Background— Obesity is a risk factor for impaired cardiac performance, particularly in women. Ani... more Background— Obesity is a risk factor for impaired cardiac performance, particularly in women. Animal studies suggest that alterations in myocardial fatty acid metabolism and efficiency in obesity can cause decreased cardiac performance. In the present study, we tested the hypothesis that myocardial fatty acid metabolism and efficiency are abnormal in obese women. Methods and Results— We studied 31 young women (body mass index [BMI] 19 to 52 kg/m 2 ); 19 were obese (BMI >30 kg/m 2 ). Myocardial oxygen consumption (MV̇ o 2 ) and fatty acid uptake (MFAUp), utilization (MFAU), and oxidation (MFAO) were quantified by positron emission tomography. Cardiac work was measured by echocardiography, and efficiency was calculated as work/MV̇ o 2 . BMI correlated with MV̇ o 2 ( r =0.58, P =0.0006), MFAUp ( r =0.42, P <0.05), and efficiency ( r =−0.40, P <0.05). Insulin resistance, quantified by the glucose area under the curve (AUC) during an oral glucose tolerance test, correlated with ...
Two fluorine-18-labeled reagents, methyl 3-[18F]fluoro-5-nitrobenzimidate and 4-[18F]fluorophenac... more Two fluorine-18-labeled reagents, methyl 3-[18F]fluoro-5-nitrobenzimidate and 4-[18F]fluorophenacyl bromide, have been prepared for covalent attachment of fluorine-18 to proteins. Both reagents can be prepared in moderate yields (30-50%, EOB) in synthesis times of 50-70 min. Reaction of these reagents with proteins (human serum albumin, human fibrinogen, and human immunoglobulin A) is pH independent, protein concentration dependent, and takes 5-60 min at mild pH (8.0) and temperature (25-37 degrees C), in yields up to 95% (corrected). The 18F-labeled proteins are purified by size exclusion chromatography.
Recent antecedent hypoglycemia has been found to shift glycemic thresholds for autonomic (includi... more Recent antecedent hypoglycemia has been found to shift glycemic thresholds for autonomic (including adrenomedullary epinephrine), symptomatic, and other responses to subsequent hypoglycemia to lower plasma glucose concentrations. This change in threshold is the basis of the clinical syndromes of hypoglycemia unawareness and, in part, defective glucose counterregulation and the unifying concept of hypoglycemia-associated autonomic failure in type 1 diabetes. We tested in healthy young adults the hypothesis that recent antecedent hypoglycemia increases blood-to-brain glucose transport, a plausible mechanism of this phenomenon. Eight subjects were studied after euglycemia, and nine were studied after ∼24 h of interprandial hypoglycemia (∼55 mg/dl, ∼3.0 mmol/l). The latter were shown to have reduced plasma epinephrine (P = 0.009), neurogenic symptoms (P = 0.009), and other responses to subsequent hypoglycemia. Global bihemispheric blood-to-brain glucose transport and cerebral glucose me...
International Journal of Radiation Applications and Instrumentation. Part B. Nuclear Medicine and Biology, 1988
The ligands currently used for PET studies of the dopamine receptor are fluorine-18-labeled spipe... more The ligands currently used for PET studies of the dopamine receptor are fluorine-18-labeled spiperone (FSp) and carbon-l 1 or fluorine-l&labeled N-methyl-spiperone. All three of these hgands have drawbacks in either their chemical preparation or their biological behavior. We have previously prepared a series of N-fluoroalkyl-spiperone derivatives which are simple to prepare in high radiochemical yield. N-['sF]fluoropropyl-spiperone (3-F-Pr-Sp) and N-[lsFjfluoroethyl-spiperone (2-F-Et-Sp) were the most promising ligands. In vitro competitive binding studies showed affinities for the dopamine receptor of 3-F-Pr-Sp > FSp > 2-F-Et-Sp. Brain extraction studies in a primate model showed that FSp, 2-F-Et-Sp, and 3-F-Pr-Sp were not completely extracted by the brain. High bone uptake and kidney clearance was observed with 3-F-Pr-Sp, while 2-F-Et-Sp cleared through the intestine in rats. This is in contrast to FSp where clearance is through the kidney. Studies to evaluate the extraction of metabolites in the brain were carried out by administering large doses (10 mCi) of FSp, 2-F-Et-Sp and 3-F-Pr-Sp to rats and reinjecting the metabolites in blood into other rats. These experiments showed that ~0.02% of the metabohtes from FSp and 3-F-Pr-Sp entered the brain, while 0.5% of the metabolites from 2-F-Et-Sp entered the brain. The majority of the activity present in the cerebellum after the administration of 2-F-Et-Sp is metabolites; therefore 2-F-Et-Sp is unsuitable for PET imaging studies. PET imaging studies in baboons and in one normal human volunteer with 3-F-Pr-Sp showed a high striatum-to-cerbellum ratio, showing that 3-F-Pr-Sp can replace ligands currently in use to study dopamine receptors.
