontrolled release
1 cm2, can give a skin dose 1.82 Sv per hour
(Ballance et al. 1992). Curran (1986) also provides (thresholds are defined at which notification is
a similar consistent estimate for skin contamination mandatory).
* Not storing sources with certain other materials
with 32P.
that may increase the likelihood of dispersal (e.g.
inflammables, explosives, etc.).
Radiation protection in radioiodine * Leak testing, etc., as described above.
therapy
Up to 0.1% of 131I activity administered to patients Personnel monitoring
has been found to be released into the air from a
therapy ward (Lassmann et al. 1994). This reinforces Staff working in radiopharmacies or PET radiochem-
the need for all such areas to be well ventilated. It has istry laboratories may be designated as classified
also been calculated that patients returning home, radiation workers, Whether they are so designated
after being hospitalised for two days following will probably depend on the volume of work they
radioiodine therapy, may give up to 0.2 kBq to the are individually required to do. Staff in an average-
thyroids of family members, resulting in an equiva- sized radiopharmacy will probably not be designated
lent dose to the thyroid of up to 4.7 mSv for adults as classified workers as they will be unlikely to
and 20 mSv for children (Wellner et al. 1998). exceed 3/10 of any relevant dose limit, whereas
However, other workers have performed practical those in a very large radiopharmacy may very well
measurements on families of radioiodine therapy be classified workers. If staff are classified it is more
patients in their own homes at various times post likely to be due to the extremity dose (hand) than a
treatment that have indicated that ingested doses whole body dose.
are nowhere near this high level and generally give Both classified and non-classified staff working
rise to acceptable doses, even to children in the fam- with radioactive patients or radiopharmaceuticals
ily (Barrington et al. 2008). should wear a personal dosemeter to give an estimate
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Radiation protection | 37

the dose to the finger tip may be estimated from

the dose measured on a ring dosemeter. Sometimes a
finger stool may be used and this may be on the finger
receiving the highest dose, in which case no further
consideration is necessary. If this is not the case, again
a factor may be employed to ensure that dose limits
are not being exceeded and that a person who is not
classified is not receiving more than 3/10 of a dose
limit.
Figure 3.3 Opened-up personal dosemeter showing filters Williams et al. (1987) showed that when the TLD
and detecting material (on left). (Photograph courtesy of was worn on the proximal phalanx of the middle fin-
Landauer, Inc.)
ger or on one of the adjacent fingers, the dose so
recorded was about 30% less than that received from
of effective dose and many will wear a dosemeter on an the mean dose to the whole hand.
extremity to monitor their skin/extremity dose. Batchelor et al. (1991a,b, 1994) carried out a more
Personal dosemeters are usually in the form of detailed study of the distribution of dose to the hands
a badge that is clipped or pinned to the clothing or in dispensing, injecting and formulating in nuclear
in a form that can be worn on extremities, being medicine and also for radiochemistry formulation, dis-
mounted in a finger stool or ring. They generally pensing and injecting in clinical PET. The results
work using either a crystalline material (which is showed that choice of location of the dosemeter can
able to absorb the radiation energy and either give give a result between 33% and 200% of the mean
it up later when heated or exposed to laser light) or a hand dose
small film (using the latent exposure effect on a pho- The work of Batchelor et al. (1991a) also showed
tographic emulsion). They contain filters so that the that pre-placing a short (95 mm) butterfly cannula in a
differential exposure of the sensitive material can be vein before handling the radioactive syringe can
used to assess radiation type/energy and exposure reduce doses to 47% and 72% of the doses received
situations. A typical whole body dosemeter is shown without using these devices for the left and right hands,
in Figure 3.3. respectively. Employing an unnecessarily long catheter
will actually increase the dose received due to the
activity in the tubing exposing the operator.
The importance of where to wear
It is important that the hands are regularly checked
the extremity dosemeter
for contamination. There are two reasons for this:
Whereas it may not be crucial exactly where on a hand
these dosemeters are worn if the dose received is sig- * Firstly, the dose to the skin and possible
nificantly less than 10% of a dose limit, it does become subsequent ingestion are a particular hazard
important as the dose approaches the dose limit (or that can be reduced if decontamination
3/10 of the limit if staff are not classified). This is measures are taken as soon as contamination is
because the dose received in most situations is not detected.
uniform across the hand. Under legislation that is con- * Secondly, a contaminated dosemeter will show
sistent with the recommendations of ICRP103, the a very high dose if the contamination is left on
dose to the skin can only be averaged over 1 cm2, the surface of the dosemeter. This is generally
whereas before 1999 it could be averaged over not the skin dose received as the TLD shields
100 cm2. There have been several articles dealing the skin and also the dosemeter would be
with the determination of regional factors that relate removed after work with radiation has ceased,
the hand dose to the exposure of the hand from dif- although the irradiation of the dosemeter
ferent work activities (Williams et al. 1987; Batchelor continues. This can lead to a dose limit
et al. 1991a,b; Batchelor et al. 1994; Allen et al. 1997). apparently being exceeded and an incorrect
If the work activity is similar to this published work, report to a regulatory body.
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38 | Physics applied to radiopharmacy

Extremity dosemeters are also of value in assessing invaluable in ensuring that doses to staff are kept as
new techniques and in checking that ‘ALARP’ is being low as possible.
followed when a member of staff starts performing a
new work activity. Wearing the dosemeter for a tran-
Special considerations in positron
sient period only is useful. There are now also avail-
emission tomography (PET)
able electronic extremity dosemeters that can log dose/
radiochemistry laboratories
time events and hence show at what stage of a pro-
cedure these doses were received. Some workers PET procedures generally have the potential to result
(Guy et al. 2005) have incorporated a cine file from in a higher dose to the operator.
a simple small camera connected to a laptop alongside The reasons for this are simple:
this electronic real-time dosemeter so that a visual * Each disintegration is accompanied by the
record is available of what operations were being per-
emission of positrons which, if unshielded, result
formed when a high dose was received.
in a high skin dose.
Electronic personal dosemeters usually employ * Each emission eventually results in two g-ray
detecting elements that are either Geiger or solid-state
photons (photons from the annihilation of
and the whole instrument is pocket sized. Some have
the positrons).
even been produced the size of a credit card and * These photons, having energies of 511 keV, are
include bar codes to provide area access information.
harder to shield than those from 99mTc.
It is important with all dosemeters that due con-
sideration for energy response is made so that the Unsurprisingly, this has implications for the design
instrument is suitable for its use or allowance is made and operation of PET facilities.
for poor energy response for the radiation being The specific g-ray constant for PET nuclides (i.e.
18
measured. F, 15O, 13N, 11C) is an order of magnitude higher
Dosemeters must not be kept in an area of than that for 99mTc and it should be remembered that
increased (above background) radiation level while this does not allow for the skin dose that would be
not being used. This may sound obvious advice but it received from the positrons (specific g-ray constants
is not rare for dosemeters to be found inside investiga- relate only to gamma emission).
tion rooms, etc. Similarly, it is important that the The tenth value thickness in lead is 15 times
hands of the person distributing or collecting these greater for the PET 511 keV g-ray photons compared
devices are not contaminated with radioactivity. to those from 99mTc. It is therefore not surpris-
ing that distance is used in design wherever possible,
as the amount of lead needed to reduce dose rates
Communication of results to individuals
considerably is much greater (and sometimes less
wearing dosemeters
practical) than when using most other conventional
It is imperative that individuals are informed of their nuclear medicine radionuclides.
results as soon as possible after their dosemeters are Concrete density equivalent bricks are available
returned for processing. In the case of an external and a two-course wall (approximately 200 mm) gives
service this may be one to two months after the end an attenuation of just under a factor of 10; a single
of the monitoring period. It is found that if people are course gives only a factor of 2.
aware of their doses and can compare them with those PET facilities frequently include a cyclotron on-
received by others then there is a general tendency for site, unless there is one nearby with spare capacity
their dose to decrease over time. If the system is such to supply the PET tracers. A dedicated PET tracer-
that viewing their dose is not made easy then the producing cyclotron operates generally in the region
reverse is true. Similarly a policy of telling workers of 10–11 MeV and often has its own primary shield,
their dose only when there is a problem also tends to which may be operated on hydraulic rams. These
encourage complacency in the workers’ attitude to the machines, though often located in a vault, are actu-
ALARP principle. A radiation protection supervisor ally designed to be able to function alongside other
who undertakes his or her duties conscientiously is rooms. Allowance must be made for service work as
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Radiation protection | 39

there is a considerable level of activity remaining in delivered straight into the collection vial
the target area after bombardment (not just the within a radionuclide calibrator
intended PET tracer; there may be high activities (Batchelor et al. 1994).
from induced radionuclides in the cyclotron for seve-
All of these measures generally require some local
ral hours after the end of bombardment). Indeed, this
skill and expertise together with on site workshop
induced activity has to be declared on the operator’s
facilities.
‘site licence’ issued by the Environment Agency or the
Scottish Environment Protection Agency in the UK.
The automated chemistry to facilitate the produc-
tion of the more routine PET tracers (e.g. 18F-labelled Pregnancy and working with
FDG [fluorodeoxyglucose]) may result in release of radiation
volatile by-products during synthesis and this also
has to be allowed for in the arrangements agreed with The dose to the fetus should be as low as reasonably
the regulatory bodies. It is essential to fit a monitoring practicable. The ICRP (ICRP 2007) recommends that
system on the extractor from the cyclotron room, the a fetus should receive no more radiation than a mem-
chemistry unit and any shielded fume cupboards (‘hot ber of the public and so should not receive more than
cells’) so that data can be continuously logged and 1 mSv during the declared term of pregnancy. This
emissions automatically recorded. Additionally an gives a risk of 3.0  105 or about 1 in 33 000 of
abatement system can be deployed whereby such emis- developing a fatal malignancy up until the age of 15
sions are reduced through storage and decay. years, which compares with the natural risk of 1 in
Hand doses of the PET radiochemist/radiophar- 1300. A fetal dose of 1 mSv can be interpreted as
macist have the potential to be high and so it is advis- broadly equivalent to a dose at the surface of the abdo-
able to monitor hand doses and to employ devices to men of a pregnant woman of about 2 mSv for X-rays,
reduce doses received as much as possible. but a lower level, possibly 1.3 mSv for higher-energy
Possible dose-saving measures are: radiation from radionuclides such as 99mTc and 131I,
and here advice from the RPA will be required.
* Use of large Perspex syringe shields that protect Most of the routine activities performed by tech-
the skin from positrons and also employ distance nologists in nuclear medicine would not result in an
to reduce dose. These can be more effective than a external radiation dose of this magnitude. However,
lead or tungsten shield. where a radiopharmacist or technologist is dealing
* An arrangement for assaying each patient dose with potential or actual contamination (including vol-
with the H215O tracer remaining in the lead atility/aerosol droplets), and is in the presence of a high
transit pot to avoid direct unshielded radiation field, this dose could be exceeded. Hence it is
manipulation (Marsden et al. 1994). Due to the advised that it best for staff known to be pregnant who
short half-life of 15O (2 minutes) it is necessary for are working in nuclear medicine to avoid the following
high activities to be administered to patients and tasks (Harding, Mountford 1993):
even higher activities to be dispensed in the
* Dealing with radioactive spills
radiochemistry laboratory. This can potentially
* Using aerosols or unshielded krypton generators
lead to high operator doses if the syringe of H215O
* Imaging very ill patients
is removed from its shield and assayed in a
* Preparing radionuclide therapy doses.
radionuclide calibrator in the normal way. To
avoid this, the tracer, inside its shielded pot, is Because of the potential for an incident, it
placed at a defined point alongside the exterior would seem prudent that a radiopharmacist, work-
shield of a radionuclide calibrator ionisation ing single-handed, should not continue working
chamber and an appropriate modified activity with radioactivity while pregnant. The radiophar-
calibration factor is employed. macist may still be involved in supervising the work
* Possible modifications to delivery systems for of a colleague, as being several metres away from
the automated chemistry, so that tracers are the formulation process should reduce risks to an
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40 | Physics applied to radiopharmacy

acceptable level. The anxiety factor that an expec- to an equivalent contamination level
tant mother may have in this situation, even after (in Bq/cm2). If contamination persists, carry
being given reassurance, should be remembered. It out decontamination procedures as described
is often possible for the person to change duties with in the appropriate section below. Monitoring
a colleague and work in a non-radiation area, where should be carried out before and after each
the source of the anxiety can be removed entirely. stage of the decontamination procedure.
In assessing potential fetal doses it may be * Tritium should be monitored using wipe tests;
helpful to consult the ‘Notes for Guidance on the surfaces should be swabbed using filter papers;
Clinical Administration of Radiopharmaceuticals these are then transferred to a vial containing
and the Use of Sealed Radioactive Sources’ (HPA organic scintillant and the activity is measured
2006) Other useful publications are ICRP (2001) on a scintillation counter. It should be assumed
and ICRP (2003). There are also many leaflets that that 10% of the contamination is transferred to
give advice to the worker and manager (HSE the swab. Results of wipe tests should be
2001; HPA 1988) recorded.

Decontamination procedures
Monitoring for contamination
Decontamination can be described as any process that
will reduce the level of any radionuclides from a con-
In this section, practical advice is given on monitoring
taminated surface. It is important to realise that it will
for radioactive contamination.
usually be impossible to remove all the contamination.
For both controlled and supervised areas, there
It is difficult to be prescriptive since the decontam-
should be routine systematic contamination monitor-
ination procedures employed will depend largely on
ing of surfaces at regular intervals as well as at the end
the individual circumstances prevalent at the incident.
of individual work procedures involving radionu-
This protocol, therefore, gives a general and adaptable
clides. In any situation where monitoring is carried
set of procedures for dealing with surface and personal
out – i.e. routine or in contamination incidents, the
contamination. Further information can be obtained
following points are important:
from Mountford (1991).
* Select the appropriate monitor for the radio-
nuclide used. (Note that tritium [3H] is generally
not detectable except by wipe test – see below).
Personal contamination
Switch the monitor on and check battery status. In incidents involving suspected personal contamina-
* Measure the background count rate in an area not tion, the RPA or other radiation safety staff should be
used for handling radionuclides. Record the informed first. It is advisable to undertake personal
result. decontamination as a first priority before other decon-
* Remove gloves used during the work procedure, tamination procedures are carried out.
wash hands and monitor them. Record the Contaminated persons must not leave the desig-
measured count rate. nated area or laboratory where the incident is
* Monitor all work surfaces (including the interior assumed to have occurred to avoid the risk of spread-
of fume cupboards if appropriate), tools and ing contamination to other areas.
laboratory equipment used in the work Persons assisting in personal decontamination
procedure, items removed from the work area should wear protective clothing.
during the procedure, and floors. Systematically
move the monitor probe over each surface/article, Eye contamination
without touching, and record the maximum count Suspected contamination in the eyes should be treated
rates encountered. immediately by irrigating outwards with copious
* For both hands and work surfaces, etc., convert amounts of sterile eye wash solution. Ensure that the
any reading significantly above background fluid does not spread to other parts of the body – in
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Radiation protection | 41

particular the orifices. The Appointed Doctor should by normal washing of hands, face and, if necessary,
be consulted. hair using water and mild soap in the hand washing
basin (not the waste disposal sink). It will not be
Ear contamination feasible to collect the water as liquid radioactive
Trained hospital staff should be asked to syringe out waste.
contaminated ears with water at body temperature Where local areas of personal contamination
(37 C). persist, detergent and soft nail brushes should be
used. Care should be taken not to be too abrasive
Nasal contamination to the point of injury to the skin since this will
increase the risk of allowing the contamination
The contaminated person should blow their nose into
into the body. If necessary, affected areas of hair
paper tissues and expectorate into a disposable cup.
should be trimmed and the clippings retained for
The products should be monitored.
monitoring.
If nasal contamination is still high, irrigation
For serious contamination of the hands only, a
should be considered under medical supervision. The
saturated solution of potassium permanganate fol-
subject should be seated in front of a designated sink
lowed by decolorisation by 5% sodium bisulfite solu-
or hand basin with a waterproof cover over the trunk
tion may be considered. No other chemical treatments
and lap. A receptacle should be placed in the sink to
should be used on the skin.
collect the irrigation fluid (saline or sterile water). The
Clothes and shoes removed should be checked for
subject should tilt their head forward over the sink so
contamination. Contaminated articles should be
that the nasal bone is approximately vertical – the
sealed in a plastic bag and retained for decontamina-
irrigation fluid should flow back out of the nostrils
tion before being returned to the owner.
rather than into the frontal sinuses or nasopharynx.
An irrigation tube should be placed just inside the
nostril and the flow of the irrigation fluid controlled Contaminated wounds
by pinching the tube. Any foreign objects should be removed from the
wound. The surrounding skin should be decontami-
Contamination of nails nated following the procedure described above.
As much as possible of the contaminated nail should Bleeding from the wound should be encouraged by
be cut away with scissors and retained for monitoring. applying pressure above the wound to occlude the
The area immediately around and under the nail venous system – this will aid dispersal of the contam-
should be decontaminated following the procedure inant. The wound should then be irrigated using saline
for skin below. Alternatively, calamine lotion can be or sterile water, taking care not to spread contamina-
applied, allowed to dry, then brushed off with the tion, and dried by wiping away from the edges.
hand inside a plastic bag to collect the contaminated Monitor before and after bleeding and irrigation.
dust powder. Small skin tags should be cut away. The wound should
be surgically excised if gross beta-contamination is
Skin/hair contamination left.

If the contamination is localised to an area of the

body, then decontamination should be restricted to Mouth/Internal contamination
that localised area only. This should avoid the spread If contamination of the mouth is suspected, any
of contamination to other parts of the body, parti- dentures should be removed for separate cleaning.
cularly the eyes and orifices. Showers should not be The person should be warned not to swallow. The
used – they are more likely to dilute but spread con- mouth should be rinsed immediately with water at
tamination to other areas of the body, risking inges- the hand basin and the teeth should be brushed
tion via the orifices. away from the gums. If ingestion is suspected, the
The first stage for more major contamination RPA and the Appointed Doctor should be consulted
is the careful removal of outer clothing followed immediately.
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42 | Physics applied to radiopharmacy

Surface contamination Table 3.5 (continued)

The following principles should be followed: Object Comments

* Stop any operations that might add to the Potassium permanganate

contamination.
* Sodium bisulfite
Take obvious containment measures.
* Warn others not to enter the area in which Saline Several sealed containers each of
material has been spilled. 500 mL
* Mark the area using chalk or marker pen.
*
Sterile water As above
Inform the Radiation Protection Supervisor.
* Using the laboratory spills kit, carry out Calamine lotion
decontamination of personnel following the
Potassium iodate/iodide Tablets or solution (monitor expiry
procedures set out above.
date)
* Put on (fresh) protective gloves, protective clothes
and overshoes. Other proprietary agents
(Decon, Lipsol, Camtox,
Table 3.5 shows the contents of a typical spill Countoff, RBSA 350)
kit. Table 3.6 shows useful methods for decontaminat-
Miscellaneous equipment
ing equipment.
Large warning sign Trefoil plus worded warning – 'Do
capable of standing up on not Enter, Radioactive
ground Contamination'

Table 3.5 Decontamination spill kit Contamination monitor Keep one monitor with kit for
speed of access in emergency
Object Comments (remember to keep within
calibration)
Protective clothing
Radiation hazard adhesive
Overalls/lab coat Overalls are more appropriate if
tape
the spill presents a very serious
hazard to clean up staff Coloured rope to control To be used with adhesive tape to
access keep in place
Gloves Different pairs may be indicated for
different situations Impermeable material to
cover floor.
Face masks
Absorbent tissue, large/
Wellington-type boots small rolls

Disposable overshoes These may be heavy duty or Polythene waste bags with Minimum size 2 L
lightweight radiation warning symbol
These should not be absorbent the
whole way through from outside to Plastic bucket
inside onto shoe/sock
Tweezers and tongs 1 pair, medium size (e.g. blades
Decontamination agents (various sizes) about 125 mm long)

Soap As a liquid to quickly make into Notebook, pen

solution and as a bar
Scissors
Cetrimide solution Concentration should be written
on container Soft brush

'Swarfega' Marker pen

( continued overleaf )
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Radiation protection | 43

Table 3.6 Decontamination procedures for polythene, plastics, glassware, trays, sinks and metal tools

Object Procedure

Paintwork, polished linoleum, epoxy resin floor Clean with detergent and water, in severe cases with a long half-life contaminant, remove
coverings paint with paint stripper or consider physical removal of surface. If the half-life is short,
covering with impermeably coated paper or strong polythene sheeting may be
appropriate. For all removals of radioactive waste, consider disposal before creation of the
waste

Glassware Clean immediately with detergent. Ammonium citrate or chelating agents such as EDTA
may be useful

Plastics Dilute nitric acid may be useful since it usually does not attack plastics. Care is needed if
using ketonic solvents and certain chlorinated hydrocarbons that dissolve plastics. Note
that no organic solvents have any effect on polythene

Metal tools, trays, workbenches and sinks Use a heavy-duty detergent followed if necessary by specific chelating agents. If lipids are
involved, 1,1,1-trichloroethane or EDTA mixed with Swarfega may be used. An abrasive
cleaner can be used as a last resort

General order of decontamination clothing worn by the operator, this should be

done in such a way as to prevent
1 Decontamination will start with
personal contamination. The items
contaminated floors, bench surfaces and
replaced should be deposited in a
articles nearest to the entry route into
receptacle.
the area.
9 When all decontamination procedures
2 Particular attention should be paid to
have been completed, all materials used
areas known to be highly contaminated.
including floor coverings should be carefully
Areas should be decontaminated as the
collected into separate receptacles as solid
operator reaches them following the specific
and liquid radioactive waste.
procedures set out below.
10 The entire area including all personnel
3 At each stage in the treatments,
involved should be re-monitored at the end
monitoring should be carried out to assess
with any residual readings recorded.
the success of the operation.
4 Portable articles may, if necessary,
be wrapped up and removed from the area Specific decontamination procedure
for more efficient procedures to be used later. Absorb spilt liquid using absorbent, disposable paper
5 Suitable thickness lead pots (see Table 3.1) tissues or cloths. Place used ones in the waste disposal
may be used to secure any solid radioactive sink if convenient, otherwise in a strong plastic bag.
materials found in the contaminated area. Continue until the area is dry. Dry spills should be
6 Having decontaminated the floor and bench removed by wet methods, using wet absorbent paper
surfaces the operator may then start on the to prevent dispersion.
walls. The first treatment is with the mildest cleaning
7 In cases where there are several operators or agent, e.g. water or solvents to remove grease.
the area to be decontaminated is large, this may Copious amounts of cleaning agent and absorbent
be started before the other surfaces have been materials should be used without risking the spread
finished. of the contamination. If the first treatment is not suf-
8 If it becomes necessary during these ficient then the use of detergent for a second treatment
procedures to remove or replace any protective in the same manner is advised.
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44 | Physics applied to radiopharmacy