Using positron emission tomography (PET) and nitric oxide radiolabeled with nitrogen-13 (half-lif... more Using positron emission tomography (PET) and nitric oxide radiolabeled with nitrogen-13 (half-life 9.97 min) we probed the distribution and kinetics of inhaled nitric oxide in anesthetized dogs. The washout of this gas after inhalation was much slower than that observed for [13N]nitrogen gas, demonstrating its uptake by lung tissue. The small fraction of radioactivity found in the plasma was determined to be in the form of [13N]nitrate. The administered gas contained < 1 ppm of nonradioactive nitric oxide, which is believed to be below the physiologic threshold for vasorelaxation.
Reports have implicated neuronal nitric oxide synthetase (nNOS) in the pathological effects of ne... more Reports have implicated neuronal nitric oxide synthetase (nNOS) in the pathological effects of neurodegenerative diseases. S-Methyl-Lthiocitrulline (MTICU), a potent and selective nNOS inhibitor («¡=1.2 n/W),was chosen as our initial target molecule for positron emitter labeling as a potential nNOS tracer. We report the synthesis, biological evaluation and primate brain images of S-[11C]methyl-Lthiocitrulline ([11C]MTICU). Methods: The two-step synthesis of [11C]MTICU consisted of the S-alkylation of a-N-Boc-L-thiocitrulline t-butyl ester with [11C]Mel followed by TFA hydrolysis and HPLC purification. The final product was obtained within 50 min (yield = 9.1%-12.5%, based on [11C]Mel SA=27-680 Ci/mmol at end of synthesis). The lipophilicity of [11C]MTICU was determined by octa nol/water partition coefficient (LogP). Blood stability of this tracer in vitro and in vivo was measured by HPLC analysis. Biodistribution using female Sprague-Dawley rats was performed, including exam
Mitomycin Biosynthesis by Streptomyces verticillatus Sir : The mitomycins (I, mitomycin B; 11, mi... more Mitomycin Biosynthesis by Streptomyces verticillatus Sir : The mitomycins (I, mitomycin B; 11, mitomycin C) are a group of anticancer antibiotics which contain a unique carbon-nitrogen ring skeleton' and which are produced by Streptomyces verticillatus and other strains of Streptomyces. Previous studies on their biosynthesis have shown that L-[methyl-14C]methionine provides 0and N-methyl groups but not the C-methyl that L-[guanidino-14C]arginine labels the carbamoyl group,l that label from ~-g l u c o s e~ and from ~-r i b o s e~ appears in the methylbenzoquinone moiety, and that D-[ 1-14C,6-3H, 15N]glucosamine is incorporated in a manner suggesting its utilization as an intact unit.4j6 To further examine the intact incorporation of this amino sugar, D-[ 1-I3C, 15N]glucosamine was prepared from D-arabinose, [ 15N]benzylamine (99 atom I5N), and HI3CN (90 atom % 13C).' Fifty milligrams of
Journal of Cerebral Blood Flow and Metabolism, 1998
Few data regarding early developmental changes in cerebral (blood-to-brain) glucose transport (CT... more Few data regarding early developmental changes in cerebral (blood-to-brain) glucose transport (CTXglc) and CMRglc are available for humans. We measured CBF, CTXglc, and CMRglc with positron emission tomography at 4 to 7 days of life in six preterm human infants whose estimated gestational age was 25 to 34 weeks. The Michaelis-Menten constants Kt and Tmax were estimated from CTXglc and
relation between p320 and mammalian high molecular weight MAPs is suggested by the observation th... more relation between p320 and mammalian high molecular weight MAPs is suggested by the observation that antibody against hog brain MAP 2 reacts weakly with trypanosomal p320, and vice versa (20). The only MAP whose complete sequence has been published so far is the tau protein of mouse brain (29). No similarity between p320 and tau primary sequence is observed. However, the tau sequence also contains three repetitive stretches of 18 amino acids. This, together with proteolysis experiments with mammalian MAP 3 (30) and direct prot9in sequencing of a 180-kD MAP from the spindle apparatus (31) suggest that a repetitive motive may be a common feature in MAP architecture.