Monitor the contaminated area, taking care that medicine it is useful to allow radioactivity to decay
the monitor itself does not become contaminated. If to lower levels. Technetium-99m, for example, can
the reading exceeds, further decontamination is needed. be left to decay until it is below the definition of being
Ascertain the correct decontaminating agent for radioactive under the Radioactive Substances Act
the surface/radionuclide. Using the appropriate solu- 1993 (i.e. 0.4 Bq/g). Use of non-radioactive methods
tion, wash the area thoroughly using disposable tis- should be promoted where possible, and care should
sues, working inwards towards the centre, and be taken that waste that may be clearly identified as
avoiding use of large volumes of liquid. Take care to non-active (e.g. packaging after checking for contam-
avoid the spread of contamination. Dry the area, and ination) is not be put in the active waste bin.
re-monitor. If contamination persists, a Radiation The waste should also be ‘streamed’ according to
Safety Physicist should be informed. its activity level. Very low-level waste (VLLW) is waste
For more serious spills it may be appropriate for that may go out with normal refuse to landfill provided
the contingency plan to direct staff to summon the special conditions are met. Above this level, waste may
Radiation Protection Adviser at the outset (or that be low-level waste and this may be incinerated by a
person’s team), who may be more appropriate to deal licensed company that is named on the user’s authori-
with a more hazardous situation. sation. Other solid sources (particularly sealed sources)
may go to an external organisation for special disposal.
This may require a special authorisation from the
Radioactive waste arising from
Regulator if it is not built into the user’s authorisation
decontamination procedures
and falls outside of the relevant exemption orders.
All disposals arising from decontamination proce- It is important to be able to demonstrate that at any
dures should be fully recorded (i.e. date, radionuclide, time one can show the amount of waste in storage. The
and an estimate of the activity disposed). easiest way of doing this is in some form of spreadsheet
so that automatic correction for decay occurs each
time the file is accessed. Hard-copy records of dispo-
Spillage in transit
sals should also be available together with copies of
Movement of radionuclides within an establishment waste consignment notes.
must be by trained members of staff and in carrying
boxes specifically designed for the purpose. However,
Features of a radioactive waste store
if a spill does occur in transit it is important to stop
people entering the contaminated area. Staff should The store should have adequate space, be secure, be
stay with the spill and they should ask someone to easily decontaminated and be adequately ventilated
contact their RPS or department manager (or RPA). and shielded, unless it is isolated and a radiation risk
The hospital switchboard may also have emergency assessment has demonstrated this is not necessary.
contact details of the radiation safety team. When bags are despatched to the waste contractor,
the correct streaming should prevent all but the min-
imum amount of re-handling.
Management of radioactive waste Radioactive waste from nuclear medicine depart-
ments may often also be clinical waste. The biological
Any producer of radioactive waste in the UK has, by hazards need to be taken into account as well as the
law, to ensure that they are minimising the volume and radiological ones. Further reference is made to the
activity of waste that they create. Also, to ensure that HHSC publication The Management of Radioactive
radioactive waste is minimised at the point of transfer Waste in Laboratories, Handbook No 19 (McLintoch
to a waste company, it is generally necessary for it to be 1996), which gives clinical waste a further five catego-
separated at creation into bins according to half-life. If ries of subdivision. These subdivisions then determine,
the half-life is too long for decay storage to make a from a clinical waste perspective alone, how the mate-
significant difference (tritium, carbon-14) disposal rial may be disposed of (no choice but incineration or
should take place as soon as possible. In nuclear possible landfill routes, and so on).
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Radiation protection | 45

Transport of radioactive waste It is likely that each bin containing several

bags will be an excepted package and so it
Radioactive waste will need to be transported within
will be a minimum requirement that the total
the organisation or from the central store to the con-
activity of each of the nuclides present is
tractor’s disposal point.
documented.
It is important that the waste is moved between
* The dose rates at the surface of the container
rooms and to the central store in a manner that does
must be less than 5 mSv/h.
not cause spillage or contamination of adjacent areas.
* There must not be a level of non-fixed
Hence when the waste is ready to be moved on to the
contamination on the external surface that
next stage of the disposal cycle a further precaution of
exceeds 0.4 Bq/cm2.
‘double containment’ should be taken. This means
* The warning label declaring that the package
that it should be double-bagged (clear heavy-gauge
contains radioactive material must only be on the
polythene with trefoil is good as a copy of the trans-
inside part of the package.
port documents can be added between the clear bags to
* The package should remain intact during the
facilitate auditing at a later stage). While it is in the
conditions it is likely to meet during routine
store waiting to be picked up by a contracted waste
transportation. This means that if another
company, a rigid outer container should be used so
package rolls over on it or if it moves suddenly
that any spillage is contained should a bag become
during heavy braking of the vehicle, it should
torn. If this container is lined with absorbent material,
retain the contents without contamination.
it will help prevent contamination spreading from the
container. Further information on transport of radioactive
The containers should have appropriate labels materials should be obtained from the employer’s
describing their contents, and their security is also Radiation Protection Adviser.
important. They should not be left unattended in a
courtyard for any length of time. The entire procedure
needs to be governed by local rules, as it is in itself a
work activity involving radiation. References
The transport of waste off site by a contractor does
Allen S et al. (1997). Comparison of radiation safety aspects
not remove the responsibility from the waste producer between robotic and manual systems for the preparation of
to ensure that certain legal criteria are being met (‘duty radiopharmaceuticals [Abstract]. Nucl Med Commun 18:
of care’). Generally, radioactive waste from laborato- 295.
ries and hospitals will come within the category of Ballance PE et al. (1992). Phosphorous 32: Practical
Radiation Protection. HHSC Handbook No. 9. Leeds: H
excepted packages under the transport regulations. and H Scientific Consultants Ltd.
This means that they still come under the regulations Barrington SF et al. (2008). Measurement of the internal dose
but are exempt from certain requirements of the reg- to families of outpatients treated with 131I for hyperthy-
ulations provided certain conditions are met. An obvi- roidism. Eur J Nucl Med Mol Imaging 35: 2097–2104.
Batchelor S et al. (1991a). Radiation dose to the hands in
ous exception to this could be the disposal of certain nuclear medicine. Nucl Med Commun 12: 439–444.
closed sources. Batchelor S et al. (1991b). Radiation dose distribution to the
It must also be remembered that certain waste (e.g. hands of a radiopharmacist. Pharm J Hosp Pharm Suppl
used liquid scintillation solvent) must conform to the 247: 38–39.
Batchelor S et al. (1994). Staff and patient dosimetry issues in
special waste regulations. clinical positron emission tomography. Abstracts of the
World Congress on Medical Physics and Biomedical
Engineering, Physics in Medicine and Biology, 39a (part2)
'Excepted package' conditions (abstract OS32-3.4), 820.
Bolton, AE (1985). Radioiodination Techniques: Review 18.
Even for radioactive waste that comes under excepted
Amersham: Amersham International plc.
packages, it is required that: Connor, KJ, McLintock, IS (1997). Practical Radiation
Protection. Radiation Protection: Handbook for
* Consignment notes must be correctly filled Laboratory Workers No 14, 2nd edn. Leeds: H and H
out that identify each container of the shipment. Scientific Consultants Ltd, 17–22.
Sampson's Textbook of Radiopharmacy
Chapter No. 3 Dated: 24/11/2010 At Time: 11:8:59

46 | Physics applied to radiopharmacy

Curran AR (1986). Calculation of the dose to the basal layer ICRP (2001). Doses to the Embryo and Fetus from Intakes of
of the skin from beta/gamma contamination. J Soc Radiol Radionuclides by the Mother. ICRP Publication 88.
Protect 1: 23–32. Oxford: Pergamon Press. [Annals of the ICRP 31(1–3):
Guy MJ et al. (2005). Development of a combined audio- 19–515].
visual and extremity dose monitoring software tool for ICRP (2003). Biological Effects after Prenatal Irradiation
use in nuclear medicine. Nucl Med Commun 26(12): (Embryo and Fetus). ICRP Publication 90. Oxford:
1147–1153. Pergamon Press. [Annals of the ICRP 33(1–2): 5–206].
Harding LK, Mountford PJ (1993). Editorial: Pregnant ICRP (2007). The 2007 Recommendations of the
employees in a nuclear medicine department. Nucl Med International Commission on Radiological Protection.
Commun 14: 345–346. ICRP Publication 103. Oxford: Pergamon Press. [Annals
Health & Safety Commission (2000). Approved Code of of the ICRP 37(2–4): 1–332].
Practice and Guidance to IRR99, ‘Work with Ionising IPEM (2002). Medical and Dental Guidance Notes: A good
Radiation’ L121. London: Health & Safety Commission. practice guide on all aspects of ionising radiation protec-
ISBN 0-7176-1746-7. tion in the clinical environment. York: Institute of Physics
HMSO (1978). The Medicine (Administration of and Engineering in Medicine. ISBN 903613 09 4.
Radioactive Substances) Regulations 1978. ISBN 0-11- Jackson S, Dolphin GW (1966). The estimation of internal
084006-2. radiation dose from metabolic and urinary excretion data
HMSO (1993). Radioactive Substances Act 1993 Chapter 12. for a number of important radionuclides. Health Phys 12:
HMSO (2000a). The Ionising Radiation (Medical Exposure) 481–500.
Regulations 2000. Lassmann M. et al. (1994). Measurement of 131I-activity to
HMSO (2000b). The Ionising Radiation Regulations 1999 air emitted from a radioiodine therapy ward. In: Koelzer,
Statutory Instrument 1999 number 3232. ISBN 0-11- W, Maushart, R, eds. Strahlenshultz: Physik und
085614-7. Messtechnik. Koln: TUV Rheinland, 719–722.
HMSO (2005). The High Activity Sealed Radioactive Source Marsden PK et al. (1994). A system for measuring and
and Orphan Sources Regulations 2005. injecting PET radiopharmaceuticals [abstract]. Nucl Med
HMSO (2006). The Ionising Radiation (Medical Exposure) Commun 15: 259.
(Amendment) Regulations 2006. McLintoch IS. (1996). The Management of Radioactive
HMSO (2007). The Carriage of Dangerous Goods and Waste in Laboratories, Handbook No. 19. Leeds: H and
Use of Transportable Pressure Equipment Regulations H Scientific Consultants Ltd.
2007. Mountford PJ (1991). Techniques for radioactive decontam-
HMSO (2010). The Environmental Permitting Regulations ination in nuclear medicine. Semin Nucl Med 21(11):
2010 (SI 2010 No 675). 82–89.
HPA (1988). Diagnostic Medical Exposures: Advice on NCRP (1977). Protection of the Thyroid Gland in the Event
Exposure to Ionising Radiation during Pregnancy. of Release of Radioiodine. Report No. 55. Washington,
London: Health Protection Agency. ISBN 0-85951-420-X. DC: National Council on Radiation Protection and
HPA (2006). Notes for Guidance on the Clinical Measurement. ISBN 0-913392-37-5.
Administration of Radiopharmaceuticals and the Use Prime D. (1985). Health Physics Aspects of the Use of
of Sealed Radioactive Sources. London: Health Radioiodines. Science Reviews Occupational Hygiene
Protection Agency. Monograph No. 13. Leeds: H and H Scientific
HSE (1999). Work with Ionising Radiation. Ionising Consultants.
Radiation Regulations 1999. Approved Code of Practice Underwood E. J. (1977). Trace Elements in Human and
and Guidance. London: HSE Books. ISBN 0 7176 1746 7. Animal Metabolism, 4th edn. New York: Academic Press.
HSE (2001) Working Safely with Ionising Radiation: Wellner U et al. (1998). The exposure of relatives to patients
Guidelines for Expectant or Breastfeeding Mothers. of a nuclear medical ward after radioiodine therapy by
http://www.hse.gov.uk/pubns/indg334.pdf (accessed 28 inhalation of 131I in their home. Nuklearmedizin 37:
June 2010). 113–119.
ICRP (1989). Radiological Protection of the Worker in Williams ED et al. (1987). Monitoring radiation dose to the
Medicine and Dentistry. ICRP publication 57. Oxford: hands in nuclear medicine: the location of dosemeters.
Pergamon Press. [Annals of the ICRP 20(3): 1–83]. Nucl Med Commun 8: 499–503.
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4
Detection of radiation
Alan C Perkins and John E Lees

Introduction 47 Scintillation detectors 52

Detector principles and properties 48 Solid-state detectors 56

Gas-filled ionisation detectors 49 Probe systems 57
Radionuclide activity calibrators 51 Personal radiation dosemeters 58

Introduction For applications with low levels of radioactivity,

measurement of the amount is nearly always as a count
Radioactive substances produce ionising radiation rate in counts per second (cps) or counts per minute
as a result of nuclear transformation. In nuclear (cpm). The becquerel is a relatively small unit for
medicine the radiation emitted from the radionuclide, radiopharmaceutical work, so that the multiples kBq
for example a g-ray, is used as the ‘reporter signal’ (103 Bq), MBq (106 Bq) and GBq (109 Bq) are used in
for imaging, or a b-particle can be used to deliver practice. It is worth noting that the former unit of the
a therapeutic dose to tumour cells. Radioactivity is curie (Ci; equivalent to 37 GBq) and its submultiples
defined in the British Pharmacopeia (BP) as ‘the mCi (37 MBq) and mCi (37 kBq) are still used in the
number of nuclear transformations per unit time in USA and in many other countries. It is also important
a given amount of the [radioactive] preparation’. to note that some instruments are calibrated to
The SI unit of radioactivity is the becquerel (Bq). produce a reading in units of exposure or dose in
This is equivalent to an average transformation sieverts, for example dosemeters that normally read
rate of one atom per second. When undertaking any in mSv or mSv.
practices involving the human administration of The absolute measurement of radioactivity is
radiopharmaceuticals it is essential to use sensitive difficult and time consuming and requires equipment
instrumentation for the detection and measurement that is only available in specialist laboratories such as
of radioactive emissions. This allows a practical the National Physical Laboratory (NPL) in the UK.
measure for dispensing the low amounts required The BP sets limits of
10% (or 15% in some cases)
for diagnostic uses and an accurate measure of for the radioactivity of most licensed radiopharma-
therapeutic levels of radioactivity. This is also ceuticals. In practice in the radiopharmacy it is
especially important for experimental work contri- generally necessary to measure the radioactivity of
buting to scientific knowledge relating radiation dispensed radiopharmaceuticals to a precision within
doses to biological effects. about 2–5%.
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48 | Physics applied to radiopharmacy

Detector principles and properties the type and energy of radiation to which they
respond, and the time required to obtain the reading.
Ionising radiations have the property of producing The performance of an instrument generally varies
ions when they interact with matter. These radiations with the nature and volume of the detector. Most
can be subdivided into directly ionising and indirectly instruments require calibration with a ‘standard’
ionising radiation. Directly ionising radiation includes source of known activity to ensure that it is performing
alpha- and beta-radiation. These consist of highly within accepted limits and that it is working in a
energetic ionised particles that interact directly with reproducible manner. The factors governing the
atoms to produce charged ion pairs. Indirectly ionising choice of a detector are described below.
radiation includes X- and gamma-radiation. These Sensitivity
consist of photons that interact primarily with orbiting Instruments of various sensitivities are required for
electrons that can be ejected and then interact with different purposes. It is necessary to measure high
other atoms to produce charged ions. amounts of radioactivity for the assay of therapeutic
Radiation detectors generally function in two amounts of radioactivity, e.g. iodine-131, while very
ways: low amounts have to be measured in surveys of surface
1 The radiation causes ionisation within a medium contamination and levels of natural background
it is passing through and the ions produced are radiation.
detected and measured. Response to different radiation types
2 The radiation causes electronic excitation in The types of radiation to be measured in a clinical
atoms or molecules, which then dissipate this environment include X-rays, g-rays, a- and b-particles
excess energy by some mechanism that can be and possibly neutrons. No instrument is capable of
detected and measured. measuring all of these radiations. In the radiophar-
Three main types of counting systems are used for macy the most commonly used radiopharmaceuticals
the quantitative determination of radioactivity: gas emit g-rays and b-particles. Some instruments are
ionisation chambers (e.g. Geiger–Mueller or GM designed so that they can measure X-rays and g-rays
detector), scintillation detectors (e.g. sodium iodide plus b-particles; then, by placement of a simple filter in
crystals or liquid scintillants) and semiconductors front of the detector, only the X-rays and g-rays are
(e.g. lithium-drifted germanium). Each detector is detected, the contribution from the b-particles being
suitable for a certain situation. The most common given by subtraction of the second reading from the
types of measuring instruments include GM counters, first.
ionisation chambers, scintillation detectors and
Energy of the radiation
thermoluminescent detectors. No one instrument is
The energy of the radiation being measured affects the
suitable for measuring every type and energy of
response of an instrument. Instruments generally do
radiation. Ionisation detectors include GM detectors
not respond equally to equal doses at all energies of
and gas-filled ionisation chambers and are based on
radiation, even if the radiation is all of one type. Some
the collection of the charged ions produced by the
instruments have peaks in their response curves; that
radiation passing through a gas-filled chamber.
is, at some energies they are particularly sensitive to
Scintillation detectors use visible photon energy that
the radiation and therefore give a high reading that can
is emitted from a scintillant when an excited electron
make accurate measurement and interpretation of the
returns to its normal state. Photographic detectors use
results difficult.
the excited electron energy to produce a latent image
in the emulsion grains. Most personal radiation Detector volume
monitors depend on electron excitation, e.g. film The volume of the detector affects the sensitivity of
badges and thermoluminescent dosemeters (TLDs) the instrument. The larger the volume of the detector,
described subsequently. the more sensitive the instrument, providing the cross-
The instruments that are available to measure section of the radiation beam is big enough to irradiate
ionising radiation vary in their sensitivity to radiation, the whole of the detector.
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Detection of radiation | 49

Source geometry calibrated. For example, large-volume detectors are

In addition to the volume of the detector itself, the usually calibrated with the radiation source normal
efficiency of most radiation instruments varies with to (i.e. at right angles to) the window of the detector,
the detector–source geometry. Radiation intensity and with the whole volume of the detector exposed.
decreases with distance from the source according to If either of these two conditions is not met, the
the inverse square law and, whenever comparisons are calibration of the instrument will not apply, and the
to be made between activities of a number of sources, reading obtained will be inaccurate. Each instrument
care must be taken to ensure that the source–detector used for making measurements needs to be calibrated
distance and geometrical configuration remain the prior to use, and then at regular intervals as part of an
same. This is particularly important in the radiophar- ongoing programme of quality control.
macy when measuring different samples of radioactiv- Dead time
ity. The accuracy of the measurement may depend
Every instrument requires time for processing of
upon the tube or vial size, and for accurate measure-
the individual detected events. This occurs within both
ments of different samples it is often necessary
the detector volume and the electronic circuits.
to adjust sample sizes to the same volume before
A characteristic of counting systems is that some
measurement or assay.
radiation passing through the detector may be missed
Time to obtain the reading because the system is processing a previously detected
The time taken to obtain the reading has to be event. This is known as the detector dead time or pulse
considered when selecting an instrument. If the level resolving time. The dead time for a GM tube is of
of radiation is constant, or changes only slowly, an the order of 50–200 ms and for sodium iodide and
instrument with a fairly long time constant will be semiconductor detectors is in the range 0.5–5 ms.
acceptable. However, such an instrument would give Dead-time effects can result in a loss of counting
a dangerously false reading if used to measure a pulse efficiency at increasing levels of activity. For any given
of radiation, such as that from an X-ray computed instrument it is very important to know the level of
tomography scanner (‘CT’ scanner), where the X-ray activity when significant dead time effects occur. The
beam is on for periods of much less than a second. Such count rate response should be linear over the working
an instrument would not have time to respond fully, or range of the counting system.
at all, and would not, therefore, record the full dose of The following sections describe the common types
radiation received. of detectors used in nuclear medicine and radio-
Another application in which the time for the pharmacy.
readout can be very important is in personal dosim-
etry. It is common for a personal dosemeter to be
worn for a week or a month before being processed
Gas-filled ionisation detectors
and read, so there is a considerable delay before the
The operating principle of all ionisation detectors
result is known. This may be unacceptable if the
is fairly simple. The detector consists of a gas-filled
radiation levels to which the worker is exposed vary
chamber containing two electrodes (one is usually
greatly, or if there is the possibility of accidental
the chamber wall) that are maintained at a suitable
irradiation that must be detected and corrected. In
potential difference by a high-voltage supply (extra
such cases it is usual for an additional instrument to
high tension or EHT) (see Figure 4.1). When ionising
be used, such as an electronic personal dosemeter.
radiation (e.g. a g-ray) enters the chamber it may
This will give an immediate readout of any radiation
interact with electrons in the gas molecules. The
dose that has been encountered and may be set with
interaction energy is sufficient to strip an electron from
an audible warning that will sound if levels exceed a
the molecule, leaving a positive ion. The negatively
pre-set level.
charged electrons, being light and highly mobile, drift
Calibration rapidly towards the positively charged anode, which
A counting instrument must be used under the same then acquires a small negative charge. The magnitude
conditions as those for which it was designed and of the charge depends on the number of electrons
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50 | Physics applied to radiopharmacy

To high voltage

GM tube R V (t )

Signal

Figure 4.1 Schematic diagram of a gas-filled Geiger–Mueller ionisation chamber.

collected and is proportional to the number of ionising detectors. The GM detector is often referred to as a
photons or particles that enter the chamber. The ‘GM counter’, but it is simply a detector – the counting
charges are small and require electronic amplification is always done by the associated electronics. The
for their detection and display of their value. When electronic counting circuit is called a scaler.
small numbers of ionising particles are to be measured, These devices form the basis of a number of
ionisation detectors are designed to generate an commercial ionisation chambers used for the routine
electrical pulse for each ionising event. Electronic measurement of radioactivity and determination of
equipment is used to detect, amplify and count these radiation exposure doses. The effect of electrode
pulses so that the count rate (e.g. counts per minute, potential is illustrated in Figure 4.2. As the voltage
cpm) is directly proportional to the amount of radia- (EHT) is increased, all the primary ions formed by
tion entering the detector and to the radioactivity of the initial ionising event are collected and a further
the source emitting the radiation. The Geiger–Mueller increase in EHT does not affect the count rate (region
(GM) detector is an example of this family of pulse I, saturation) or charge collected. If the EHT is

Pulse
amplitude Geiger–
(log scale) Müller
region

2 MeV
Limited
prop.
1 MeV
region
Proportional
Ion region
saturation
Applied voltage

Figure 4.2 Voltage–response curve for ionisation chambers. This shows the effect of the voltage differences between electrodes
on the electric current recorded by an ionising chamber per ionisation event detected.
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Detection of radiation | 51

increased beyond this plateau the primary ions are all but the weakest emitters, with typical counting
accelerated and generate secondary ions by collision efficiencies for 32P being 30% with a GM counter.
with gas molecules. These secondary ions are collected Low-energy gamma-emitting nuclides can be
and so the count rate or charge increases (region detected using gas ionisation detectors, particularly
II, proportional region). Further increase in EHT detectors filled with high-atomic-number counting
generates more secondary ions until saturation is gases, such as krypton and xenon. Indeed, for X-ray
achieved (region III, Geiger–Mueller region). At these emitters (i.e. those nuclides decaying by electron cap-
voltages a single ionising particle generates an ture), a gas ionisation detector may be more efficient
avalanche of secondary ions, and the GM tube than a crystal scintillation detector. For high-energy
produces a single large pulse that is independent of gamma photons (above 500 keV), gas-filled detectors
the initial particle energy. Increasing the EHT beyond are virtually useless, having detection efficiencies less
the Geiger plateau causes spontaneous electron than 0.1%. Crystal scintillation detectors are excellent
emission and may cause damage to the detector. in the energy range from 50 keV to 2 MeV, but at
higher energies these also have lower detection
efficiencies. To some extent, this decline in counting
Choice of instrument efficiency can be offset by increasing the size of the
The choice of an instrument for a particular applica- crystal, although this soon becomes a very expen-
tion is dependent upon a number of factors. Some sive way of achieving relatively small increases in
instruments vary in sensitivity with the direction of efficiency. Most semiconductor detectors have rather
the incoming radiation and are calibrated for radiation low counting efficiencies at best, and above 100 keV
from one direction only. Some are inaccurate if cannot be regarded as serious competitors for the
subjected to interference from electric or magnetic crystal scintillation detectors.
fields. Some give a rapid but not very accurate reading,
while others have good accuracy but take longer to
produce a reading. The larger instruments must be Radionuclide activity calibrators
rested on a firm surface, or may only be read in certain
orientations. Most instruments vary in sensitivity with The radionuclide activity calibrator is an example
radiation energy, and this is generally the most of an ionisation chamber filled with gas, normally
difficult problem to deal with. argon. This is a microprocessor-controlled device
comprising the chamber with a central access space,
X-rays and g-rays below about 100 keV
into which the vial of active material can be inserted
In this region, energy dependence is often the
and an electrometer that can be set to give a direct
dominating difficulty. GM tubes are always energy
readout of radioactivity in MBq or mCi units (Figure
dependent, but this dependency may be reduced over
4.3). This device is usually interfaced to an elec-
part of the range by the use of appropriate filters.
tronic printer that can print the label for the
Ionisation chambers are preferred for their accuracy,
activity together with other essential information on
but they must have thin walls if the energy of the
the radiopharmaceutical preparation. The user can
radiation to be measured is less than about 20 keV.
enter details of the radionuclide to be measured as a
X-rays and g-rays above 100 keV calibration factor and the individual preparation label
Measurements in the range from about 0.1 to 3 MeV can be printed with the nature of the radiopharmaceu-
pose the least problems of energy dependence. Within tical, the recorded activity, the time of measurement,
this range, it is possible to use most GM tubes, as well the volume of solution and an expiry time. Some
as ionisation chambers. devices are auto-ranging, that is they select the opti-
mum measuring range and measurement integration
time for the amount of radioactivity being measured.
Detection efficiency
It is worth noting that this instrument is commonly
For beta-emitting nuclides, the gas ionisation detectors referred to as the ‘radionuclide dose calibrator’ since
can provide quite acceptable counting efficiencies for in pharmacies it is common practice to dispense
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52 | Physics applied to radiopharmacy

procedures. They are found in a various devices in

radiopharmacy and nuclear medicine ranging from
contamination monitors to gamma cameras and have
the following characteristics:

* Very short resolving time (less than 1

microsecond)
* High detection efficiency (up to 95% with some
radiations)
* A response directly proportional to particle or
photon energy.

Scintillation detectors can be constructed for the

measurement and detection of alpha-, beta- and gamma-
radiation, although the materials used are quite differ-
ent for each type of radiation. The underlying physical
mechanism is similar. For this reason the general princi-
ples of scintillation counting are discussed before
describing the commonly used scintillation systems.

Scintillants and scintillation crystals

Figure 4.3 Photograph of a radionuclide activity calibrator.
A scintillant or scintillator is a substance that emits a
weak flash of light (scintillation) of very short duration
individual doses of a drug. However, strictly speaking whenever it is struck by an ionising radiation (e.g. an
this term is incorrect because the instrument measures a-particle) or photon (e.g. a g-ray). The intensity of the
activity and not radiation dose! It is essential practice scintillation is proportional to the amount of energy
to check the nature and amount of radioactivity of all dissipated to the molecules of the scintillator by the
preparations leaving the radiopharmacy and for the photons. The scintillations are detected by a light cell
radioactivity to be re-checked on receipt or prior to or photomultiplier that converts the light energy into
injection into the patient. Separate measuring instru- electrical pulses that are then amplified and counted.
ments are used at clinic locations for this purpose. It is Different scintillators are used for the detection of
good practice to check that all instruments remain in various types of radiation. Alpha particles can be
calibration by measuring a standard sample, such as detected by zinc sulfide arranged as a thin layer on
caesium-137, with a relatively long physical half-life. the photomultiplier window. Beta particles, especially
A decay correction can then be applied if necessary. It low-energy particles from soft beta emitters such as 3H
is also worth noting that operation of the radionuclide and 14C, are detected efficiently by dissolving the radio-
calibrator may change from day to day as a result of active sample in a suitable liquid scintillant and placing
changes in atmospheric pressure. It may be necessary the mixture in a glass tube near the photomultiplier.
to perform a manual readjustment of the instrument to Gamma and X-ray photons are best detected with crys-
bring the calibrator back within the specified tolerance tals of thallium-activated sodium iodide (NaI(Tl)),
limits set by measuring with a standard source. which is dense enough to absorb energetic photons.
The basic scintillation mechanism is the same in
all these scintillation materials. The incoming particle
Scintillation detectors or photon loses energy in the scintillator and this is
then transferred to the scintillant ions or molecules,
Scintillation detectors are highly sensitive devices that causing excitation of electrons to a higher energy; on
are particularly suitable for the measurement of small return to the ground state, the excess energy is emitted
amounts of radioactivity used in nuclear medicine as visible photons.
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Detection of radiation | 53

Nal(TI) crystal HV

Preamplifier

Photomultiplier tube Amplifier

xxx
xxx
Scaler-timer PHA
xxx
ratemeter

xxx

Figure 4.4 Schematic diagram of a single-crystal photomultiplier scintillation detector and associated electronics. HV ¼ high
voltage; PHA ¼ pulse-height analyser.

Instrumentation can be investigated by pulse-height analysis (PHA).

Although the crystal and photomultiplier are protected
The basic components of a scintillation counting sys-
from background radiation by lead shielding and
tem are the scintillator, photomultiplier, high-voltage
from extraneous light by a thin (gamma-transparent)
supply and counting electronics. A schematic diagram
aluminium casing around the crystal, thermal election
of a single-crystal photomultiplier device used for the
noise increases appreciably as the HV is increased. For
detection of gamma radiation is shown in Figure 4.4.
high-activity gamma sources, the optimum HV can be
The photomultiplier (PM) must be supplied with a
determined by inspection of the source and background
stable source of high voltage (HV). The scintillation
count–voltage curves.
flashes fall on the photocathode of the photomulti-
plier tube and cause the emission of photoelectrons.
These electrons are accelerated by the HV applied
Beta scintillation counting
between a series of electrodes of the photomultiplier
tube, known as dynodes At each dynode secondary For the assay of a sample containing beta emitters it is
electron multiplication occurs, producing successive necessary to suspend or dissolve the activity in a liquid
amplification of the electron current. The overall gain, scintillant. The radioactivity-containing sample is
or multiplication factor, depends on the number of mixed with an aromatic solvent (e.g. benzene or tolu-
dynode stages and the applied HV, so that the heights ene) and fluors (fluorescent dye) known as a ‘cocktail’.
of the pulses produced by the tube depend on the The samples are placed in small transparent or trans-
applied voltage. lucent (glass or plastic) vials that are loaded into an
Pulses from the PM tube are passed to a preampli- instrument known as a liquid scintillation counter.
fier that is usually a transistorised follower circuit and Beta particles emitted from the sample transfer energy
brought to a suitable level for transmission to the main to the solvent molecules, which in turn transfer their
amplifier and analyser circuits. Amplified pulses are energy to the fluors that dissipate the energy by emit-
analysed in a number of ways before registration and ting light. In this way, each beta emission results in a
counting on the scaler. Since the photomultiplier output pulse of light that may be detected using photomulti-
pulse height is proportional to the energy of the parti- plier tubes. The scintillation cocktails often contain
cles or photons, the output from the linear amplifier is additives that shift the wavelength of the emitted light
also directly proportional to these energies, and the to make it more easily detected. High-energy beta
spectrum of amplified pulse heights will be very similar emitters such as 32P may also be counted in a scintil-
to the energy spectrum of the radiation. With the choice lation counter without the cocktail. This technique is
of suitable analyser circuits, the pulse-height spectrum known as ‘Cherenkov counting’.
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54 | Physics applied to radiopharmacy

Table 4.1 Physical properties of crystal scintillators used in nuclear medicine instrumentation

Scintillator Atomic number, Z Density, r Decay time Wavelength Relative light

(g/cm3) (ns) (nm) output (% of
Nal(TI))

NaI (TI) 50 3.67 200 415 100

CsI (TI) 54 4.5 1000 550 45

CsI (Na) 54 4.51 630 420 85

LaBr3:Ce 47 5.3 25 360 160

Gamma scintillation counting The demand for high-performance imaging in terms of

increased sensitivity and spatial resolution has led to
For the majority of the common gamma-emitting radio-
the introduction of a number of new scintillators.
nuclides used in nuclear medicine (such as 99mTc, 123I,
131 Some basic physical properties of the main scintilla-
I, 111In, 201Tl), thallium-activated sodium iodide
tion crystals are given in Table 4.1.
(NaI(Tl)) crystals are used for scintillation detection in
combination with a photomultiplier tube (Figure 4.4).
Pulse-height analysis
The efficiency of detection depends on a number of
factors, of which the following are the most important. One of the main advantages of the direct proportion-
ality between the voltage and the initial gamma
* Gamma photon energy: highly energetic
energy is that it is possible to plot the energy of the
photons may pass completely through the
gamma events by pulse-height analysis. A spectrum
crystal without energy dissipation.
is usually plotted to show the number of detected
Low-energy photons may be absorbed in the
events on the y-axis and the energy (or analyser volt-
outer layers of the crystal away from the
age) on the x axis (Figure 4.5). The low-energy
photomultiplier tube.
region of a spectrum is generally known as the area
* Crystal size and geometry: a large crystal will
of Compton scattering and the principal peak is
absorb high-energy photons more efficiently than a
known as the photopeak. By setting the level of
small crystal, but the size is limited by the optical
upper and lower discriminators it is possible to set
transmission of scintillations. For this reason,
a window so that the activity within the peak may be
larger crystals are commonly used for more
determined. Since the energy spectrum of each radio-
energetic gamma emitters such as 131I. The shape
nuclide is unique, this allows production of a gamma
of the crystal will also influence detection
efficiency. A gamma-emitting source placed near
the surface of a cylindrical crystal will give a
lower count rate than the same source placed inside
a well drilled in the centre of a similar crystal.
Counts

FWHM
* Photomultiplier high voltage: at low voltages,
the potential between successive dynodes is
not sufficient to produce an electrical pulse.
Pulses are produced at higher voltages; at
Energy (keV)
excessive voltage, spontaneous electron emission
Scattered radiation Photopeak
and thermal noise contribute greatly to the
observed count rate. Figure 4.5 Gamma spectrum produced by a multichannel
analyser unit. The energy resolution of the system can be
For imaging purposes and in probe detectors, expressed as the full width at half maximum (FWHM) of the
an increasing range of scintillation crystals are used. photopeak.
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Detection of radiation | 55

Lead cover

Nal(TI) well crystal

Photomultiplier

Lead shield

HV supply Scaler

Figure 4.6 Schematic diagram of a well scintillation counter.

spectrum that may be used for analysis of radio- maximum height (FWHM) and expressed as a per-
chemical purity. Alternatively, spectrum analysis centage of the maximum value.
may be used for the identification of the composition For simple detection and counting of gamma
of complex mixtures of different radionuclides. The activity (as in radiochemical analysis, chromatogram
energy resolution of the system is the ability to dif- scanning, and radioimmunoassay with 125I-labelled
ferentiate between the peaks of different gamma materials) a thin-walled NaI(Tl) well crystal can be
energies. This is usually determined by measuring used with a scaler-timer equipped with a HV supply,
the full width of the gamma peak at half the photomultiplier detector inputs, and a lower discrim-
inator, or threshold. The well detector is used since
the crystal almost completely surrounds the sample
and therefore provides high detection efficiency. A
schematic diagram of a well counter and photograph
of an automatic well counter are shown in Figures
4.6 and 4.7, respectively. Typical hand-held survey
monitors are shown in Figure 4.8.

Figure 4.8 Hand-held survey monitors for determination

of the levels of laboratory radioactivity and surface
Figure 4.7 Photograph of an automatic sample counter. contamination. Left: scintillation detector. Right: GM detector.
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56 | Physics applied to radiopharmacy

Solid-state detectors the partial quadratic sum of R and A must obviously

be minimised.
Solid-state detectors offer many advantages for For silicon and germanium, the Fano factors (at an
measurement of high-energy gamma rays over either operating temperature of 77 K) are 0.143 and 0.129,
gas detectors or scintillation counters, one major respectively, and the accepted values for electron–hole
advantage being their higher energy resolution. The pair creation energy, w, are 3.76 eV and 2.96 eV.
dimensions of solid-state detectors can be much smal- Therefore, if the detector were Fano limited (R and
ler than the gas detector of equivalent performance as A equal to zero in equation (4.1)) then the energy
they normally have densities approximately 1000 resolution, at 59.5 keV would be 0.422 keV for
times greater than commonly used gases. Solid-state Si and 0.355 keV for Ge.
detectors come in a variety of materials, but they are Silicon diodes are available as compact, real-time
predominantly based on silicon or germanium. Other personnel dosemeters. These devices continuously
materials in use or under development include monitor the radiation environment, unlike film or
diamond and semiconductor compounds such as thermoluminescent dosemeters, and can give higher
CdTe, CdZnTe, GaAs, SiC and AlGaAs. levels of protection for the user. However, the
Radiation impinging on a solid-state detector response of this type of device is dependent on the
results in the direct creation of a number of energy of the incident photon, with the sensitivity
electron–hole pairs, unlike in a scintillator which decreasing for higher-energy radiation. This effect
has the intermediate optical photon generation pro- can be taken into account by using metallic absorbers
cess. The number of electron–hole pairs generated around the detector to provide ‘energy compensation’.
in the detector is related to the energy of the inci- For efficient detection of high-energy gamma rays
dent photon (particle) and the material’s properties. (>200 keV) with excellent energy resolution, germa-
Electrons and holes are swept away under the in- nium detectors are the only viable choice. Unlike
fluence of the electric field controlled by a bias silicon detectors, which cannot be thicker than a few
voltage applied across the device. The resulting millimetres, germanium can have sensitive thicknesses
charge is collected to give a measure of the incident of several centimetres, and therefore can be used as a
energy and, in the case of imaging detectors, the total absorption detector for gamma rays up to few
position of interaction. Detectors based on silicon MeV. Widely available types are lithium-doped ger-
and germanium are typically operated at low tem- manium, Ge(Li) and high-purity germanium (HPGe)
peratures to improve the signal to noise and energy detectors. A major disadvantage of germanium detec-
resolution. tors, however, is the requirement to operate them at
The energy resolution of semiconductor detectors liquid-nitrogen temperatures (77 K).
can be described by the sum of the three independent Diamond has many interesting properties for use
terms under the square root sign in equation (4.1). The in radiation detectors; the detectors can be operated at
first term relates the variance of the number of primary room temperature, have low noise and intrinsic high
electron–hole pairs, where F is the Fano factor, E is the radiation tolerance, and have near ‘tissue equivalent’
incident energy (eV) and w is the energy required to absorption. High-quality diamond for detectors is
generate an electron–hole pair. slowly becoming available as manufacture and costs
issues are being resolved.
rffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffi Compound semiconductor devices offer alterna-
FE
DE ¼ 2:36v þ R2 þ A2 ð4:1Þ tives to silicon and germanium detectors and have
v
the potential to overcome some of the limitations of
The second term, R2, relates to the readout noise and these widely used materials. The most widely investi-
arises from the loss of charge during collection, drift or gated compound semiconductors, CdTe, CdZnTe and
transfer. The last term, A2, is associated with the HgI2, can all operate at room temperature with
amplifier noise (pre-amplifier, main amplifier and respectable energy resolution and good detection
signal processing electronics) with A in units of elec- efficiency. The higher effective atomic number of
tronvolts. To achieve Fano limited energy resolution the compound materials translates into significantly
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Detection of radiation | 57

Probe casing and shielding

Power supply
Isotope selector
‘Energy window’
Display (counts/s)

Sound generator

Detector

Figure 4.9 Schematic diagram of the main components of a gamma probe system suitable for use during surgery.

better photoelectric absorption and hence higher scanners. These were based on the mechanical scan-
detector efficiency per unit thickness. Widespread ning of collimated probes across the length of the
adoption of these materials for radiation detectors patient.
for medical application will require improvements in Probe systems have been used for a range of appli-
manufacture and processing to reduce the costs to cations in intensive care and surgical exploration.
levels competitive with silicon and germanium. Intraoperative probe systems consist basically of two
Solid-state detectors have mostly been used in component parts, the hand-held detector and the
electronic autoradiography units, and probe systems electronic processing and display unit; these two are
for intraoperative detection. However, this type of usually coupled together by an electrical cable (Figure
detector is now becoming more frequently used for 4.9). At the tip of the probe is a collimated detector
imaging such as in small gamma cameras, scintimam- element that provides the directional properties of the
mography units and digital X-ray systems. The most system. This is mounted on a shaft that widens to form
widely known imaging devices based on silicon are the handle and often contains some electronics such as
charge coupled devices (CCDs), found in many the pre-amplifier unit. The majority of commercial
high-end consumer cameras and CMOS devices probe systems are manufactured from high-grade
typically used in web cameras. These imaging devices metal such as stainless steel or anodised aluminium
offer very good spatial resolution and digital output. that may be cleaned and sterilised often using ethylene
CCD-based cameras for dental imaging utilise a oxide gas (Figure 4.10). At least one prototype
scintillator (Gadox or CsI) to covert the X-rays and
gamma rays to optical photons that the device can
image efficiently. Simpler direct imaging and use
of lower levels of activity are some of the main benefits
of these devices.

Probe systems
Since the very beginning of clinical nuclear medicine
practice, probe systems have been used for monitoring
radiopharmaceutical uptake in vivo. The very first
clinical investigations were based on the use of
Geiger counters to monitor the uptake of radioiodine
in the thyroid gland (thyroid uptake). Subsequently,
probe systems have used single NaI(Tl) scintillation
crystals with a photomultiplier since these are recog- Figure 4.10 Photograph of hand-held surgical probes.
nised as being the most sensitive form of radiation These can be sterilised or placed in a sterile sheath for
detector. The first imaging systems were the rectilinear intraoperative use.
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58 | Physics applied to radiopharmacy

commercial system has a ‘single-use’ disposable connected to the mains supply during operation, leak-
handle and cable. age currents to the patient are well below 10 mA and
The probe is designed to be as slim as possible to are not considered to be hazardous.
facilitate access through small surgical incisions. The
active detector element is generally a scintillation crys-
tal, NaI(Tl) or CsI(Na), coupled to a photodiode or Personal radiation dosemeters
photomultiplier tube, or a solid-state detector, usually
CdTe with adjacent signal pre-amplification, built into All personnel working with radioactive materials and
the handle. In the case of scintillation detectors the ionising radiations are required to wear personal radi-
design should facilitate good optical coupling of the ation dosemeters as part of health and safety regula-
detector crystal to the electronics, since the use of long tions. These are basically one of three types, electronic,
fibreoptic cables has been found to be unreliable. thermoluminescent, and film as shown in Figure 4.11.
With both scintillation and solid-state devices, These monitors are usually calibrated by a dose-
increasing the diameter of the detector increases monitoring service and results are provided in micro-
sensitivity but reduces spatial resolution. Scintillation sieverts (mSv). The more traditional type is the film
detectors tend to be physically larger but have much badge dosemeter. This uses a small piece of X-ray film
higher sensitivity. The higher sensitivity of scintillation sandwiched between two plastic covers containing
devices arises from a combination of increased a combination of filters (Figure 4.12). The badge is
intrinsic detection efficiency and the efficiency of worn for a period of time and with appropriate cali-
collection of the electrical signal from the detector. bration the density of the film exposure can be related
CdTe detectors collect charge less efficiently as to the absorbed dose.
detector size increases. A 1 mm thick CdTe crystal One of the simplest and most reliable radiation
has an intrinsic stopping power of about 50%, and monitors is the thermoluminescent personal dose
typical probes that use 2–3 mm thick CdTe wafers monitor. The dosemeters are usually supplied in the
do not show exponential increases in overall efficiency form of a whole-body monitor or a finger badge. The
due to falling charge collection efficiency. active component is lithium fluoride powder placed in
Accurate spatial localisation of the sites of tracer a specially designed holder that incorporates screening
uptake depends upon the directional properties of the materials to differentiate between the different
probe. This is primarily affected by the degree of col- radiations received. When ionising radiation interacts
limation, which usually comprises 5–10 mm thickness with the crystals it causes electrons in the atoms to
of tungsten. Although it is desirable for the probe to be jump to higher energy states, where they remain
physically small, significant errors may result if there is trapped due to the influence of impurities such as
insufficient shielding around the detector.
The electronic unit will provide the electrical power
source, usually in the form of rechargeable batteries,
signal processing circuitry, a pulse-height analyser and
some form of display. Different probe systems have
different means of output (digital count-rate meters,
scalers and audible outputs). Audible outputs generally
produce a series of clicks or tone bursts with the fre- (a) (b)
quency proportional to count rate, and this is the main
means of relaying the count rate to the surgeon while
his vision is focused on the operating field. A threshold
or ‘squelch’ control is usually available, which can be
set to a level below which there is no audible output. (c) (d)
However, a digital display is recommended since this
facilitates a numerical reading that may be recorded Figure 4.11 Personal dosemeters: (a) electronic dosemeter,
in the surgical notes. Since the electronics are not (b) TLD finger monitors, (c) film badge, (d) TLD body monitor.
Sampson's Textbook of Radiopharmacy
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Detection of radiation | 59

3 mm plastic 0.5 mm plastic Electronic dosemeters are usually solid-state devices

window window
that are used for general monitoring of personal radia-
Open window tion doses. These have the advantage of providing an
immediate reading on a digital display. They can also
Lead window be set with an audible output and an alarm that can
be triggered at pre-set level. These are particularly use-
Light alloy
window ful when undertaking a risk assessment of individual
procedures that may result in significant radiation
doses to personnel.
All staff monitoring and record keeping of
personal radiation doses should be undertaken by an
approved monitoring service with the support of the
hospital radiation protection officers, normally the
Figure 4.12 A schematic diagram of the casing of the film
radiation protection supervisor (RPS) and radiation
badge dosemeter. The filters are used to discriminate the
different types and energy of radiation. protection adviser (RPA).