Lactate is a key myocardial energy source. Lactate metabolism is altered in a variety of conditio... more Lactate is a key myocardial energy source. Lactate metabolism is altered in a variety of conditions, such as exercise and diabetes mellitus. However, to our knowledge, noninvasive quantitative measurements of myocardial lactate metabolism have never been performed ...
The aim of this study was to investigate whether compartmental modeling of 1-11 C-glucose PET kin... more The aim of this study was to investigate whether compartmental modeling of 1-11 C-glucose PET kinetics can be used for noninvasive measurements of myocardial glucose metabolism beyond its initial extraction. Methods: 1-11 C-Glucose and U-13 C-glucose were injected ...
The ligands currently used for PET studies of the dopamine receptor are fluorine-18-labeled spipe... more The ligands currently used for PET studies of the dopamine receptor are fluorine-18-labeled spiperone (FSp) and carbon-11 or fluorine-18-labeled N-methyl-spiperone. All three of these ligands have drawbacks in either their chemical preparation or their biological behavior. ...
International journal of radiation applications and instrumentation. Part B, Nuclear medicine and biology, 1991
Two 18F-labeled analogues of dexetimides, 2-[18F]fluorodexetimide (2-FDEX) and 4-[18F]fluorodexet... more Two 18F-labeled analogues of dexetimides, 2-[18F]fluorodexetimide (2-FDEX) and 4-[18F]fluorodexetimide (4-FDEX), were prepared and evaluated in vivo as possible agents for the study of the muscarinic acetylcholine receptor (mAChR) with PET. Two synthetic approaches, a 2-step reductive alkylation procedure and a 4-step alkylation approach, were investigated. The alkylation approach with higher overall radiochemical yields was used to prepare 2- and 4-FDEX for biodistribution studies. The overall synthesis time for both compounds was 2.5 h and the overall radiochemical yield at end-of-synthesis was 12%. The specific activity was found to be greater than 600 mCi/mumol. Biodistribution studies of 2-FDEX in rats produced striatum-to-cerebellum and cortex-to-cerebellum ratios of 8.6 +/- 1.1 and 8.4 +/- 1.0 at 1 h after injection, and 12.1 +/- 2.1 and 10.7 +/- 2.2 at 3 h, respectively. Substantial radioactivity detected in bone indicated the in vivo defluorination of 2-FDEX. The striatum-t...
Background— Obesity is a risk factor for impaired cardiac performance, particularly in women. Ani... more Background— Obesity is a risk factor for impaired cardiac performance, particularly in women. Animal studies suggest that alterations in myocardial fatty acid metabolism and efficiency in obesity can cause decreased cardiac performance. In the present study, we tested the hypothesis that myocardial fatty acid metabolism and efficiency are abnormal in obese women. Methods and Results— We studied 31 young women (body mass index [BMI] 19 to 52 kg/m 2 ); 19 were obese (BMI >30 kg/m 2 ). Myocardial oxygen consumption (MV̇ o 2 ) and fatty acid uptake (MFAUp), utilization (MFAU), and oxidation (MFAO) were quantified by positron emission tomography. Cardiac work was measured by echocardiography, and efficiency was calculated as work/MV̇ o 2 . BMI correlated with MV̇ o 2 ( r =0.58, P =0.0006), MFAUp ( r =0.42, P <0.05), and efficiency ( r =−0.40, P <0.05). Insulin resistance, quantified by the glucose area under the curve (AUC) during an oral glucose tolerance test, correlated with ...
Two fluorine-18-labeled reagents, methyl 3-[18F]fluoro-5-nitrobenzimidate and 4-[18F]fluorophenac... more Two fluorine-18-labeled reagents, methyl 3-[18F]fluoro-5-nitrobenzimidate and 4-[18F]fluorophenacyl bromide, have been prepared for covalent attachment of fluorine-18 to proteins. Both reagents can be prepared in moderate yields (30-50%, EOB) in synthesis times of 50-70 min. Reaction of these reagents with proteins (human serum albumin, human fibrinogen, and human immunoglobulin A) is pH independent, protein concentration dependent, and takes 5-60 min at mild pH (8.0) and temperature (25-37 degrees C), in yields up to 95% (corrected). The 18F-labeled proteins are purified by size exclusion chromatography.