Further reading
manganese or magnesium in the crystal, until heated.
Brown BH et al. (1999). Medical Physics and Biomedical
After the designated period of wearing, the badge is
Engineering. Bristol: IOP Publishing. ISBN 0-7216-
returned and the exposure reading is taken. Heating 8341X.
the crystals causes the electrons to drop back to their Cherry SR et al. (2003). Physics in Nuclear Medicine.
ground state, releasing energy in the form of light Philadelphia: Saunders.
Knoll GF (2000). Radiation Detection and Measurement,
photons equal to the energy difference between the
3rd edn. New York: Wiley. ISBN 0-471-07338-5.
trapped state and the ground state. The light output Sharp PF et al. Practical Nuclear Medicine 3rd edn. London:
is converted into an absorbed dose level. Springer 2005. ISBN 185233-875-X.
Sampson's Textbook of Radiopharmacy
Chapter No. 4 Dated: 24/11/2010 At Time: 11:22:51
Sampson's Textbook of Radiopharmacy
Chapter No. 5 Dated: 24/11/2010 At Time: 11:28:40

5
Physics applied to radiopharmacy:
imaging instruments for nuclear
medicine
Brian F Hutton

Introduction 61 Positron emission tomography (PET) 65

The gamma camera 61 Preclinical imaging 67

Emission tomography (general) 62 Recent developments 68
Single-photon emission computed
tomography (SPECT) 65

Introduction localisation and can also be used for attenuation

correction. In this chapter a basic overview of these
Central to the role of nuclear medicine is the ability to imaging systems will be presented, primarily for
obtain an image that accurately reflects the spatial systems designed for human use. There is also
distribution of an administered radioactive tracer increasing interest in imaging systems used for
and its variation in time. Traditionally the Anger preclinical imaging in small animals; these systems
gamma camera has been the standard instrument used are based on similar principles and will be covered
for planar imaging, permitting static, dynamic or briefly. The chapter concludes with a brief overview
gated acquisition. Of more interest now is the ability of current developments in nuclear medicine instru-
to obtain images of the three-dimensional distribution mentation. References have been limited to key
of activity by means of emission tomography. This papers, reviews and book chapters. For a general
involves either single-photon emission computed coverage see Cherry et al. (2003).
tomography (SPECT) based on detection of the
gamma emissions from a single photon-emitting
radionuclide (e.g. 99mTc) or positron emission tomog- The gamma camera
raphy (PET) which relies on the detection of dual
photons that arise from positron annihilation. Both The instrument most commonly used for imaging in
PET and SPECT are now available combined with nuclear medicine is the Anger gamma camera (Anger
X-ray computed tomography (CT), which aids in 1958), whose performance has improved since its
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62 | Physics applied to radiopharmacy

inception but whose design is largely unchanged. the fraction of emitted photons that are acquired;
Emitted photons are detected in a scintillation detector typically the acquired counts are relatively low,
(usually NaI with thallium impurities), in which resulting in an observed mottle or noise that is a
visible light is emitted as a result of the photon direct result of the limited statistics. In most cases the
interaction and is detected by a photomultiplier. In sensitivity can only be improved to the detriment
practice the detector is usually a single large crystal of spatial resolution and vice versa. The spatial
of dimension typically around 500 mm  400 mm resolution is limited by two factors: (1) the intrinsic
 9.5 mm. The emitted light travels in all directions ability of the detector to correctly estimate the location
and is detected by an array of photomultiplier tubes, of a photon interaction in the crystal, usually 3–4 mm
optically coupled to the scintillator, in which the FWHM (FWHM is the full width at half maximum
light is further converted to a small electrical signal value for an image of a point source, the normal
and amplified. The distribution of light across the measure of spatial resolution); (2) the limited angle
photomultiplier array provides an estimate of the of acceptance defined by the collimator geometry (by
spatial location of the photon interaction; the summed far the primary effect as resolution at 10 cm is typically
light signal is proportional to the energy deposited in 8 mm; this geometric resolution worsens linearly
the crystal during interaction. The availability of an with distance from the collimator). The resolution
energy signal permits discrimination of photons could be improved by narrowing the collimator holes,
that have undergone Compton scattering prior to but this would reduce the number of detected photons,
detection, because these photons will have lower i.e. worsen sensitivity. The number of acquired counts
energy; since these photons are deflected, their origin could be increased by acquiring for a longer time; this
is uncertain. The remaining essential component is a is clearly limited for practical reasons. Alternatively,
collimator, without which the origin of the emitted administering a larger activity of radionuclide would
gamma photon would be unknown. The collimator increase the photon flux, but this is limited by the
consists of a lead or tungsten ‘honeycomb’ with long acceptable radiation dose delivered to the patient.
narrow holes that ideally permit only photons Even when optimised, nuclear medicine images are
travelling normal to the scintillator to be detected typically blurred (i.e. of limited resolution) and
(Figure 5.1). A range of collimators is available, somewhat noisy (i.e. of limited sensitivity) compared
each designed to provide optimum image quality for with other modalities such as X-ray CT.
specific emission energy. A further parameter of interest is the energy reso-
The acquired data are normally digitised so that lution or ability to discriminate energies of the detected
each detected photon whose energy falls within a photons. In the case of NaI(Tl) this is 9–10%; i.e. for
selected range, so as to minimise scatter, is simply the single-energy emission of 99mTc an energy window
added to a picture element (pixel) that corresponds width of 20% is required to capture 95% of the
to the physical location on the detector. Each pixel detected primary photons (with approximately 35%
accumulates counts proportional to the activity of the total detected counts being scattered photons).
exposed to that pixel. A visible image is constructed
by converting the summed counts in the array of pixels
to a corresponding array of display elements, where Emission tomography (general)
shades of grey or colours are used to represent the
range of acquired counts. The result is a planar image As outlined above the standard Anger camera is a
of the activity distribution being viewed. planar imaging instrument which does not permit
The image quality that is obtained with a gamma identification of the origin of emission at depth in
camera is a consequence of the instrument design. The tissue (like planar radiography). However, by acquir-
most important parameters are the spatial resolution ing information at multiple angles around the patient
and sensitivity of the system. Spatial resolution a three-dimensional distribution of the activity
describes the ability to discriminate points of activity distribution can be mathematically reconstructed; this
that are closely spaced (i.e. the ability to image fine is referred to as tomography (similar to CT). The
detail in the activity distribution). Sensitivity refers to method of acquiring data is different for single-photon
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Detector

To display and
X Y Z computer
Position/energy circuits

Photomultiplier tubes

NaI(T1) crystal Light

Collimator Gamma-ray

(a)

(b)

Figure 5.1 (a) Schematic of gamma camera operation showing collimator, crystal and photomultiplier assembly. (b) Commercial
dual-head gamma camera (Siemens Healthcare). Most systems are mounted on a stable gantry to facilitate SPECT and some also
incorporate a CT system.

emitters (SPECT) or positron emitters (PET), but the emission can be ‘modelled’ given knowledge of the
principles of tomographic reconstruction are similar acquired projection counts. The simplest model
for both (and for CT); it is therefore logical to consider assumes that all photons must originate along lines
this separately. perpendicular to the point where measured; given no
There are essentially two methods available for knowledge of the depth of origin, the best that can be
reconstruction from projections: filtered back projec- done is to simply back project the measured counts,
tion (FBP) and iterative methods, both being routinely distributing these along the perpendiculars (Figure
used (see Hutton et al. 2006; Tsui, Frey 2006). Both 5.2a). This results in a build-up of counts due to con-
methods are based on the assumption that the origin of sistent measurement at different angles, but data
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remain blurred. This blurring can be exactly rectified distribution. The appeal of this method is that it does
by use of an appropriate filter (the ramp filter) to not require filtering (and has usually better noise char-
produce an analytical solution. Unfortunately, the acteristics). The method is also very flexible and can
process amplifies noise and so a smoothing filter must easily cater for a much more complex model of the
also be applied. The technique is also subject to emission process including attenuation, scatter and
streaking and sensitive to missing data. variation in resolution at distance from the detector
The alternative is to use an iterative approach, (Tsui et al., 1994; Hutton et al., 1997; King et al.
most commonly maximum likelihood–expectation 2004). The accelerated OS-EM algorithm is in
maximum (ML-EM) reconstruction (Lange, Carson widespread clinical use particularly in PET where
1984) or an accelerated version of this, e.g. ordered the improved noise characterisation in low-count
subsets EM (OS-EM) (Hudson, Larkin 1994). The background regions facilitates lesion detection
principles of the iterative methods can be considered (see Hutton et al. 1997).
as an extension to the back projection described The image quality obtained in emission tomogra-
above. If instead of simply back projecting measured phy, as in planar imaging, depends on a number of
projections, an initial guess is made regarding the factors. There is the usual trade-off between noise
distribution of activity (usually assuming this to be and resolution (or contrast); for FBP this is largely
uniform), one can estimate what would be acquired controlled by choice of filter, but for ML-EM or
for this activity distribution using the inverse of the OS-EM the result depends on the number of iterations
back projection process (forward projection), which in used. There are other factors that affect image quality
its simplest form involves summing along rows of the and quantitative accuracy. Emitted photons undergo
image orthogonal to each projection angle. The Compton scattering in tissue, which results not only in
estimated projections can then be compared with misplaced photons but also loss of counts (referred to
the actual measurements to determine errors in the as attenuation). This loss is significant, resulting in
estimate; the resultant errors are back projected and typically only 10% of emitted photons leaving the
used to correct the original estimate (Figure 5.2b). body (<5% for PET). Correction for attenuation is
The process continues with further forward and therefore an important consideration. In addition,
back projection until the estimated and measured pro- the limited resolution results in loss of contrast for
jections are in agreement; at that stage the estimated small objects (and at times inability to detect small
activity distribution should match the true activity objects); motion also limits contrast but also can give

(a) 1 angle 2 angles 4 angles 16 angles 128 angles

Measured
projections
Compare Reconstructed
Back
(ratio or error map
project
difference)
Estimated
projections Update
reconstruction

Forward Current
project estimate
(b)

Figure 5.2 (a) Simple illustration of reconstruction by filtered back projection. The cancellation of back projection errors
as the number of projection angles increases can be seen. (b) Schematic of iterative reconstruction: the reconstructed image is
obtained by ensuring that estimated projections match the measured projections.
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rise to additional serious artefacts. Some of these attenuation coefficients appropriate for the gamma
factors will be discussed in more detail in relation to emission energy of the specific radionuclide, normally
SPECT or PET. using a bilinear function. Care should be taken that
the CT does not contain artefacts (e.g. streaking) or
metallic implants as these can result in errors in the
Single-photon emission computed attenuation correction. Misalignment between emis-
tomography (SPECT) sion and transmission data can also be problematic
(e.g. due to acquisition at different respiratory phases).
In the case of SPECT the most commonly used system Correction for other factors affecting SPECT
involves the rotation of one or more gamma cameras quantification continues to be a research topic.
around the patient, acquiring planar images at multi- There have been numerous suggestions for methods
ple angles (see Figure 5.5). For the set of acquired to correct for scatter (see, for example, reviews
angles, each row of the acquired planar images can by Buvat et al. (1994) and by Zaidi and Koral
be selected to reconstruct a single cross-sectional slice. (2006)), but many are difficult to implement in a
As outlined above, reconstruction can be performed clinical setting. Probably the most popular method
using either FBP or iterative methods. The attraction involves the acquisition of additional energy windows
of the rotating gamma camera is that the same above and below the photopeak, which are used to
instrumentation can be used for both planar and estimate the scatter within the photopeak window
tomographic acquisition, providing great flexibility. (Ogawa et al. 1994). Unfortunately, subtraction of
The use of an Anger camera for SPECT places extra scatter enhances noise although image quality can be
demands on the system. The camera must have a good improved by simply adding the measured scatter in the
uniformity as errors are amplified in SPECT; a small forward projection during iterative reconstruction.
uniformity defect at the centre of the detector can give Partial volume effects are particularly problematic
rise to a serious defect on reconstruction. In addition, for SPECT given the limited spatial resolution (at best
the rotational stability of the system must be ensured the resolution is equivalent to the planar resolution
(both electronic and mechanical stability caused at the centre of rotation; typically 12–16 mm using
problems in early systems). Both uniformity of parallel-hole collimators; at best 8 mm for brain
detector response and the alignment of the electronic SPECT using a fanbeam collimator). Corrections for
and mechanical centre of rotation should be checked partial volume effects have been devised for brain
regularly as part of routine quality control procedures. SPECT using aligned high-resolution anatomical
Correction for attenuation in SPECT is not trivial, images, but, in general, correction is difficult and
especially when there is non-uniform attenuation as in rarely exact. Only recently has more careful attention
the chest. Approximate correction (Chang 1978) can been given to motion effects, particularly those due to
be implemented post reconstruction in the case of uni- involuntary motion as a result of respiration. Owing to
form attenuation, sufficient for visual interpretation. the slow acquisition involving detector rotation,
However, in the case of non-uniform attenuation there effects of motion can be somewhat unpredictable.
is need to acquire a measured transmission map;
correction then can be achieved by incorporating
this known attenuation directly into the model used Positron emission tomography
for iterative reconstruction. There have been various (PET)
approaches for transmission measurement using
gamma-emitting sources (see review by Bailey 1998), Imaging using positron emitters is always tomographic
although the commercial application of these systems and the principles of acquisition are unique to this
has proved to be unreliable (O’Connor, Kemp 2002). modality. When a positron is emitted, it travels a short
Recently, combined SPECT/CT systems have become distance in tissue, loses energy, and eventually interacts
available wherein the CT provides an improved with an electron, the two particles annihilating with
transmission map as well as a means of anatomical emission of two 511 keV gamma photons that travel in
localisation. The CT values must be converted to opposite directions. PET is designed using a ring of
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11

(a) 3
(b)

Figure 5.3 (a) PET detects the two collinear gamma photons that are emitted when a positron annihilates with an electron (1). The
two photons are detected in coincidence, permitting localisation of a line-of-response (2). The activity distribution (3) is determined
normally via iterative reconstruction. (b) Most PET detectors utilise a block design with multiple crystals connected to a small
number of photomultiplier tubes.

small detectors around the patient, specifically commonly used system is currently based on block
designed to detect events only when pairs of gamma detectors where a small array of detectors is coupled
photons arrive within a short time of each other (i.e. in to a small number of photomultiplier tubes which, like
coincidence; in practice typically within 8–12 ns). the Anger camera, decode the interaction location
When an event is detected (assumed due to a single based on the detected light distribution (Figure 5.3b).
positron emission) the line joining the two detectors The set of acquired projection lines (or lines of
defines the origin of the annihilation without the need response) at first appears quite different from the data
for physical collimation (Figure 5.3a). The lack of a acquired in SPECT, but in fact these can easily be
physical collimator results in approximately 100 times reordered so as to represent a set of parallel projec-
higher sensitivity than in a typical SPECT system. tions. Consequently reconstruction is very similar to
The scintillators used for PET are not NaI (al- that used for SPECT. Many PET studies are performed
though PET systems have previously been designed by acquiring the whole body (or at least neck to thigh);
using this material) but are selected to have high stop- this is achieved by acquiring for a set time (2–4 min-
ping power and fast light output. Table 5.1 lists prop- utes) in each of several bed positions. These bed posi-
erties of detector materials in commercial use at the tions are spaced so as to achieve constant sensitivity
time of writing compared with NaI(Tl); lanthanum along the patient’s length (typically requiring 6–7 bed
bromide (LaBr3) is included as a promising new detec- positions).
tor material (Moses, Shah 2005). A variety of detector A specific property of PET is that owing to the
designs have been suggested, although the most coincidence detection of dual photons the probability

Table 5.1 Comparison of scintillation materials used for PET

Density (g/cm3) Relative light output (%) Decay timea (ns)

NaI(Tl) 3.67 100 230

BGO 7.13 30 300 (60)

LSO 7.35 80 40

GSO 6.31 40 60 (600)

LaBr3 5.06 165 16

a
Secondary component in brackets.
BGO, bismuth germanate; LSO, lutetium oxyorthosilicate; GSO, gadolinium oxyorthosilicate.
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of event detection is affected only by the total att- derive from independent positron sources. These events
enuation along a line of response and is independent are a further source of error, but they are corrected
of the location along that path; consequently, attenu- either on the basis of calculating the random coinci-
ation measured externally for that specific line of dence rate with knowledge of the recorded single event
response provides an exact correction for the attenua- rate (photons detected without a second photon being
tion along that path. The ease of correcting for atten- necessarily detected in the coincidence timing window)
uation resulted in PET being considered ‘quantitative’, or by direct measurement using a delayed coincidence
although the modality is subject to problems similar window (see, for example, Wernick and Aarsvold listed
to those affecting SPECT (scatter, resolution, motion). in Further Reading for detail). The main consequence is
A limitation to the original approach to the attenua- that random events correction and scatter correction
tion correction was noise from the transmission both contribute to the noise in the final reconstruction.
measurement that propagated into the reconstructed Partial volume effects are less serious than experienced
emission images; consequently transmission measure- in SPECT owing to the better resolution (typically
ments traditionally occupied almost the same time as around 4–6 mm FWHM). Motion has a more notice-
the emission measurement. Nowadays PET is sup- able effect, however. Research continues on methods
plied with CT, permitting high-quality transmission to detect and correct for motion.
measurement of the whole body in less than a minute A significant contributor to the high quality of
(Beyer et al. 2000). As in the case of SPECT, the CT PET images is the reconstruction algorithm. Iterative
data must be converted to appropriate attenuation algorithms are now implemented to permit full 3D
coefficients; also artefacts and areas of abnormally reconstruction that can incorporate a model of emis-
high attenuation can give rise to artefactual PET sion that includes attenuation, scatter and resolution
activity distribution. Mismatch of emission and as well as detector normalisation and correction for
transmission can still occur as the measurements are random events. A feature of iterative reconstruction is
sequential and respiration and heart motion remain that noise is proportional to signal and reduction of
involuntary. The availability of dual modality noise in low-count areas greatly enhances the ability to
PET/CT has revolutionised the clinical use of PET. detect low-contrast lesions, a common requirement of
18 18
F-fluorodeoxyglucose (FDG), though somewhat F-FDG studies. See Bailey et al. (2005) for a useful
non-specific, has very high sensitivity for lesion coverage of PET.
detection, but localisation can be difficult. The addi-
tion of high-resolution CT not only enables accurate
localisation but also the combined information can Preclinical imaging
further clarify diagnosis. As a result virtually all PET
systems are now supplied as PET/CT configurations. In recent years there has been growing interest in the
Early PET systems included lead septa that development of instrumentation specifically for
separated the axial planes, permitting a set of two- imaging of small animals. This is proving important
dimensional (2D) acquisitions and 2D reconstruction. in streamlining the preclinical development of suitable
However, it is now more common for these septa to be tracers by permitting ultra-high-resolution imaging
removed so that data acquisition and reconstruction are of tracer kinetics and distribution without the need
both performed in three dimensions. A consequence is for dissection of multiple animals. These systems
that there is increased scatter, potentially similar to the have further appeal in being able to evaluate pharma-
fraction encountered in SPECT. As with SPECT, there ceutical distribution as well as monitoring response to
are several approaches to scatter correction, typically drug administration. The use of these systems is likely
now implemented as standard processing by the suppli- to expand further in response to an increasing need for
ers. Note that scatter in PET can give rise to events efficient evaluation of new potential therapies
outside the patient boundary, unlike SPECT in which tailored for specific diseases or tumour types. Both
scatter is limited to the area within the body boundary. PET and SPECT systems are commercially available
One type of event unique to PET is random coincidence, as well as CT and MRI. Performing dual or multiple
a result of detecting two photons in coincidence that modality studies is therefore quite feasible.
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Micro-PET operates on the same principle as the optical pinhole

camera. An inverted and magnified image of the object
Several systems have been designed for preclinical
is obtained on the detector when the pinhole aperture
PET, most notably deriving from work of Simon
is placed close to the object and the aperture–detector
Cherry. Recent systems have been based on scaled-
distance exceeds this distance. As a result of the mag-
down versions of clinical systems based on block
nification, the resolution achieved can be significantly
detectors. A particular concern in systems with small
less than the intrinsic resolution of the detector (the
detector ring radius is the uncertainty in line-of-
effective intrinsic resolution component is reduced
response as a result of interaction at depth in one
by the magnification factor). By using a large number
of several crystals, with degraded resolution as a
of small-diameter apertures, the sensitivity can be
consequence. Some recent designs attempt to correct
maintained. The example illustrated in Figure 5.4 is
for this effect using some form of depth encoding,
of the U-SPECT system (MILabs), in which 75
usually using multiple crystal layers.
pinholes with gold inserts view a small volume of a
The highest resolution achievable to date has been
mouse, the final whole-body image being obtained by
of the order of 1 mm; in fact the theoretical limit of
translating the animal’s position relative to the colli-
resolution for PET is due to physical limitations of
mator. Alternative systems image the whole animal
positron emission. On emission, a positron travels a
with lower magnification, sometimes permitting over-
finite distance prior to annihilation, this distance being
lap of acquired images (multiplexing) which is
dependent on the positron emission energy. For 18F the
decoded during reconstruction (Wirrwar et al. 2001).
range is relatively small (mean 0.6 mm), for more ener-
The principles of reconstruction are identical to those
getic positron emitters such as 82Rb this can be more
used in human systems, mainly based on the same
significant. What is measured is the point of annihila-
iterative reconstruction algorithms.
tion rather than the point of positron emission. The
main limitation in resolution, however, is due to the
fact that there can be some loss of momentum during
annihilation, which results in a small angular devia-
Recent developments
tion from the expected collinear emission of dual
There continue to be developments in instrumentation
photons (0.2 ). Though small, this angular deviation
for nuclear medicine. This section describes a few
is sufficient to introduce a spatial uncertainty in local-
recent developments at the time of writing that are
isation that limits the achievable resolution to around
likely to influence the range of instrumentation
1 mm. As with clinical systems micro-PET is combined
available for clinical and preclinical use.
with micro-CT and more recently MRI (see Rowland,
Cherry 2008).
Detector components
There is a continuing search for better detector mate-
Micro-SPECT
rials that permit improved performance. There is
Surprisingly, preclinical SPECT systems can signifi- currently strong interest in the scintillator lanthanum
cantly out-perform PET as there are no physical lim- bromide (see Table 5.1 for properties). This material
itations to the achievable resolution similar to those has very good stopping power and fast, high light
influencing micro-PET. At the time of writing, resolu- output. There is also increasing interest in using
tion of 0.35 mm had been demonstrated (Beekman, solid-state detectors such as cadmium zinc telluride
van der Have 2007). The main contributor to this (CZT) (see Wagenaar 2004); their stability and cost
excellent spatial resolution has been the pinhole colli- have improved to a stage where these detectors are
mator, whose properties are very well suited becoming economically viable. These developments
to imaging of small animals. Unlike parallel-hole are complemented with development of readout
collimators, the pinhole can be utilised to provide systems as an alternative to photomultiplier tubes.
both high resolution and high sensitivity provided it Examples are avalanche photodiodes, silicon PM
is used close to a small object. The pinhole collimator tubes, electron-multiplying CCDs and silicon drift
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U-SPECT: 75 pinholes
Resolution: 0.35 mm

Figure 5.4 Preclinical SPECT using 75 pinholes with three detectors (MILabs, the Netherlands). The system images a very
small volume and performs a 'rectilinear' scan of the animal to provide a whole-body SPECT study. Reproduced with permission
from F. Beekman, MILabs, The Netherlands.

diodes (see Pichler, Ziegler 2004 for review). Though holes in the axial direction but pinhole in the transax-
detailed description is beyond the scope of this ial direction) with resultant improvement in sensitivity
chapter, all of these systems offer promise for future (about threefold).
detectors; some are already in use in laboratory A further novel system is D-SPECT (Figure 5.5),
settings. An intrinsic resolution of 1 mm is readily which utilises nine CZT detectors that each rotate
achievable. The challenge remains to design systems around their axes so as to acquire data within
that take best advantage of this improvement in programmable arcs; the combination of wide-beam
intrinsic resolution as conventional parallel-hole collimation and region-centric acquisition permits a
collimators dominate performance. There is now sensitivity gain of up to 8 and hence either a significant
interest in utilising alternative collimators including reduction in acquisition time, or reduced radiation
multiple-pinhole, crossed-slit and slit-slat collimators. dose. Other suggested approaches involve use of mul-
tiple pinholes or multiple-segment slant-hole collima-
tors. Again central to the success of these systems are
Organ-specific SPECT systems
the iterative reconstruction algorithms that are tai-
There is a current trend to design systems optimised lored to the specific geometry of acquisition. In
for specific purposes (Patton et al. 2007). Clearly particular the inclusion of resolution models in these
better performance can be achieved than for the more algorithms is proving to be useful in providing not only
general-purpose but flexible conventional systems. enhanced reconstructed resolution but also improved
Of particular interest has been recent development of noise properties; the commercial interest in improving
systems dedicated for cardiac studies, mainly driven by noise has been to permit reduction in imaging time and
the need for high throughput of myocardial perfusion more efficient system utility. Other dedicated systems
studies to meet clinical demand. Examples of these for breast scanning are also under development.
systems are the CardiArc and MarC systems, both of Systems for brain imaging were developed in the past
which utilise rotating slit-slat collimators (parallel and may resurface to meet the growing demand for
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70 | Physics applied to radiopharmacy

Figure 5.5 Example of system designed specifically for cardiac SPECT (D-SPECT, Spectrum Dynamics, Israel). Nine CZT
detectors acquire counts during programmed rotation so as to maximise counts from the cardiac region. To optimise sensitivity,
the rotation of each detector is programmed in a scan pattern that centres on the heart. Reproduced with permission from
D-SPECT, Spectrum Dynamics, Israel.

brain studies on the basis of the recent resurgence of strong magnetic fields employed by MRI systems.
specific tracers for neurological applications (e.g. Optical fibres are also used to transfer the scintillation
various studies of receptor systems and amyloid light from detectors outside the main magnetic field
deposits). prior to decoding. The first commercial human system
was released in 2007. Work is also in progress to
develop SPECT/MRI systems.
Recent PET developments
Of particular interest in PET has been the reintroduc-
tion of systems that utilise time-of-flight information. References
When the two annihilation photons are emitted, they
both travel at the speed of light but, depending on the Anger HO (1958). Scintillation camera. Rev Sci Instrum 29:
27–33.
location of the annihilation, there will be a time
Bailey DL (1998). Transmission scanning in emission tomog-
difference in their detection. If this time difference raphy. Eur J Nucl Med 25: 774–787.
could be measured accurately, the exact location Bailey DL et al., eds. (2005). Positron Emission Tomography:
of the annihilation could be determined without Basic Sciences. London: Springer.
Beekman F, van der Have F (2007). The pinhole: gateway
reconstruction. However with current technology the
to ultra-high-resolution three-dimensional radionuclide
measurement of this small time difference is limited imaging. Eur J Nucl Med Mol Imaging 34: 151–161.
(500–600 picoseconds) so the location can only be Beyer T et al. (2000). A combined PET/CT scanner for clinical
estimated to within around 8 cm. Nevertheless this oncology. J Nucl Med 41: 1369–1379.
Buvat I et al. (1994). Scatter correction in scintigraphy; the
additional information can be incorporated in the
state-of-the-art. Eur J Nucl Med 21: 675–694.
reconstruction model with a resultant improvement Chang LT (1978). A method for attenuation correction in
in signal-to-noise ratio, which is particularly beneficial radionuclide computed tomography. IEEE Trans Nucl
in large patients (where statistical quality can be a Sci 25: 638–643.
Cherry SR et al. (2003). Physics in Nuclear Medicine. New
concern). Time-of-flight PET systems were built in
York: Elsevier Health Sciences.
the 1980s based on barium fluoride detectors, but Fulton R et al. (1994). Use of 3D reconstruction to correct for
these tended to be unstable; more recently the main patient motion in SPECT. Phys Med Biol 39: 563–574.
suppliers have released systems based on newer Hudson HM, Larkin RS (1994). Accelerated image recon-
struction using ordered subsets of projection data. IEEE
detector materials (e.g. LYSO) (Karp et al. 2008).
Trans Med Imaging 13: 601–609.
A further development of interest is the recent Hutton BF et al. (1997). A clinical perspective of accelerated
introduction of PET/MRI, at this time specifically for statistical reconstruction. Eur J Nucl Med 24: 797–808.
application in the brain. Several preclinical systems Hutton BF et al. (2006) Iterative reconstruction methods. In:
Zaidi H, ed. Quantitative Analysis in Nuclear Medicine
have been designed before (Shao et al. 1997) that
Imaging. New York: Springer, 107–140.
exploit the use of readout technologies that, unlike Karp JS et al. (2008). Benefit of time-of-flight in PET: exper-
conventional PM tubes, can operate near or within imental and clinical results. J Nucl Med 49: 462–470.
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Physics applied to radiopharmacy: imaging instruments for nuclear medicine | 71

King MA et al. (2004). Attenuation, scatter and spatial reso- Tsui BMW, Frey E (2006). Analytic image reconstruction
lution compensation in SPECT. In: Wernick MN, Aarsvold methods. In: Zaidi H, ed. Quantitative Analysis in
JN, eds. Emission Tomography: The Fundamentals of Nuclear Medicine Imaging. New York: Springer, 82–106.
SPECT and PET. San Diego, CA: Elsevier. Tsui BMW et al. (1994). The importance and implementation
Lange K, Carson R (1984). EM Reconstruction algorithms of accurate 3D compensation methods for quantitative
for emission and transmission tomography. J Comput SPECT. Phys Med Biol 39: 509–530.
Assist Tomogr 8: 306–316. Wagenaar DJ (2004). CdTe and CdZnTe semiconductor
Moses WW, Shah KS (2005). Potential for RbGd2Br7:Ce, detectors for nuclear medicine imaging. In: Wernick MN,
LaBr3:Ce, LaBr3:Ce, and LuI3:Ce in nuclear medical imag- Aarsvold JN, eds. Emission Tomography: The Fundamen-
ing. Nucl Instrum Methods Phys Res A 537: 317–320. tals of SPECT and PET. San Diego, CA: Elsevier.
O’Connor MK, Kemp B (2002). A multicenter evaluation Wirrwar A et al. (2001). High resolution SPECT in small
of commercial attenuation compensation techniques in animal research. Rev Neurosci 12: 187–193.
cardiac SPECT using phantom models. J Nucl Cardiol 9: Zaidi H, Koral K (2006). Scatter correction strategies in
361–376. emission tomography. In: Zaidi H, ed. Quantitative
Ogawa K et al. (1994). Accurate scatter correction in single Analysis in Nuclear Medicine Imaging. New York:
photon emission CT. Ann Nucl Med Sci 7: 145–150. Springer, 205–235.
Patton JA et al. (2007). Recent technologic advances in
nuclear cardiology. J Nucl Cardiol 14: 501–513.
Pichler BJ, Ziegler SI (2004). Photodetectors. In: Wernick
MN, Aarsvold JN, eds. Emission Tomography: The Fund- Further reading
amentals of SPECT and PET. San Diego, CA: Elsevier.
Rowland DJ, Cherry SR (2008). Small-animal preclinical Wernick MN, Aarsvold JN, eds. (2004). Emission
nuclear medicine instrumentation and methodology. Tomography: The Fundamentals of SPECT and PET.
Semin Nucl Med 38: 209–222. San Diego, CA: Elsevier.
Shao Y et al. (1997). Simultaneous PET and MR imaging. Zaidi H, ed. (2006). Quantitative Analysis in Nuclear
Phys Med Biol 42: 1965–1970. Medicine Imaging. New York: Springer.
Sampson's Textbook of Radiopharmacy
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Sampson's Textbook of Radiopharmacy
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6
Production of radionuclides
Steve McQuarrie

Introduction 73 Nuclear reactors 81

Nuclear reactions 73 Conclusion 83

Cyclotrons 77

Introduction radionuclides will be discussed in this chapter; a nuclear

reactor in which a neutron is used to initiate the required
No textbook on radiopharmacy would be complete nuclear reaction, and a cyclotron in which a charged
without a chapter on alchemy. This chapter is where particle such as a proton is added into a nucleus, trans-
the reader will find information on the conversion of forming it into the desired radioactive product.
one element into another and where the ‘radio’ part of The material in this chapter should provide sufficient
radiopharmacy comes from. Although one of alchemy’s information for the radiopharmaceutical scientist to:
best known goals was the transmutation of lead into * understand the principles of nuclear transformation
gold, it was the discovery of radioactivity by Becquerel * understand and work with equations that can be
in 1896 and the Curies in 1898 and Ernest Rutherford’s used to determine how much of a radionuclide can
series of experiments on radioactivity in 1911 that led be produced
to the realisation that elements could be transmuted. In * understand the principles of cyclotron operation
1919 Rutherford managed to bombard a nitrogen as they apply to radionuclide production
nucleus with an alpha (a-)particle (from radon), trans- * evaluate the specifications of a cyclotron in order
forming it into a nucleus of oxygen followed by the to select the most appropriate one for their
emission of a proton (Rutherford 1919). The dream anticipated needs
of medieval alchemists, the transmutation of the chem- * understand the principles of radionuclide
ical elements, had finally been achieved. production in a nuclear reactor and
The key to producing radioactive elements, or radio- * understand and evaluate some of the confounding
nuclides, is to find a mechanism for altering the nucleus issues related to radionuclide production in both a
of an atom to make it unstable. Through the process of nuclear reactor and a cyclotron.
radioactive decay, the radionuclide returns to a stable
form, and it is this process of decay that allows the Nuclear reactions
radiopharmaceutical scientist to visualise the location
of the radionuclide (and hopefully, the molecule to The production of fluorine-18 (18F) by a cyclotron
which it is attached). Two methods for producing will be used as an example, in which a proton is
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74 | Physics applied to radiopharmacy

introduced into the nucleus of the non-radioactive Example 1

element oxygen-18 (18O). This nuclear reaction is In the case 18O(p, n)18F, the Coulomb barrier is
typically written in short hand as 18O(p, n)18F which
1:2  8  1
may be translated as: B¼ MeV
ð181=3 þ 11=3 Þ ð6:3Þ
target atomðincoming particle; B ¼ 2:65 MeV
outgoing particleÞproduct atom
However, nuclear reactions can take place for proton
18
Several factors dictate how much F can be pro- energies below this value due to an effect known as
duced from 18O and these include the number of target quantum mechanical tunnelling (Heyde 2004).
atoms, the number of protons, the energy of the pro- A second effect that relates proton energy to the
ton, and the probability of occurrence of the desired likelihood of a particular nuclear reaction occurring is
nuclear reaction. the conservation of energy. In any nuclear reaction, the
Based on the relationship between the proton total energy must be conserved, which means that
energy and the production cross-section described the total energy, including the rest mass of the starting
below, it is important to select a proton energy products (18O and p) must equal the total energy,
that will maximise the production of the desired including the rest mass of the final products (18F and
product while avoiding the production of un- n). The observed change in energy is called the Q-value
wanted contaminants. However, other factors must and its value may be positive or negative. If the sum of
be considered when selecting the energy of the the rest masses of the starting products exceeds that
bombarding particle. The first is based on the fact of the rest masses of the final products, the Q-value
that both the bombarding particle (proton) and of the reaction is positive, with the decrease in rest
the target nucleus (18O) are positively charged, mass being converted into a gain in kinetic energy.
so that the incoming particle must have sufficient The mass deficit energy equivalent Q is given by:
energy to overcome this electrostatic repulsion or Q ðMeVÞ ¼ 931:494 043 DM ð6:4Þ
Coulomb barrier. The Coulomb barrier is related
to the charge of the two particles and is given by where
the equation: DM ¼ ðmb þ MT Þ  ðme þ Mp Þ amu ð6:5Þ

Zze;2 and mb is the bombarding particle mass, MT is the

B¼ ð6:1Þ target mass, MP is the product mass, me is the emitted
4pe0 R
particle mass.
where B ¼ the Coulomb barrier for the reaction, If Q < 0 the reaction is endoergic; conversely,
Z ¼ the atomic number of the target, z ¼ the atomic if Q > 0 the reaction is exoergic. If the reaction is
number of the bombarding particle, e ¼ the elemen- endoergic, then sufficient energy must be added to
tary charge (1.6  1019 C), e0 ¼ the permittivity of the nuclear reaction in an amount greater than the
free space (8.854  1012 C2 N1 m2), and R ¼ the Q-value. The threshold for an endoergic nuclear reac-
distance between the charges (m). tion will then be the Coulomb barrier energy plus the
The distance between the charges (R) can be esti- Q-value. If the reaction is exoergic, energy is released
mated from the experimentally determined nuclear as a result of the nuclear reaction and the threshold
radius hR0 (a1/3)i, where R0 ¼ 1.2  1015 m, so that energy will be just that of the Coulomb barrier.
R ¼ R0(A1/3 þ a1/3) where A ¼ the mass number of the
Example 2
target and a ¼ mass number of the bombarding parti-
Calculation of the Q-value for the 18O(p, n)18F reac-
cle. The conversion from joules to MeV is
tion (data from NNDC 2003a and NIST 2010) using
1 J ¼ 6.24  1012 MeV. Equation (6.1) can then be
simplified as: mb ¼ 1.007 825 032 amu
MT ¼ 17.999 160 4 amu
1:2 Zz MP ¼ 18.000 937 7 amu
B¼ MeV ð6:2Þ
ðA1=3 þ a1=3 Þ me ¼ 1.008 664 915 60 amu
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Production of radionuclides | 75

Using the expanded form of equation (6.4): The nuclear cross-section may be described as
the probability that the desired nuclear reaction
Q ðMeVÞ ¼ 931:494 043 ½ðmb þ MT Þ  ðme þ Mp Þ
will occur. If one visualises a proton as a sphere
¼ 931:494 043 ð19:006 985 43  19:009 602 62Þ
and the 18O nucleus as another sphere, then it is
¼  2:44 MeV possible to imagine that a nuclear reaction can only
ð6:6Þ occur if these two spheres overlap. Once this hap-
pens, an intermediate nucleus comes into existence
A service offered by the National Nuclear Data
that has the mass of the target nucleus plus the mass
Center at Brookhaven National Laboratory provides
of the bombarding particle. This intermediate
an interactive online estimate of Q-values (NNDC
nucleus or compound nucleus exists as an excited
2003b).
nucleus that can decay in a variety of ways; in this
The threshold energy for the 18O(p, n)18F nu-
example, through the emission of a neutron. This
clear reaction is made up of both the Coulomb
whole process occurs over a very short time and
barrier (2.65 MeV) and, because this reaction is
appears instantaneous to the observer. This prob-
endoergic, the Q-value (2.44 MeV), which must also
ability is expressed in units of barns, where 1 barn
be taken into account. The bombarding proton
¼ 1  1024 cm2. This expression arose from the
should then be at least 5.1 MeV in order for this
fact that the probability for the proton to interact
reaction to be energetically possible. However, due
with the 18O atom is proportional to the cross-sec-
to quantum mechanical tunnelling through the
tional area of its nucleus, which when compared to
Coulomb barrier, this energy requirement is lower
the size of the proton, appeared ‘as big as a barn’. In
and the accepted value for the threshold energy is
the case of the 18O(p, n)18F reaction, the maximum
2.574 MeV (NNDC 2003b). For a more comprehen-
cross-section is about 500 mb or 0.5  1024 cm2
sive description of the nuclear reaction thres-
(Figure 6.1). The peaks in this figure represent an
hold, including a discussion on the conservation of
increased likelihood of 18F formation at a particu-
momentum, the reader is referred to the introductory
lar energy but the overall production yield is
book by Heyde (2004).
related to the area under this curve when integra-
ted from the maximum energy of the proton enter-
Yield of a nuclear reaction
ing the 18O target to the reaction threshold
This section illustrates the methodology used to (2.574 MeV). In order to estimate the amount of
18
determine the amount of a radionuclide that can be F that can be made, the following series of equa-
produced. An equation will be developed that will tions are introduced to illustrate the important
permit the user to estimate the yield of a nuclear considerations when designing a particular pro-
reaction; the production of 18F via the 18O(p, n)18F duction scheme. These will then be simplified in
reaction will again be used to illustrate the applica- order to make them more accessible for radiophar-
tion of this equation. maceutical applications.

18
600.0 O(p,n)18F

500.0
Cross-section(mb)

400.0

300.0

200.0

100.0

0.0
0.0 5.0 10.0 15.0 20.0 25.0 30.0 35.0
Energy (MeV)

Figure 6.1 Cross-section for the 18O(p,n)18F reaction. (Data from IAEA-1.)
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76 | Physics applied to radiopharmacy

The rate of production for a radionuclide depends l ¼ the decay constant of the product; and
on several factors including the nuclear reaction N ¼ the number of radioactive nuclei produced in
cross-section (a function of bombarding particle the target.
energy), the energy of the bombarding particle, the To simply this relation and make it more generally
number of bombarding particles and the thickness of usable, equation (6.8) will be modified to:
the target (number of target atoms). The rate of pro-
duction (R) is expressed by: Y EOB ¼ ASAT Ið1  e  lt Þ ð6:9Þ

ZE0 The term I in equation (6.9) represents the num-

sðEÞ ber of bombarding particles (protons) in the produc-
R ¼ nt I dE ð6:7Þ
dE=dx tion equation and, for the purposes of this equation
Ef
is measured as beam current in microamperes (mA).
where R ¼ the number of nuclei (18F) formed per sec- ASAT represents the maximum amount of activity
ond; nt ¼ the number of target atoms (18O) in nuclei that could be produced if you irradiated the target
per cm2; I ¼ the bombarding particle flux (p) per sec- forever; in practice irradiating a target for 3 half-
ond and is related to beam current; s(E) ¼ the reaction lives will produce 87.5% of this maximum. ASAT is
cross-section, or probability of interaction, expressed obtained by the integration of equation (6.7) over the
in cm2, and is a function of energy (see Figure 6.1); energy range experienced by the proton as it loses
E ¼ the energy of the bombarding particles; x ¼ the energy during its pass through the target. Rather
distance travelled by the bombarding particle; the than performing this integration, its value can be
integration is carried out from the initial energy (E0) read off a graph (or table) that has been previously
to the final energy (Ef) of the bombarding particle calculated. (For 18O(p,n)18F see http://www-nds.
along its path through the target atoms; and dE ¼ the iaea.or.at/medical/o8p18f0.html.) The relevant data
differential loss in energy and dx ¼ the differential for the 18O(p, n)18F reaction are shown Figure 6.2.
distance travelled by the particle. The final term (1  elt) is often referred to as the
However, when radionuclides are made, they are saturation factor and accounts for the fact that while
also decaying. This leads to a modification of equation the radionuclide is being produced, it is also decay-
(6.7) to include a decay term (lN) so that the overall ing away.
rate of production is given by: Going back to our example for the production
ZE0 of 18F, a sample calculation will be performed to
sðEÞ calculate the amount of 18F that can be made from
AðtÞ ¼ nt I dE  lN ð6:8Þ
dE=dx irradiating 95% enriched 18O-water using 50 mA of
Ef
16 MeV protons. Assumptions are that all of the
where A(t) ¼ the activity at time t; t ¼ the time since protons are stopped within the water target and the
the start of bombardment or irradiation time; irradiation time is 1 hour. Use equation (6.9) to

18
20.0 O(p,n)18F

16.0
Yield (GBq/µA)

12.0

8.0

4.0

0.0
0.0 5.0 10.0 15.0 20.0 25.0 30.0 35.0
Energy (MeV)

Figure 6.2 Yield (in GBq/mA) calculated from the recommended cross-sections for the 18O(p,n)18F reaction. (Data from IAEA-2.)
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Production of radionuclides | 77

calculate the yield, where ASAT ¼ 12.8 GBq/mA (from Cyclotrons

IAEA-2), I ¼ 50 mA, l ¼ ln 2/(half-life 18F) ¼ 0.693/
110 minutes ¼ 0.0063 min1. In the previous section we saw the necessity for a
 0:006360 source of high-energy charged particles that are
Y EOB ¼ 12:8 GBq=mA50 mA ð1  e Þ
¼ 201 GBq required to initiate the nuclear reaction leading to
the desired radionuclide. These particles are raised to
(Note: the exponent must be dimensionless – use the the appropriate energy by causing them to travel at
same time units for both l and t.) very high speeds and they are then smashed into a
To take into account that the target is only target nucleus with enough energy to transform it,
95% enriched in 18O, the answer must be multi- typically into the desired radioactive nucleus. The
plied by 0.95, yielding 191 GBq. The 5% 16O in machines that perform this feat are collectively known
the target material will lead to a radioactive con- as particle accelerators and all particle accelerators
taminant 13N via the 16O(p,a)13N reaction. This operate on the principle of the interaction between
radionuclidic impurity is generally not an issue electrical charges. Like charges repel each other and
because (1) it decays away with a shorter half-life unlike charges attract. As most radionuclides produc-
(10 minutes) and (2) subsequent radiochemical trap- ed for medical applications use cyclotrons to provide
ping and syntheses are designed for fluorine chem- the high-energy bombarding particles, the following
istry so that 13N will not be incorporated into the discussion will focus on their design and operation.
final radiopharmaceutical. A cyclotron operates on the principle of the attrac-
Some of the commonly used radionuclides are tion and repulsion of charged particles. A simplified
listed in Table 6.1, including their half-lives and the depiction of a cyclotron will be used to illustrate the
usual nuclear reactions used in their production. basic principles behind its operation using a proton as
Note that when 123I is produced from 124Xe, this is a the accelerated bombarding particle. The acceleration
multistage reaction in which first 123Xe is made and of the proton takes place inside the cyclotron where
collected followed by its decay into 123I, the desired the accelerating force is generated by the cyclotron
product. Ease of recovery and separation from other ‘dees’ (Ds) (Figure 6.3). Imagine a proton that has been
unwanted radioisotopes of iodine are the main advan- introduced into the middle of the cyclotron and that
tages of this production route. one of the dees is positively charged and the other
A discussion of the source of bombarding protons negatively charged. The positively (or negatively)
and a short review of the physical aspects of the target charged proton will be attracted to the oppositely
environment appear in the next section. charged dee and repelled from the like-charged dee,

Table 6.1 Common radionuclides produced by charged-particle accelerators

Radionuclide Half-life Production Radionuclide Half-life Production

reaction reaction

11 14 64 64
C 20.3 min N(p,a) Cu 12.7 h Ni(p,n)
64
Zn(a,2n)

13 16 86 86
N 9.97 min O(p,a) Y 14.7 h Sr(p,n)

15 15 123 123
O 2.03 min N(p,n) I 13.2 h Te(p,n)
14 124
N(d,2n) Xe(p,pn)
! 123Xe
! 123I

18 18 124 124
F 110 min O(p,n) I 4.2 d Te(p,n)
nat
Ne(d,a)

d, day; h, hour; min, minute.

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78 | Physics applied to radiopharmacy

Electromagnet
(north pole)

Acceleration gap

Hollow electrode
chambers

Particle’s path
Charged particle

Target

Alternating
Electromagnet current source
(south pole)

Figure 6.3 Schematic diagram of a cyclotron illustrating a simplified dee structure (shown as hollow electrode chambers). The
magnetic field is in the vertical plane to the circulating particles.

during which the proton will gain energy. If this pro- and used a potential of 1800 volts to accelerate hydro-
cess is repeated many times, the proton will gain the gen ions up to energies of 80 000 electronvolts (eV). In
necessary energy to cause the nuclear reaction. summer 1931 they built an 11-inch (28 cm) cyclo-
The energy gained from each push/pull is related to tron that achieved particle energy of a million electron-
the magnitude of the electric charge on each of the dees volts. Ernest Lawrence was awarded the 1939 Nobel
and the charge of the accelerated particle. However, Prize in Physics ‘for the invention and development of
the accelerated proton will travel in a straight line the cyclotron and for results obtained with it, espe-
and would exit the cyclotron after only one push/pull cially with regard to artificial radioactive elements’.
cycle, in this case not having gained enough energy to The modern cyclotrons used for the production of
cause a nuclear reaction. medically useful radionuclides are based on these same
Ernest Lawrence came to the rescue to solve this design principles and today produce proton beams
dilemma when, in 1929 after reading about the work with energies that typically range from 10 to 19 mil-
of a Norwegian engineer, Rolf Wider€ oe (Waloschek lion electronvolts (MeV).
2002), Lawrence was inspired to think about how How does it all work? A brief description of the
one could use the same accelerating potential multiple acceleration process is given next in order to pro-
times instead of just once. He solved this problem vide an understanding of another critical aspect of a
when he realised that in order for this acceleration cyclotron: the radiofrequency field used to push/pull
process to continue, the proton must be bent within the protons around the inside of the cyclotron.
the cyclotron in order to experience another round of Lawrence realised that if a constant accelerating volt-
acceleration. Lawrence thought to use a magnetic field age were used on the dees then the acceleration pro-
to force the proton into a circular path, leading it cess would stop after one period when the positively
through the dees many times until it had reached the charged proton approached the positively charged
appropriate energy to cause a nuclear reaction. dee (and was repelled instead of experiencing further
Lawrence started construction on his cyclotron in acceleration). He realised that the push/pull force
early 1930, and in January 1931 Lawrence and his exerted by the dees must be timed such that as the
graduate student, M. Stanley Livingston met with their protons cross the space between the dees, the acceler-
first success (Lawrence, Livingston 1932). The first ating potential will change in a manner to keep the
cyclotron was about 4.5 inches (11.5 cm) in diameter acceleration process going. A radiofrequency field is
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Production of radionuclides | 79

used to provide this ever-changing push/pull on the so that it can be steered and focused by electric and
proton and is timed to provide the appropriate accel- magnetic fields (remember that it is possible to con-
eration across the dee gap where the acceleration takes trol the path of particles if they are electrically
place. A typical value of the dee voltage is 50 kV so that charged). In the case of negative-ion cyclotrons (the
the proton would receive 2  50 kV ¼ 100 kV of accel- most common type used for radionuclide produc-
eration push/pull per orbit. For the proton to reach an tion), the hydrogen molecule is converted into
energy of 16 MeV under these conditions, the proton atomic hydrogen and the atoms are given a second
would stay in the cyclotron for 160 orbits. electron by streaming the gas through an electron
This acceleration process takes place in high vac- beam, perpendicular to the flow of gas. The two
uum so that the protons being accelerated will not common types of ion sources used to produce pro-
collide with gas molecules inside the cyclotron, which tons for a cyclotron are the hot filament Penning ion
would prevent their further acceleration and ulti- gauge (PIG) type (Rickey, Smythe 1962) and the cusp
mately remove their potential to produce radionu- type (Leung et al. 1983).
clides. Cyclotrons typically operate under vacuum The second step involves removing the protons
conditions in the range of 1  106 torr, where from the ion source and directing them into the cyclo-
1 torr ¼ 1 mmHg ¼ 133.322 Pa. tron so that they can be accelerated to the appropriate
Once the proton has reached the appropriate energy. In the case of an external ion source, the pro-
energy it is usually steered out of the cyclotron tons enter in at right angles to the accelerating region
towards the target where the radionuclide is to be of the cyclotron, and must be bent into the plane of
produced, such as an 18O target for the production of acceleration and then given a push to get them moving
18
F. As negative-ion cyclotrons are commonly used in the right direction. Conceptually this is similar to a
for the production of medical radionuclides, the child sliding down a circular slide; their vertical
extraction process for this type of cyclotron will be potential energy at the top of the slide is converted
briefly discussed. The negatively charged ions (H into horizontal velocity at the bottom of the slide
atoms with 2 electrons) are constrained by the mag- (Figure 6.4). Once the proton enters the gap between
netic field to move in a circular path within the the dees, it is accelerated as described above. A high
cyclotron; however, if the negatively charged ions capacity vacuum pump in the ion source removes the
were to become positively charged, the magnet field uncharged gas, and helps maintain the high vacuum in
would have the reverse effect and cause the ions to the cyclotron.
bend in the opposite direction and be steered out of Inside the cyclotron target is where all the ac-
the cyclotron. These electrons are removed by pass- tion takes place. It is here that the transmutation
ing the ion beam through a very thin carbon foil, process manifests itself, where the target atoms are
leaving only the positively charged protons. After transformed into the desired radionuclides. If we
the protons leave the cyclotron, they are directed to
the target where the appropriate nuclear reactions
are initiated to produce the required radioactive pro-
ducts (such as 18F).
How one gets the protons into the cyclotron in
such a manner that leads to their efficient accelera-
tion is a problem whose solution is a closely guarded
secret of the major cyclotron manufacturers. In many
cases this is a two-step process, the first being the
production of protons from hydrogen gas, followed
Figure 6.4 The drawing on the left illustrates a proton (·)
by an extraction process in which the protons are entering from the top and being electromagnetically
directed into the cyclotron. In general terms the steered into horizontal plane where it can be accelerated by
source of protons is provided by hydrogen gas that the dees. The schematic diagram of a slide on the right
is ‘leaked’ into the high vacuum environment of the shows a proton sliding down to illustrate this change in
cyclotron. This hydrogen must first be given a charge direction process.
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80 | Physics applied to radiopharmacy

understand that the purpose of a cyclotron target is to the energy loss to the proton passing through it;
ensure that the conditions for the required nuclear these foils are usually cooled with helium gas.
reaction are optimal, then the following conditions Because of its high tensile strength, a metal alloy
must be met. The target body housing the target atoms known as Havar is usually used to make these thin
should be designed to keep the target atoms in the foils. Some targets may also have a target foil (B)
proton beam during irradiation and facilitate the to separate the target material from the helium foil
removal of the radioactive products at the end of bom- cooling subsystem.
bardment. The target body should be constructed from * The target body holds the target atoms in such a
a material that will not react with either the target way as to maximise the production and recovery
atoms or the resulting radionuclide(s) that are pro- of both the target material and the radionuclide.
duced. The target body should be capable of with- The target body must also be electrically isolated
standing the expected increase in temperature and to permit assessment of the number of protons
pressure experienced during irradiation. For example, entering the target (the beam current). This
if a 15 MeV proton beam at 100 mA was absorbed in parameter is used to optimise radionuclide
the target, this would impart heat energy at a rate of production and to estimate to amount of the
about 1.5 kW. Thus, efficient cooling of the target is radionuclide being made.
mandatory to prevent molecular dispersion in gas tar- * The recovery system is designed to remotely load
gets, liquid targets from boiling away, or solid targets and unload the targets for radiation safety
from melting; all these processes tend to remove the considerations and to efficiently recover the
target atoms from the proton beam and hence nega- sometimes expensive enriched target material.
tively impact production yield. The recovery system is frequently connected
A schematic diagram of a cyclotron target used to directly to automated chemistry modules that
produce 18F is shown in Figure 6.5. Several compo- are used to manufacture radiopharmaceuticals
nents illustrated in this figure are common to most and at the same time recover the enriched
external targets: target atoms.

* The vacuum foil (A) is used to separate the high When making 18F from an 18O-water target, each
vacuum in the cyclotron from the pressure inside of the above considerations must be taken into
the target. Design considerations usually demand account. Target bodies have been made from materials
that this foil be made as thin as possible to reduce such as aluminium, silver, niobium and tantalum, each

C E
18
O target water
High vacuum
inside G
Target body housing

Proton beam
A B
Entrance foil assembly

D H

Figure 6.5 Schematic of an 18O-water target used to produce 18F; where A and B are the vacuum and target entrance foils,
C and D are the helium cooling ports for the foils, E and H are the enriched water loading and unloading ports, respectively. G is
the reflux headspace on top of the water target.
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Production of radionuclides | 81

with its own advantages and disadvantages. Silver is Neutron

a good choice for heat removal, but the target body

requires more maintenance to remove chemical con-
taminants that can affect downstream chemistry.
Target
Niobium and tantalum are more inert and require nucleus
much less maintenance but do not remove the heat
produced during irradiation as efficiently. Most mod-
ern water targets for 18F now use niobium targets as
adequate heat removal can be achieved with high-flow Neutron Neutron
water cooling. Note that all water targets use the in-
target boiling/reflux method to optimise heat removal
from the target (Berridge, Kjellstrom 1988) (G Fission Fission
product product
in Figure 6.5).
Another consideration that may impact on subse-
Neutron
quent radiopharmaceutical labelling of bioactive com-
pounds is that of chemical contaminants produced in Figure 6.6 Schematic diagram of nuclear fission.
the cyclotron target. For example, during the produc-
tion of 18F in an 18O-water target, the formation of
water-soluble contaminants has been observed, which their yield and some considerations on sample prepa-
affected the reactivity of 18F and resulted in a decrease ration are presented.
in labelling yield of radiopharmaceuticals (Kilbourn Nuclear reactors operate on the principle of
et al. 1985; Solin et al. 1988). In the last few years, nuclear fission (see Atomic Archive 2008), a process
refractory metals such as niobium and tantalum have in which a fissionable nucleus such as 235U is split
been the materials of choice for chamber targets for the into two smaller fragments resulting in the release
irradiation of aqueous targets. The use of these metals of energy and 2 or 3 additional neutrons. This pro-
has lengthened the maintenance interval of targets cess is illustrated schematically in Figure 6.6. The
without sacrificing the reactivity of fluoride (Zeisler resulting neutrons from this process can be used to
et al. 2000; Berridge et al. 2002; Satyamurthy et al. initiate another nuclear reaction leading to the
2002). Although entrance foils of these materials desired product, generally by the (n, g) reaction.
would be also favourable for the production of fluo- The other route used to obtain radionuclides from
ride, the materials’ weak mechanical properties limit a nuclear reactor is based on the creation of radio-
their use as foils, making them unsuitable for the rou- active fission products during the fission process
tine production of 18F under pressurised conditions. (Figure 6.6). Both production methods, with
One solution is the use of niobium-coated Havar foils selected examples will be reviewed in the following
for the production of reactive fluoride under high- sections.
power irradiation conditions (Wilson et al. 2008).
These foils combine the robust mechanical properties
(n,g) Production
of Havar with the excellent chemical inertness of
niobium. The neutrons produced from the fission process yield
on average about 2.3 neutrons per event. These neu-
trons are emitted over a large energy range; however, it
Nuclear reactors is the very low-energy neutrons, known as thermal
neutrons, which are most commonly used for this type
Another method routinely used to produce radionu- of radionuclide production.
clides for the radiopharmaceutical sciences uses neu- In addition to keeping the chain reaction going in
trons from a nuclear reactor to initiate the appropriate the nuclear reactor, some of these thermal neutrons
nuclear reaction. In this section a review of the pro- are used to produce radionuclides. In a manner anal-
duction nuclear reactions, equations used to estimate ogous to that of charged particle production, a
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82 | Physics applied to radiopharmacy

neutron (instead of a proton) is inserted into the bombarding particles, in this case neutrons. Similarly
target nucleus to create a radioisotope; this process to the argument developed for protons, the neutron
most often results in the emission of a gamma (g-) cross-section varies with the energy of the neutrons. In
ray. This (n,g) reaction is also commonly referred to general, a slower-moving neutron has a greater prob-
as radiative capture. For example, a common radio- ability of causing the desired nuclear reaction. These
nuclide produced by the (n,g) reaction is: slow-moving neutrons are called thermal neutrons.
The other difference when using neutrons to initiate
59
Coðn; gÞ60 Co ðs ¼ 36 barnsÞ the nuclear transformation is that there is no coulomb
Note that the product radionuclide is an isotope of barrier to overcome.
the target element itself and hence cannot be chemi- Owing to the many confounding factors involved
cally separated. Therefore, the specific activity is in the production of radionuclides using a nuclear
limited by the neutron flux available in the reactor. reactor, only an estimate of the desired radionuclide
A special case of the (n,g) reaction can be used in yield (Y) will be presented (equation 6.10).
which a short-lived intermediate radionuclide is pro- Y ¼ Nfsð1  e  lt Þ ð6:10Þ
duced which then decays into the desired product. An
where N ¼ the total number of atoms present in the
example of this is the production of 131I through the
target; w ¼ the neutron flux in neutrons cm2 s1; s ¼
irradiation of 130Te. The simplified reaction equation
the cross-section in cm2; t ¼ time in seconds from the
is:
start of irradiation; and (1  elt) is the decay term.
130
Teðn; gÞ131 Te; and then 131
Te ! 131 Iþb  Equation (6.10) illustrates that, for a constant tar-
get size, the main factor affecting the yield of a radio-
In this case, the product can be chemically separated
nuclide is the neutron flux, where typical neutron
from the target as it is a different element from the
fluxes are around 1014 neutrons cm2 s1.
starting material (Te). This two-stage method has
In practice, the activity induced in the target under
the potential of producing carrier-free 131I, lead-
irradiation will be less than the activity calculated
ing to the added benefit of high-specific-activity
using equation (6.10). Some of the main confounding
radiopharmaceuticals. Table 6.2 lists some com-
factors are summarised below.
monly used radionuclides in the radiopharmaceuti-
cal sciences that are produced in a nuclear reactor. * The self-shielding effect in the target.
Self-shielding will reduce the product yield when
the target has a high activation cross-section (s)
Yield calculations
and the geometry of the target material is such that
As developed above, the probability of the desired target nuclei in the centre of the sample experience
radionuclide being formed is governed by the cross- a reduced neutron flux due to neutron absorption
section, the number of target nuclei and the number of by the outer layer of target material.

Table 6.2 Common radionuclides produced in a nuclear reactor

Radionuclide Half-life Production Radionuclide Half-life Production

reaction reaction

3
H 12.3 y 6
Li(n,a) 131
I 8.0 d 130
Te(n,g)131Te !
131
I
or 235U(n,f)

14 14 133 35
C 5730 y N(n,p) Xe 5.3 d U(n,f)

99 98 137 35
Mo 66 h Mo(n,g) Cs 30.0 y U(n,f)
or 235U(n,f)

a ¼ alpha particle, n ¼ neutron, p ¼ proton, g ¼ gamma ray, f ¼ fission.

y, year; d, day; h, hour.
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Production of radionuclides | 83

* There is generally a variation in the neutron flux Encapsulation of the target material must take into
(w) in the reactor, either due to core design or the account the physical parameters that exist in the high
effect of neighbouring samples. neutron flux in the special sample ports in the reactor
* Transformation of the product due to subsequent core. The target material is encapsulated inside a con-
neutron capture, particularly if this subsequent tainer that will maintain an appropriate environment
transformation has a high thermal neutron for the sample during irradiation; not only must it
cross-section. This burn-up (or conversion to the provide for physical containment of the sample during
product radionuclide) of the target nuclei may be a irradiation using a leak-tight seal but the capsule
problem for the longer irradiation times of targets should also be chemically inert and easily cooled.
with high activation cross-sections, such as in Post-irradiation considerations include use of a con-
the production of 60Co. Irradiation times may be tainer that does not become radioactive and is
as long as 3 years. designed to facilitate handling of intensely radioactive
targets.
The amount of activity actually produced in the
Common containers are made from aluminium,
target compared with the activity calculated using
Zircaloy and stainless steel. Aluminium is a popular
equation (6.10) depends on the cumulative effects of
choice because it has a low absorption cross-section
the confounding factors referred to above. The exper-
for neutrons, and the radionuclides produced in alu-
imental yield should be empirically determined by a
minium are very short lived and contribute little to the
test irradiation.
radiation field from the irradiated target material.
Aluminium also has good thermal conductivity, so
Fission production that heat produced within the target is easily trans-
ferred to the coolant system.
The other source of radionuclides arises from proces- One of the advantages of radionuclide pro-
sing the fission products of 235U. These fission pro- duction using a nuclear reactor is the ability to irra-
ducts fall into two groups, one light group with mass diate large volumes of target material in multiple
number around 95 and a heavy group with mass num- irradiation sites. This leads to the production of large
ber around 140. Analogously to the production of 131I amounts of the radionuclide and, as the production
presented above, some fission products undergo suc- of other radionuclides is possible in the other sites
cessive decays, leading to production of the desired within the reactor, the simultaneous production of
product via a fission-initiated decay chain. Some many different radionuclides is routinely achieved.
important fission products that have found wide- This unique aspect of reactor production has led to
spread use in radiopharmacy are 90Sr, 99Mo and 131I. the economic production of this class of radio-
Both 90Sr and 99Mo are used in the generator systems nuclides and their subsequent adoption as medical
to produce 90Y and 99mTc, respectively. These gener- and industrial tracers.
ator systems and their principles of operation are
described elsewhere in this book.
Conclusion
Sample preparation
This chapter has presented information that should
The target material should be selected to maximise the be sufficient to allow the radiopharmacist to under-
production of the desired radionuclide and may stand the basic concepts of how artificial radionu-
include enriched isotopes to reduce unwanted radio- clides are produced. This information, coupled with
nuclidic impurities. Selection of the physical form of the resource material from other chapters, should
the target should be based on optimising sample cool- assist the radiopharmacist in the design of radio-
ing and reducing neutron self-absorption effects while pharmaceutical synthesis methods and their ultimate
facilitating post-irradiation handling. Under irradia- use as tracers for better understanding of human
tion conditions, the target material should be stable physiology at the molecular level, in both healthy
and not explosive, pyrophoric, or volatile in nature. and disease states.
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84 | Physics applied to radiopharmacy

NNDC (2003a). Atomic Mass Adjustment. Upton, NY:

References National Nuclear Data Center, Brookhaven National
Laboratory. http://www.nndc.bnl.gov/amdc/masstables/
Atomic Archive (2008). Nuclear Fission: Basics. http://www. Ame2003/mass.mas03 (accessed 11 May 2010).
atomicarchive.com/Fission/Fission1.shtml (accessed 11 NNDC (2003b). Q-value Calculator. Upton, NY: National
May 2010). Nuclear Data Center, Brookhaven National Labo-
Berridge MS, Kjellstrom R (1988). Fluorine-18 production: ratory. http://www.nndc.bnl.gov/qcalc/ (accessed 28 June
new designs for [18O] water targets. J Labelled Comp 2010).
Radiopharm 26: 188. Rickey M E, R Smythe R (1962). The acceleration and extrac-
Berridge MS, Voelker KW et al. (2002). High-yield, low tion of negative ions in the C.U. cyclotron. Nucl Instrum
pressure [18O]water targets of titanium and niobium for Methods 18–19: 66–69. doi:10.1016/S0029-554X(62)
[18F] production on MC-17 cyclotrons. Appl Radiat Isot 80010-X.
57: 303–308. Rutherford E (1919). Collision of alpha particles with light
Heyde K (2004). Basic Ideas and Concepts in Nuclear Physics: atoms; an anomalous effect in nitrogen. The Philosophical
An Introductory Approach. Baton Rouge: CRC Press. Magazine 37(222): 537–587.
IAEA-1 (2003). Recommended Cross Sections for 18O(p,n)18F Satyamurthy N et al. (2002). Tantalum [18O]water target for
reaction. http://www-nds.iaea.or.at/medical/o8p18f0.html the production of [18F]fluoride with high reactivity for the
(accessed 11 May 2010). preparation of 2-deoxy-2-[18F]fluoro-D-glucose. Mol
IAEA-2 (1999). Charged-particle Cross Section Database for Imaging Biol 4: 65–70.
Medical Radioisotope Production. http://www-nds.iaea. Solin O et al. (1988). Production of [18F] from water targets.
or.at/medical/ (accessed 11 May 2010). Specific radioactivity and anionic contaminants. Appl
Kilbourn MR et al. (1985). An improved [18O]water target Radiat Isot 39: 1065–1071.
for [18F]fluoride production. Int J Appl Radiat Isot 36: Waloschek P, ed. (2002). The Infancy of Particle
327–328. Accelerators: Life and Work of Rolf Wider€ oe.
Lawrence EO, Livingston MS (1932). The production of high Braunschweig: Vieweg & Sohn/DESY-Report 94-039.
speed light ions without the use of high voltages. Phys Rev http://www.waloschek.de/pedro/pedro-texte/wid-e-2002.
40: 19–35. pdf (accessed 11 May 2010).
Leung KN et al. (1983). Extraction of volume produced H Wilson JS et al. (2008). Niobium sputtered havar foils for the
ions from a multicusp source. Rev Sci Instrum 54: 56–62. high power production of reactive [18F]fluoride by proton
NIST (2010). Atomic Weights and Isotopic Compositions irradiation of [18O]H2O targets. Appl Radiat Isot 66(5):
for All Elements. Gaithersburg, MD: National Institute 565–570.
of Standards and Technology. http://physics.nist.gov/cgi- Zeisler SK et al. (2000). A water-cooled spherical niobium
bin/Compositions/stand_alone.pl?ele¼&all¼all&ascii¼ target for the production of [18F]fluoride. Appl Radiat Isot
ascii&isotype¼all (accessed 11 May 2010). 53: 449–453.
Sampson's Textbook of Radiopharmacy
Section B Dated: 16/11/2010 At Time: 16:42:2

SECTION B
Radiopharmaceutical
chemistry
Sampson's Textbook of Radiopharmacy
Section B Dated: 16/11/2010 At Time: 16:42:2
Sampson's Textbook of Radiopharmacy
Chapter No. 7 Dated: 16/11/2010 At Time: 16:36:17

7
Radiopharmaceutical chemistry:
basic concepts
Philip J Blower

Introduction 87 Hydrophilic versus hydrophobic 91

Organic versus metallic 89 Metal complexes 92

PET versus single-photon imaging 90 Radionuclide survey of the periodic table 97

Introduction principles that underpin radiopharmaceutical chem-

istry, with reference to other texts and reviews to
A radiopharmaceutical is essentially a partnership provide background in specific areas as necessary.
between two components – a radionuclide providing It is followed by a more detailed exposition of the
the signal or cytotoxic effect, and a vehicle to deliver it chemistry of the key radionuclides.
selectively to a specific tissue in response to specific The challenge for the radiopharmaceutical chemist
physiological conditions or gene expression patterns. is not only to make imaginative use of these diverse
The useful radionuclides come from all parts of the chemical resources to incorporate a suitable radionu-
periodic table (see Figure 7.1), including the ‘organic’ clide into a suitable targeting vehicle (Blower 2006),
elements characterised by covalent bonding (carbon, but also to devise a methodology to make the synthesis
nitrogen, oxygen, phosphorus, sulfur, and the of the radiopharmaceutical feasible under the rather
halogens) and all the metallic groups and periods restrictive conditions imposed by the radioactivity
including both transition and non-transition elements itself and the regulatory environment associated with
(Blower 2006). The types of molecules or targeting the use of the materials in humans (Blower 2006).
entities are also very wide-ranging and non-exclusive: In the radiopharmaceutical ‘partnership’, the role
we may be dealing with a small organic molecule, a of the radionuclide in achieving selective, targeted
metal coordination complex, a polymer, a particulate delivery varies from peripheral to central. At one
or nanoparticulate material, a biomolecule such as a extreme, it may be merely a passenger with little influ-
protein, a peptide, a carbohydrate, a lipid, etc., or a ence on the targeting, as for example in bioconjugates
combination of any of these. Multiplying these two such as radiolabelled monoclonal antibodies
sources of diversity generates a field of enormous (Dearling, Pedley 2007; Goldenberg, Sharkey 2007).
breadth that cannot be covered fully in a specialist For the purposes of this chapter, this type of radio-
volume such as this. The purpose of this chapter is to pharmaceutical is referred to as ‘radionuclide-tagged’.
provide an overview of the general concepts and At the other extreme, the radionuclide may be part of a
 Chapter No. 7 Dated: 16/11/2010 At Time: 16:36:17
Sampson's Textbook of Radiopharmacy
88 | Radiopharmaceutical chemistry
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18
1 2
H He

3 4 5 6 7 8 9 10
Li Be B C N O F Ne
β+ β+ β+ β+
11 12 13 14 15 16 17 18
Na Mg Al Si P S Cl Ar
T
19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36
K Ca Sc Ti V Cr Mn Fe Co Ni Cu Zn Ga Ge As Se Br Kr
β+ β+ T γβ+ β+ γ β+ T γ
37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54
Rb Sr Y Zr Nb Mo Tc Ru Rh Pd Ag Cd In Sn Sb Te I Xe
β+ T T β+ γβ+ γ T γβ+T
55 56 57 72 73 74 75 76 77 78 79 80 81 82 83 84 85 86
Cs Ba La Hf Ta W Re Os Ir Pt Au Hg Tl Pb Bi Po At Rn
* T γ T T T
87 88 89
Fr Ra Ac
T †

57 58 59 60 61 62 63 64 65 66 67 68 69 70 71
* Lanthanides La Ce Pr Nd Pm Sm Eu Gd Tb Dy Ho Er Tm Yb Lu
T T T T
89 90 91 92 93 94 95 96 97 98 99 100 101 102 103
†Actinides Ac Th Pa U Np Pu Am Cm Bk Cf Es Fm Md No Lr
T

Figure 7.1 Periodic table showing main applications of radioisotopes. Useful radionuclides (shaded) are drawn from all sections of the periodic table. Some elements have
radionuclides useful for multiple applications: g – single-photon imaging; bþ – PET imaging; T – radionuclide therapy. Therapeutic nuclides may be beta, alpha or secondary electron
emitters, and may also give imageable emissions not shown.
Sampson's Textbook of Radiopharmacy
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Radiopharmaceutical chemistry: basic concepts | 89

H3C CH3
H3C
O H3C
N O CH3
H3C CH3
H3C C CH3
H3C N N CH3 O
C + C
O O Tc–
C
Tc
C N CH3 N N N N O
O
H3C N H3C CH3
Cu O
C CH3 N N
H3C H S S H
O N
H3C
CH3 O CH
3
(a) H3C CH3 (b) (c)

Figure 7.2 Examples of radionuclide-essential radiopharmaceuticals. (a) 99mTc-sestamibi: accumulation in mitochondria

in the heart is associated with its positive charge (provided by the Tcþ ion) and its lipophilicity (provided by the alkyl groups of the
ligands). (b) 64Cu-ATSM: the redox properties, lipophilicity and planar shape (all provided by the copper2þ ion/ligand combination)
are believed to govern its selective uptake in hypoxic cells (Vavere, Lewis 2007). (c) [99mTc]pertechnetate: accumulation in thyroid is
due to the similarity with iodide, by virtue of the monoanionic charge and the size and close-to-spherical symmetry of the ion,
making it a substrate of the thyroid sodium iodide symporter (Chung 2002; Lewis 2006).

construct whose targeting properties are intrinsic to, affects their labelling chemistry. Those elements famil-
and dependent on, the chemistry of the inorganic iar in organic chemistry form single or multiple cova-
radioactive element itself. Such radiopharmaceuticals lent bonds (four for carbon, three for nitrogen, two for
are here referred to as ‘radionuclide-essential’. This is oxygen, one for hydrogen and halogens) that are kinet-
the case, for example, in the copper bis(thiosemicar- ically stable (e.g. to hydrolysis) and conform closely to
bazone) complexes for measuring blood flow and well-established rules governing bond numbers,
hypoxia (oxygen deficiency in tumours, heart disease, angles, etc. This allows us to visualise molecules as
etc.) by PET, where the redox activity of the copper is collections of atoms linked by well-defined covalent
the key to the targeting properties (Figure 7.2) bonds represented by lines in the conventional struc-
(Vavere, Lewis 2007). Other radiopharmaceuticals tural representation (e.g. as in Figure 7.2). Labelling
lie in between or have features of both. For example, with carbon-11, by replacing a carbon-12 atom in an
the radiolabel attached to a peptide radiopharm- organic molecule with no alteration at all to the native
aceutical (Signore et al. 2001; Win et al. 2007; De structure, is the ‘purest’ form of radiolabelling.
León-Rodrıguez, Kovacs 2008; Lucignani 2008) may Labelling of carbon-based molecules with halogen
not provide targeting but it may assist in other ways, radionuclides (group 17) usually involves slightly more
e.g. by altering excretion pathways or enhancing structural modification: halogen radionuclides are
stability against peptide degradation in vivo. typically incorporated into small organic molecules
and biomolecules by the formation of a single covalent
carbon–halogen bond, by replacement of a hydrogen
Organic versus metallic atom or other organic element in the native structure.
The change in structure is still relatively minor,
To understand and contribute to radiopharmaceutical although the modest change in size of the atoms and
chemistry across its full breadth one requires an appre- the dipoles of the bonds can have significant effects
ciation of basic organic and coordination chemistry as on the pharmacology (see Figure 7.3). By contrast,
well as biological chemistry, and it is beyond the scope metallic radionuclides are not restricted to formation
of this book to provide this background. The reader is of simple single covalent bonds, and cannot simply
referred to standard undergraduate-level organic, replace another atom in an organic molecule or
physical and inorganic chemistry text books for the biomolecule. Often the metal bonding cannot readily
necessary grounding. It is, however, worth drawing be represented by lines representing covalent bonds.
attention to the essential difference between the chem- The metal typically has to be surrounded by, and
istry of the organic and metallic radionuclides as it bonded to, several atoms or groups (known as ligands).
Sampson's Textbook of Radiopharmacy
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90 | Radiopharmaceutical chemistry

+
H2N NH2 H2N + NH2
OH
OH H
H NH NH
O HO O
HO OH OH
HO HO
F H OH
H H
I F

F F
OH I
(a) (b) (c) (d)

OH
HO O
HO OH
NH
O N
N + O
Tc
N O
O

(e)

Figure 7.3 Examples of structures of small-molecule radiopharmaceuticals, using space-filling representations to illustrate the
scale of modification to the molecules caused by introduction of the radiolabel. (a, b) 2-[18F]Fluoro-2-deoxyglucose (FDG, a), in
which an OH group in glucose (b) is replaced by fluoride, showing the comparable size of F and OH groups. (c, d) meta-[123I]
Iodobenzylguanidine (mIBG) and its 18F-labelled analogue, showing the relative size of I and F atoms. (e) Glucose conjugate of a
technetium tricarbonyl complex (Bowen, Orvig 2008), showing the overwhelming modification to glucose due to conjugation to
the technetium complex compared to F-labelling in (a).

The metal is most often formally positively the metal is intrinsic to the design and function. The
charged and the bonds are formed by donation of pairs modification is less significant if the molecule to be
of electrons by the ligands. Consequently, when a labelled is a larger molecule such as a peptide or
biological molecule is labelled with a metallic radio- a protein, and this is typically the setting in which
nuclide, the metal brings with it a retinue of ligands, metallic radionuclides are used.
usually chelating ligands in the form of bifunctional
chelators (see below; these are themselves usually
organic molecules), leading to a much larger and more PET versus single-photon imaging
significant structural alteration on labelling (Figure
7.3). The kinetic stability with which these ligands PET and SPECT rely on different nuclear decay phe-
are bound to the metal varies enormously between nomena leading to different detection and imaging
metals and types of ligands, and the oxidation state physics, and consequently each has commonly
(a formality defining the number of electrons discussed advantages and disadvantages in respect of
associated with the metal, and hence its charge) and resolution, sensitivity, quantification and so on (see
coordination number (the number of ligands the metal other chapters). However, a more fundamental compar-
prefers to bind) can vary, adding further to the ison arises from the chemical nature of the radionuclides
complexity of design. Metallic radionuclides are thus concerned. The most important positron emitters are
often not suitable for labelling small molecules unless grouped in the top right-hand corner of the periodic
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Radiopharmaceutical chemistry: basic concepts | 91

table – C, N, O, F, covalently bonding elements that, as and N, H and F) are highly polarised because electron
discussed above, are readily incorporated into small density is drawn towards the more electronegative
organic molecules like metabolites or drugs (Welch, atom. Thus these bonds are typically polarised with
Redvanly 2003; Schubiger et al. 2006). On the other an accumulation of negative charge at the oxygen,
hand, the most important gamma emitters are broadly nitrogen or fluorine. The dipole of one molecule is
speaking heavier elements, mostly metals, which are attracted to the dipole of another, creating a mecha-
not. Rather, they are more suitable for use in labelling nism for non-covalent bonding between molecules
larger biomolecules (peptides and proteins) using (Figure 7.4). Hydrogen bonding is an extreme form
bifunctional chelators. (Blower 2006; Dearling, Pedley of this.
2007; Goldenberg, Sharkey 2007; Win et al. 2007; These bonds are weaker and more kinetically
Bowen, Orvig 2008; De León-Rodrıguez, Kovacs labile than most intramolecular covalent bonds,
2008; Lucignani 2008). On the whole, gamma-emitting but they are strong enough to have great significance.
radionuclides (with the exception of iodine-123) are For example, hydrogen bonding accounts for
chemically unsuitable for labelling small organic meta- phenomena such as the anomalously high boiling
bolites and drugs. To exploit the potential of molecular point of water and the interactions between peptide
imaging with both small molecules and large biomole- bonds that direct the secondary structure of proteins.
cules, both kinds of radioelements are needed. Molecules (and ions) that interact strongly with the
Therefore, both PET and SPECT imaging technologies dipole of water are described as hydrophilic. By con-
are required, and they are mutually complementary. trast, molecules or parts of molecules that contain
predominantly bonds between atoms of comparable
electronegativity (e.g. C–C and C–H bonds) are not
Hydrophilic versus hydrophobic dipolar. They do not interact strongly with water or
other polar molecules, and consequently behave as
The assembly of, and interactions between, biomole- if they have a repulsion for water. Water molecules
cules and other cellular structures (membranes, interact much more strongly with other water mole-
organelles, proteins, carbohydrates, DNA), and com- cules than with non-polar groups. Intimate mixing of
partmentation of cell functions by lipid bilayer water with non-polar molecules or groups requires
membranes, is rooted at some level in the contrast the breaking of hydrogen bonds between water
between hydrophilic and hydrophobic molecules or molecules and consequently adoption of a more
parts of molecules. In turn, hydrophilicity and hydro- ordered (lower entropy) arrangement of water mole-
phobicity of molecules or parts of molecules originates cules at the interface. This is both enthalpically and
in the dipolar nature, or lack of it, of the covalent entropically unfavourable, and the new bonds formed
bonds within them. Bonds between two atoms of very between the non-polar groups and water molecules are
different electronegativity (e.g. C and O, H and O, H too weak to overcome this. Consequently, systems

δ+
H O O O
R H
N
N
H
H O R
δ− δ+ δ−
O R O H
H
H N
O H N
δ+ O O H R O

δ−
H H
(a) (b) (c)

Figure 7.4 Dipoles and hydrogen bonding. (a) dipole (arrow) in the water molecule; (b) hydrogen bonding between
water molecules due to the dipole; (c) hydrogen bonding between peptide chains due to the dipoles (arrows) in the
peptide bonds.
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92 | Radiopharmaceutical chemistry

Hydrophobic
(lipophilic)

O
O
O O
Hydrophilic
P –
O O

(a) (b)
Figure 7.5 Hydrophobic and hydrophilic groups. (a) A phospholipid. (b) Assembly of phospholipid molecules to form a
lipid bilayer (as in cell membranes, liposomes, etc.). Lipophilic molecules such as 99mTc-sestamibi and 64Cu-ATSM (Figure 7.2)
are able to penetrate the cell membrane by virtue of their lipid solubility, whereas hydrophilic polar and ionic species
generally cannot.

containing both polar and non-polar groups tend to Metal complexes

separate in the manner of ‘like attracts like’ – hydro-
philic groups associate with each other and with water, The chemistry of the metal ions is more flexible, and
and hydrophobic (non-polar) groups associate with less bound by rigid ‘rules’, than that of the organic
each other and avoid water. elements. It is usually most convenient to view metals
The phenomenon of association of hydropho- as behaving as if positively charged (to an extent
bic groups with each other is often known as depending on their oxidation state) and seeking to
‘hydrophobic bonding’, although of course it is not a gain electrons by complexing with ligands. Ligands
type of bonding at all. Rather, it is due to the presence comprise molecules or ions that have non-bonding
of stronger attractions between nearby water mole- ‘lone pairs’ of electrons that are available to form
cules, ‘squeezing’ the non-polar molecules out of this dative bonds with the metal. The ligand is viewed as
environment. These interactions manifest themselves donating a pair of electrons to form this bond.
in phenomena such as the insolubility of non-polar In principle, any atom, ion or molecule that has a
molecules in water, the folding of proteins by associ- non-bonding pair of electrons can function as a ligand
ation between hydrophobic regions or patches, and of in a metal complex (OH, H2O, Cl, N(CH3)3,
hydrophilic regions with water (secondary and quater- CH3S, etc., but not, for example, alkane hydrocar-
nary structure), recognition of signalling molecules by bons, hydrogen, or positive metal ions). Each metal
receptors (see Chapters 15 and 16) and the formation has its own preferences for oxidation state, which can
of lipid bilayer membranes that give rise to cellular to some extent be predicted from its position in the
compartmentation (see Figure 7.5). They can be put periodic table (e.g. þ7 for technetium and rhenium,
to use in analytical methods such as solvent extraction þ3 for iron, þ1 for silver). Some metals are stable in
and reversed-phase HPLC (see Chapter 35), and in the more than one oxidation state and consequently can
design of radiopharmaceuticals to influence their readily give and take electrons to and from other
ability to penetrate cells (exploiting lipid solubility molecules in reduction–oxidation (‘redox’) reactions.
to traverse cell membranes) or control excretory The process of removing an electron from a metal
pathways – as a rough rule of thumb, hydrophobic to raise its oxidation state is known as oxidation,
species tend to be excreted by the hepatobiliary system and the reverse as reduction. Other metals have such
and hydrophilic ones via the kidney (see Chapter 15). a strong preference for a particular oxidation state
Further discussion of intermolecular interactions is (e.g. Naþ, Kþ, Rbþ, Zn2þ, In3þ) that, at least under
beyond the scope of this book and is given in the early biological conditions, redox reactions are out of
chapters of many biochemistry texts. the question. Each metal in each different oxidation
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Radiopharmaceutical chemistry: basic concepts | 93

state has its own characteristics that govern its the timescale of the application. Many individual
behaviour: metal–ligand bonds do not have the required kinetic
stability and so additional measures must be taken in
* Thermodynamic preferences for type of
designing ligands to overcome this. The main design
ligand (‘hard’ ligands such as most electronegative
tool is to exploit the chelate effect (see below). Further
and least polarisable atoms – fluorine, oxygen,
discussion of this topic requires a little background
nitrogen, or ‘soft’ ligands such as the least
discussion of concepts of stability and lability. The
electronegative and most polarisable atoms
fundamental theory is presented in standard general
such as sulfur, phosphorus and carbon).
and physical chemistry texts, and a brief discussion in
* Coordination number: the number of ligand
context follows.
atoms bound to the metal, from 2 – as in the heavy
metals silver, gold, cadmium, mercury – to 9 or
more (lanthanides and actinides); these Thermodynamic and kinetic stability
preferences are governed partly by the electronic
The term ‘stability’ is used in many different contexts
structure of the metal and partly by the size of the
with different meanings. Any dynamic system, for
metal ion (larger radius leads to larger
example a simple solution containing hydrated metal
coordination number).
*
ions M and ligands L, will have a preferred arrange-
Geometric arrangement of ligands (see Figure 7.6).
*
ment at which it will ultimately arrive, given enough
Kinetic lability towards the making and breaking
time. Once it has reached that preferred arrangement,
of metal–ligand bonds with timescales varying
it is said to be at equilibrium and no further significant
from picoseconds (as in the exchange of water
change will occur. For example, the system may reach
molecules in the coordination sphere of sodium)
a state in which nearly all the metal ions are associated
to years in the most inert transition metal
with ligand molecules in solution to form a complex:
complexes with macrocyclic ligands.
M þ L › ML
For further discussion of these characteristics
among the metals, reference to standard inorganic In this process the double half-arrow indicates a
chemistry texts is suggested. dynamic equilibrium, with both forward and back-
Metallic radionuclides must be securely attached ward reactions occurring. The formation of complex
to targeting molecules by means of their ligands, so the ML may be strongly favoured, in which case most of
metal–ligand bonds must be resistant to breaking over the free (hydrated) metal will be converted to it, or it

L L
L M L
L L
M [2] Linear
L L

L
L L L
[6] Octahedral L M
L
M
L [3] Trigonal planar
L
L
L M L L
L L
[5] Square pyramid L M L
L L
L L
L M
L L L [4] Tetrahedral
M
L L
L
[5] Trigonal bipyramid [4] Square planar

Figure 7.6 Interaction of ligands with metal centres via lone (non-bonding) pairs of electrons, and geometries associated with
different coordination numbers. Coordination numbers are given in square brackets.
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94 | Radiopharmaceutical chemistry

may not be favoured, in which case most of the metal concentration than L or ML. For example, serum
will remain free (hydrated). If the complex formation albumin binds very strongly to copper, and transferrin
is strongly favoured, the rate of formation (forward binds very strongly to iron-like metals. Moreover,
reaction) will be faster than the reverse reaction. Once biological fluids also contain other metals (e.g. zinc,
the association and dissociation processes are in calcium), and also protons, which may compete with
balance and the system has reached equilibrium, the the radiometal M for binding to L. Since radiophar-
extent of complex formation can be expressed by an maceuticals are used at very low in-vivo concentration
equilibrium constant K. In this case, because the (e.g. 1 pmol/L), and the native competitors exist at
process is the association of metal and ligand, the relatively high concentration, under these conditions
equilibrium constant is known as an association even complexes with very high association constants
constant, Ka, defined as: cannot hope to survive. If dissociation of ML occurs,
the metal is much more likely to be bound by a native
½ML
Ka ¼ ligand such as albumin or transferrin than by L, and L
½M½L
is more likely to bind to a native metal or proton than
where the square brackets mean ‘concentration of’ the to re-attach to M (this is simply entropy at work).
species within them. Thus if ML formation (associa- Thus, under biological conditions, even complexes
tion) is strongly favoured, Ka will be large (1), and if with the highest association constants will not be
dissociation is favoured, Ka will be small (1). Ka is thermodynamically stable. If the system is allowed to
a measure of the thermodynamic stability of the reach equilibrium in vivo (which sooner or later it will
complex ML. Often the same property is expressed be), extensive dissociation is inevitable.
instead in terms of a dissociation constant Kd, which Therefore, in order to succeed in making a
is the inverse of Ka: complex that will survive in vivo for long enough to
perform its task, we must do everything we can to
½M½L
Kd ¼ delay the inevitable destruction of the complex. That
½ML
is, we must minimise the rate of the dissociation
A small Kd indicates a strong (‘thermodynamically process – i.e. make the complex kinetically stable.
stable’) complex. Since these constants are often very Mechanistic routes to the thermodynamic end point
large or very small numbers, it is convenient to refer to (dissociation) must be blocked or made as difficult as
their logarithms (log10 K) instead of the numbers possible. The rate of a reaction is described using a rate
themselves. If the ligand is well matched to the prefer- constant k. The rate of reaction between a metal M
ences of the metal, the complex will have a large Ka and a ligand L depends on the frequency of encounters
(or a small Kd). For example, microorganisms have between M and L in solution, which is proportional
evolved to secrete iron-binding agents into their to the concentration of each, and on the fraction of
surroundings to extract traces of iron. These ligands those encounters that result in association. For the
are finely tuned for their purpose with log10 Ka of association reaction
30–40 or more. Clearly, to link a metal to a targeting
Rate ¼ ka ½M½L
molecule with sufficient stability to exist in vivo,
it is advisable to design the ligand such that Ka is as and for the dissociation reaction
large as possible.
Rate ¼ kd ½ML
Unfortunately, the biological milieu is much more
complicated than the simple association reaction the rate constants are related to the equilibrium
referred to above. Biological media such as blood constants:
plasma contain molecules that will act as ligands for
Ka ¼ ka =kd and Kd ¼ kd =ka
the metal M, and hence will compete with L, displa-
cing it from the metal. This would break the link The optimal strategy for linking a radiometal to a
between the radiolabel and its targeting vehicle, targeting vehicle will then involve designing the ligand
rendering the radiopharmaceutical useless. Often such that the ML complex has a small value of kd,
these competing ligands are present in much higher while at the same time keeping ka large enough to
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Radiopharmaceutical chemistry: basic concepts | 95

make the radiolabelling step (association) feasible, at ligand with a metal, compared to six monodentate
high yield, in a few minutes under mild conditions. ligands. This can be simplistically illustrated by refer-
This is not easy – those features of ligand design that ence to a complex of an iron-like metal interacting
promote slow dissociation also promote slow associ- with the iron binding protein transferrin:
ation, because the same barrier must be surmounted
Six monodentate ligands:
going in either direction.
ML6 þ transferrin › MðtransferrinÞ þ
6L ðtwo molecules become sevenÞ
Chelating ligands and the chelate effect
The most useful way to design a ligand so as to increase One hexadentate ligand:
its Ka and decrease kd is to exploit the chelate effect. By ML þ transferrin › M ðtransferrinÞ þ
linking ligands together, usually by means of an
L ðtwo molecules become twoÞ
organic carbon chain, in such a way that two or
more donor atoms can coordinate to the metal at The entropy change in the former case is more favour-
the same time without straining natural bond angles, able than in the second: the increase in the number of
the fractional concentration of free metal ion in the particles allows the system to become more disordered
solution at equilibrium can be decreased by many and hence arrive at a more probable state.
orders of magnitude. Moreover, the dissociation rate Kinetically, one may visualise the increased
constant kd can be decreased, also by many orders of association rate constant in terms of the likelihood
magnitude. Ligands containing two donor atoms or that encounters between M and L will lead to complex
groups are described as bidentate, those with three formation. In an encounter between a metal and a
are tridentate, and so on. Such ligands are termed monodentate ligand, the ligand may approach the
chelators (derived from Greek chelos, a claw) or metal in different orientations, some of which allow
chelating agents, and their metal complexes are termed the donor atom to contact the metal while others
chelates or chelate complexes. The enhancement shield the donor atom from the metal. If the ligand is
of thermodynamic and kinetic stability caused by bidentate, there is a greater probability that the
chelation is known as the chelate effect. Broadly encounter will allow contact between one of the donor
speaking the strength of the effect increases as the atoms and the metal, so a higher fraction of encounters
number of donor groups increases, provided they can will lead to complexation. Moreover, once the first
all coordinate at the same time without strain (Figure donor has coordinated with the metal, the second
7.7). Some examples relevant to radiopharmacy are is held in close proximity (at a higher ‘effective
shown in Figure 7.8. concentration’), leading to higher probability of its
The origin of the chelate effect is easy to visualise coordination. Conversely, dissociation of a chelate
qualitatively. Thermodynamically, the main driver is will be slowed: breaking the first metal–ligand bond
the relatively favourable entropy change associated leaves the second intact, so the dissociated donor
with association – for example, a single hexadentate group is not free to diffuse away and has a high

L
L L
L
L L
L L L L M
L L M M
M L L
L L L L
L L L
L L
L
macrocycle

Increasing thermodynamic stability

Decreasing dissociation rate constant

Figure 7.7 Qualitative schematic summary of the chelate and macrocyclic effects.
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96 | Radiopharmaceutical chemistry

O O O O
N N N N N N
HO OH
O O H
OH HO OH N
O O O LYS
O O O
DTPA cyclic anhydride (for indium–111)
O
O O MAG3 (for technetium–99m/
O N H NH HN
N rhenium–186/188)
N O
N H SH HN O
O H
O
O
HYNIC (for technetium–99m) O
N

O O
O O
O O O
HO N N O N N N
HO O N
O N N OH O HO OH
N N O
HO O O O
TETA (for copper–64) DOTA (for indium–111, yttrium–90, gallium–68)

Figure 7.8 Some examples of bifunctional chelators and macrocycles (Blower et al. 1996; Prakash, Blower 1999; Fichna, Janecka
2003; Win et al. 2007; Bowen, Orvig 2008; De León-Rodrıguez, Kovacs 2008; Lucignani 2008).

probability of re-association. The probability of half-life is measured in years under physiological

dissociation is therefore much reduced. conditions) but heating is required to accomplish
The chelate effect is generally maximal when the labelling efficiently in a short time (Win et al.
rings formed by the coordination of two donor 2007; De León-Rodrıguez, Kovacs 2008)
atoms to the metal are five-membered, as shown
in Figure 7.7 – this is the arrangement that brings the
Bifunctional chelators
donor groups into closest proximity with the metal
with minimal additional strain in the ligand. Chelating ligands may be used to make either radio-
Occasionally six-membered rings are required to nuclide-essential metal complex radiopharmaceu-
provide the necessary flexibility to accommodate the ticals or radionuclide-tagged radiopharmaceuticals.
geometric preferences of the metal. In the latter case the chelating agent must have a
A further enhancement of thermodynamic and second, reactive structural element to enable it to
kinetic stability of complexes is generally attainable form a covalent link to the targeting vehicle (a
by linking the ends of a chain of donor groups together protein, a peptide, etc.) to form a bioconjugate.
(Figure 7.8) to make a macrocyclic chelator. This is Bifunctional chelators are chelating agents that have
known as the macrocyclic effect. Macrocyclic such a reactive group. The bifunctional chelator
complexes are often extremely resistant to dissociation serves as a prosthetic group. The reactive groups
(see Chapter 13, copper radionuclides) because the present in biomolecules, through which they can be
structures are rather rigid and a great deal of strain linked to a prosthetic group, are nearly always
in the ligand may need to be overcome in order to nucleophilic amino acid side-chains (the v-amino
break the first metal–donor bond. This exceptional group of lysine, or the N-terminal a-amino group,
kinetic stability comes at a cost: the same barriers or the thiol group of cysteine). Therefore, the
due to ligand strain are present during formation of reactive group of a bifunctional chelator is usually
the complex, often leading to slow complex formation an electrophilic group such as an active ester,
and consequently a need for harsh labelling isothiocyanate, maleimide, etc. A selection of exam-
conditions. Labelling of DOTA conjugates with ples are shown in Figure 7.8. Chelators designed
gallium-68 is a case in point: the Ga–DOTA conjugate to suit specific metals are discussed in succeeding
complex is highly inert (more so than is necessary for a chapters (Chapters 8, 9 and 13). The principles
physical half-life of 68 minutes – its dissociation underlying design and synthesis of bioconjugates
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Radiopharmaceutical chemistry: basic concepts | 97

for radiolabelling are discussed in more detail chemical covalent bonds. Thus, like the group 1
in Chapter 14. metals, they cannot be incorporated into targeting
molecules, and their use is restricted to mimicking
the normal biological functions of calcium. This
Radionuclide survey of the provides opportunities for targeted radionuclide
periodic table therapy of bone metastases using the beta emitter
strontium-89 (89Sr), which, when administered as
The following is an overview of properties of radio- SrCl2 (i.e. aqueous solution containing Sr2þ ions), is
elements in relation to their location in the periodic taken up in mineralising bone (Lin, Ray 2006). This
table and their uses in nuclear medicine. mimicking of calcium is currently being evaluated
for the alpha emitter radium-223 as a very potent
radionuclide therapy for bone metastases (McDevitt
Group 1 et al. 1998).
Group 1 of the periodic table consists of monovalent
metals (lithium, sodium, potassium, rubidium, cae-
Groups 3–12: the transition metals
sium, francium) whose chemistry is restricted to the
formation of hydrated Mþ ions in aqueous solution. The chemistry of the group 3 metals is governed by an
That is, each metal ion is surrounded by a shell of extreme preference for the formation of M3þ ions (e.g.
water molecules that constantly and rapidly exchange Y3þ). These do not exist as stable hydrated metal ions in
with water molecules in the bulk aqueous medium aqueous solution except under strongly acidic condi-
(exchange half-life is of the order of picoseconds). tions, because the polarising effect of the M3þ on coor-
Their preference for existing in this state is so great dinated water molecules results in release of protons to
that in aqueous solution they do not interact signifi- form hydroxides. However, they do interact strongly
cantly with other ligands or functional groups, nor do with polydentate chelating ligands containing anionic
they form covalent bonds. Thus, there is no chemistry oxygen (carboxylates and phosphonates especially) and
by which they can be introduced into targeting nitrogen donors. The tendency to form M3þ complexed
molecules in a stable manner. Their applications are by such ligands is not restricted to group 3, but is also
therefore restricted to those in which they mimic exhibited by iron, chromium, cobalt, gallium, indium
biological group 1 metals, i.e. sodium and potassium. and the lanthanides (see below). Despite the similarity in
The only clinically useful radionuclide in this group is coordination preferences shared by the M3þ ions, it is
rubidium-82 (82Rb, a positron emitter, half-life 1.3 unrealistic to carry the analogy too far. While the com-
minutes), which forms hydrated Rbþ that mimics the plexes formed have high thermodynamic stability, their
potassium ion Kþ in being transported by trans- kinetic lability depends strongly on the particular metal
membrane potassium transporters, e.g. the Naþ/Kþ- and on the design of the chelator. Thus, for example,
ATPase pump that maintains potassium concentration In3þ forms complexes with DTPA derivatives that have
and electrical potential gradients across cell mem- sufficient kinetic stability for imaging biomolecules
branes (Machac 2005) In practice this use is restricted labelled with 111In, but the Y3þ analogue is too labile
to myocardial perfusion imaging by PET, in which for analogous therapeutic applications (Virgolini et al.
Rbþ is accumulated quickly in cardiomyocytes of 2002). Moreover, the size of the ion affects the preferred
well-perfused myocardium via the Naþ/Kþ-ATPase coordination number, and hence the structure and bio-
pump (Chapter 13). logical properties. For example, Ga3þ and In3þ are both
chelated strongly by DOTA (Virgolini et al. 2002; De
León-Rodrıguez, Kovacs 2008), but in the case of
Group 2
indium all of the carboxylate groups are bound to the
These metals form only M2þ ions and interact mainly metal, while in the case of gallium only two are coordi-
with anionic oxygen ligands such as carboxylate, nated leaving the other two free to interact with other
carbonate and phosphate. These interactions are biomolecules. The ‘3þ metals’ are discussed in more
kinetically labile compared with most organic detail elsewhere (Chapter 9).
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The remaining transition metals (groups 4 to 12: (carbon) to strongly metallic and with more ambiva-
titanium to zinc, zirconium to cadmium and hafnium lent oxidation state at the bottom (lead, which behaves
to mercury) are characterised by a departure from the as a metal ion, Pb2þ, but also forms covalent molecules
relatively hard and fast preferences for particular containing tetravalent lead analogous to carbon).
charge/valency states and ligand types exhibited by Thus, carbon-11 (11C) is able to replace 12C in the
groups 1, 2 and 3. They can exist in a range of oxida- native structure of the molecule and is particularly
tion states (most notably from 1 to þ7 in the case of useful as a label for small organic molecules such as
rhenium and technetium), each with its own preference neuroreceptor ligands (Schubiger et al. 2006). In
for ligand type, coordination number, and kinetic reac- contrast, the heavier members tin and lead are treat-
tivity. Most important in this group in terms of clinical ed by radiopharmaceutical chemists as metals, form-
utility is technetium-99m (99mTc), which is discussed in ing cations Sn2þ and Pb2þ. Tin and lead are used in
detail later. Other transition metals gaining in impor- the form of metal chelates, usually with polydentate
tance include rhenium (186Re, 188Re) (Prakash, Blower oxygen/nitrogen ligands. Experimental examples
1999) and copper (60,61,62,64,67Cu) (Blower et al. are therapeutic use of 117mSn-DTPA complex for
1996). A wide range of ligands and chelators have been bone metastases (McEwan 1997; Li et al. 2001) and
212
designed that form highly inert complexes of metals in Pb linked to biomolecules via polydentate bifunc-
certain oxidation states, which are stable for long tional chelators (Su et al. 2005).
enough in vivo for imaging and radionuclide therapy.
Many bifunctional chelator systems have been devel-
Group 15
oped from these to allow labelling of biomolecules with
these elements. In addition, other characteristic prop- Group 15 elements again exhibit a range of proper-
erties of the transition metals, such as their participa- ties from covalent and predominantly trivalent nitro-
tion in redox and electron transfer reactions, can be gen, to increasingly ready access to higher oxidation
harnessed to achieve targeted delivery, for example to states and metallic behaviour lower down the group.
trap the radionuclide within cells by bioreductive Thus the positron emitter 13N is used exclusively
mechanisms. This has been used in the design of copper in its trivalent form as a component of covalent
radionuclide complexes for imaging of perfusion and molecules (although the complexity of these is
hypoxia (Blower et al. 1996; Vavere, Lewis 2007). severely restricted by the short half-life of this radio-
nuclide (10 minutes), and the only widely used form
is ammonia, NH3), while 32P is used exclusively in its
Group 13
pentavalent state (which is favoured under aerobic
The group 13 elements all share clearly metallic char- biological conditions) in the form of phosphate and
acteristics, with a strong tendency to form hard 3þ polyphosphates, as a beta-emitting radiotherapy
cations (with similar coordination characteristics to nuclide targeted towards bone mineral and bone
the group 3 metals). This tendency diminishes down marrow (Silberstein 2005). Bismuth, although form-
the group, to the extent that while 67Ga, 68Ga and ing relatively stable pentavalent compounds such as
111
In resemble iron and can be chelated by polydentate bismuthates, also behaves as a 3þ metal and is
nitrogen/oxygen ligands like the group 3 metals, the treated as such in radiopharmaceutical chemistry,
heaviest member, thallium, has a preference for the linked to biomolecules using polydentate nitrogen/
1þ oxidation state (Tlþ) and its biological transport is oxygen chelators for use in targeted alpha emitter
reminiscent of the group 1 metals. Thallium-201 is used therapy (Yang, Sun 2007).
as a myocardial imaging agent by virtue of its uptake via
the Naþ/Kþ-ATPase pump (Bhatnagar, Narula 1999).
Group 16
Group 16 has few useful radioisotopes to offer to
Group 14
nuclear medicine. The most important is the positron
The character of the group 14 elements varies from emitter oxygen-15 (15O), but its half-life is so short
clearly covalent and tetravalent at the top of the group (2 minutes) that, with few exceptions (Miller et al.
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2008), it is not useful in any form other than H2O, for iodine. Astatine can reach higher oxidation states even
PET imaging studies of perfusion. more readily than iodine, reflecting increasingly
metallic tendencies exhibited by the heavier of the
p-block elements (groups 13–18), but again this prop-
Group 17
erty has not been exploited with any vigour to date.
Group 17 offers a rich source of highly versatile radio- Indeed, the chemistry of astatine remains relatively
nuclides, and the more important members of the mysterious because of the lack of stable isotopes and
group are discussed extensively elsewhere in this the highly toxic nature of its radioisotopes.
volume. Their chemical behaviour consists of either
formation of stable monoanions (fluoride F, chloride
Group 18
Cl, bromide Br, iodide I and astatide At), or
covalent incorporation into organic molecules and Group 18 comprises the noble gases (helium, neon,
proteins, usually by formation of a single covalent argon, krypton, xenon, radon). Being ‘noble’ these can-
bond with carbon (e.g. mIBG and FDG, see Figure not be incorporated into any targeting molecules and
7.3). The natural biodistribution and function of the are useful only in the form of the elemental gas for lung
monoanions are exploited for imaging bone lesions ventilation studies. The gaseous state is exploited in the
with PET (18F fluoride, which becomes incorporated design of the krypton-81m (gamma emitter, half-life 13
into bone mineral) (Fogelman et al. 2005) or thyroid seconds) generator, from which the gas is eluted from a
sodium/iodide symporter activity with SPECT (123I- solid support with air directly into the inhaled air-
and 131I-iodide) or PET (124I-iodide) (Chung stream (see Chapter 20) (Lambrecht et al. 1997).
2002; Lewis 2006). The covalent character is
exploited in an extremely wide variety of labelled
Lanthanides
biologically active small molecules and proteins, for
both imaging and therapy purposes (Adam, Wilbur The nature of the lanthanides is similar to that of
2005). The monovalency means that either fluorine the group 3 and group 13 metals, in that they all
or iodine can replace hydrogen or a hydroxyl group form 3þ cations with a high affinity for oxygen/nitro-
while maintaining the approximate shape of the gen chelators. Although they all conform to this
molecule. While fluorine is small, the relatively large pattern, and can be effectively chelated by the
atomic radius of iodine, lower down the group, means same chelator (most popular is DOTA, see Figure
that this substitution can have significant effects on 7.8), there is a contraction in ionic radius towards
steric properties (see Figure 7.3) and lipophilicity, the right of the period (the ‘lanthanide contraction’),
and these effects need to be taken into account in the which affects the coordination number and can lead to
design of radiopharmaceuticals. While fluorine is significant differences in behaviour of bioconjugates in
restricted to the monocovalent and monoionic forms, which the same chelator is used. Most important are
iodine is relatively easily oxidised to higher oxidation samarium-153 (beta emitter), holmium-166 (beta
states such (IO, IO3, IO4) but these have found no emitter) and terbium-149 (alpha emitter) (Rosch,
biomedical uses to date. Forssell-Aronsson 2004).
Bromine isotopes (76Br, 77Br) have potential appli-
cations in PET and radionuclide therapy, again in the
Actinides
form of covalent molecules with carbon–bromine
bonds, often based on analogous fluorine- and The actinides form very large (high-ionic-radius) ions
iodine-labelled compounds (Adam, Wilbur 2005). with high coordination number and high charge.
Astatine is the heaviest member of the group The only actinide to have been investigated with any
and has no stable isotopes. It is potentially useful for serious intent for use in nuclear medicine is the alpha
alpha emitter therapy (211At) (Zalutsky, Pozzi emitter actinium-225 (Miederer et al. 2008). Its ionic
2004; Adam, Wilbur 2005), again usually in the form radius is larger than that of the other useful metals and
of organic molecules or proteins, labelled by means of it requires O/N chelating molecules containing a
carbon–astatine bond formation analogously to higher than usual number of chelating groupings.
Sampson's Textbook of Radiopharmacy
Chapter No. 7 Dated: 16/11/2010 At Time: 16:36:18

100 | Radiopharmaceutical chemistry

McDevitt MR et al. (1998). Radioimmunotherapy with

References alpha-emitting nuclides. Eur J Nucl Med 25: 1341–1351.
McEwan AJB (1997). Unsealed source therapy of painful
Adam MJ, Wilbur DS (2005). Radiohalogens for imaging and bone metastases: an update. Semin Nucl Med 27: 165–182.
therapy. Chem Soc Rev 34: 153–163. Miederer M et al. (2008). Realizing the potential of the actin-
Bhatnagar A, Narula J (1999). Radionuclide imaging of car- ium-225 radionuclide generator in targeted alpha
diac pathology: a mechanistic perspective. Adv Drug Deliv particle therapy applications. Adv Drug Deliv Rev 60:
Rev 37: 213–223. 1371–1382.
Blower P (2006). Towards molecular imaging and treatment Miller PW et al. (2008). Synthesis of C-11, F-18, O-15, and
of disease with radionuclides: the role of inorganic chem- N-13 radiolabels for positron emission tomography.
istry. Dalton Trans, 1705–1711. Angew Chem Int Ed 47: 8998–9033.
Blower PJ et al. (1996). Copper radionuclides and radiophar- Prakash SD, Blower PJ (1999). The chemistry of rhenium
maceuticals in nuclear medicine. Nucl Med Biol 23: in nuclear medicine. In: Hay R et al, eds. Perspectives on
957–980. Bioinorganic Chemistry. Stamford, CT:, JAI Press. 4: 91–
Bowen ML, Orvig C (2008). 99m-Technetium carbohydrate 143.
conjugates as potential agents in molecular imaging. Chem Rosch F, Forssell-Aronsson E (2004). Radiolanthanides in
Commun, 5077–5091. nuclear medicine. Metal Ions in Biological Systems, Vol
Chung J-K (2002). Sodium iodide symporter: its role in 42: Metal Complexes in Tumor Diagnosis and as
nuclear medicine. J Nucl Med 43: 1188–1200. Anticancer Agents. New York: Marcel Dekker, 77–108.
De León-Rodrıguez LM, Kovacs Z (2008). The synthesis and Schubiger PA et al. (2006). PET Chemistry: The Driving
chelation chemistry of DOTA-peptide conjugates. Force in Molecular Imaging. New York: Springer.
Bioconjugate Chem 19: 391–402. Signore A et al. (2001). Peptide radiopharmaceuticals for
Dearling JLJ, Pedley RB (2007). Technological advances in diagnosis and therapy. Eur J Nucl Med 28: 1555–1565.
radioimmunotherapy. Clin Oncol 19: 457–469. Silberstein EB (2005). Teletherapy and radiopharmaceutical
Fichna J, Janecka A (2003). Synthesis of target-specific radio- therapy of painful bone metastases. Semin Nucl Med 35:
labeled peptides for diagnostic imaging. Bioconjugate 152–158.
Chem 14: 3–17. Su FM et al. (2005). Pretargeted radioimmunotherapy in
Fogelman I et al. (2005). Positron emission tomography and tumored mice using an in vivo Pb-212/Bi-212 generator.
bone metastases. Semin Nucl Med 35: 135–142. Nucl Med Biol 32: 741–747.
Goldenberg DM, Sharkey RM (2007). Novel radiolabeled Vavere AL, Lewis JS (2007). Cu-ATSM: a radiopharmaceu-
antibody conjugates. Oncogene 26: 3734–3744. tical for the PET imaging of hypoxia. Dalton Trans,
Lambrecht RM et al. (1997). Radionuclide generators. 4893–4902.
Radiochim Acta 77