Recent antecedent hypoglycemia has been found to shift glycemic thresholds for autonomic (includi... more Recent antecedent hypoglycemia has been found to shift glycemic thresholds for autonomic (including adrenomedullary epinephrine), symptomatic, and other responses to subsequent hypoglycemia to lower plasma glucose concentrations. This change in threshold is the basis of the clinical syndromes of hypoglycemia unawareness and, in part, defective glucose counterregulation and the unifying concept of hypoglycemia-associated autonomic failure in type 1 diabetes. We tested in healthy young adults the hypothesis that recent antecedent hypoglycemia increases blood-to-brain glucose transport, a plausible mechanism of this phenomenon. Eight subjects were studied after euglycemia, and nine were studied after ∼24 h of interprandial hypoglycemia (∼55 mg/dl, ∼3.0 mmol/l). The latter were shown to have reduced plasma epinephrine (P = 0.009), neurogenic symptoms (P = 0.009), and other responses to subsequent hypoglycemia. Global bihemispheric blood-to-brain glucose transport and cerebral glucose me...
International Journal of Radiation Applications and Instrumentation. Part B. Nuclear Medicine and Biology, 1988
The ligands currently used for PET studies of the dopamine receptor are fluorine-18-labeled spipe... more The ligands currently used for PET studies of the dopamine receptor are fluorine-18-labeled spiperone (FSp) and carbon-l 1 or fluorine-l&labeled N-methyl-spiperone. All three of these hgands have drawbacks in either their chemical preparation or their biological behavior. We have previously prepared a series of N-fluoroalkyl-spiperone derivatives which are simple to prepare in high radiochemical yield. N-['sF]fluoropropyl-spiperone (3-F-Pr-Sp) and N-[lsFjfluoroethyl-spiperone (2-F-Et-Sp) were the most promising ligands. In vitro competitive binding studies showed affinities for the dopamine receptor of 3-F-Pr-Sp > FSp > 2-F-Et-Sp. Brain extraction studies in a primate model showed that FSp, 2-F-Et-Sp, and 3-F-Pr-Sp were not completely extracted by the brain. High bone uptake and kidney clearance was observed with 3-F-Pr-Sp, while 2-F-Et-Sp cleared through the intestine in rats. This is in contrast to FSp where clearance is through the kidney. Studies to evaluate the extraction of metabolites in the brain were carried out by administering large doses (10 mCi) of FSp, 2-F-Et-Sp and 3-F-Pr-Sp to rats and reinjecting the metabolites in blood into other rats. These experiments showed that ~0.02% of the metabohtes from FSp and 3-F-Pr-Sp entered the brain, while 0.5% of the metabolites from 2-F-Et-Sp entered the brain. The majority of the activity present in the cerebellum after the administration of 2-F-Et-Sp is metabolites; therefore 2-F-Et-Sp is unsuitable for PET imaging studies. PET imaging studies in baboons and in one normal human volunteer with 3-F-Pr-Sp showed a high striatum-to-cerbellum ratio, showing that 3-F-Pr-Sp can replace ligands currently in use to study dopamine receptors.
Using positron emission tomography (PET) and nitric oxide radiolabeled with nitrogen-13 (half-lif... more Using positron emission tomography (PET) and nitric oxide radiolabeled with nitrogen-13 (half-life 9.97 min) we probed the distribution and kinetics of inhaled nitric oxide in anesthetized dogs. The washout of this gas after inhalation was much slower than that observed for [13N]nitrogen gas, demonstrating its uptake by lung tissue. The small fraction of radioactivity found in the plasma was determined to be in the form of [13N]nitrate. The administered gas contained < 1 ppm of nonradioactive nitric oxide, which is believed to be below the physiologic threshold for vasorelaxation.
Reports have implicated neuronal nitric oxide synthetase (nNOS) in the pathological effects of ne... more Reports have implicated neuronal nitric oxide synthetase (nNOS) in the pathological effects of neurodegenerative diseases. S-Methyl-Lthiocitrulline (MTICU), a potent and selective nNOS inhibitor («¡=1.2 n/W),was chosen as our initial target molecule for positron emitter labeling as a potential nNOS tracer. We report the synthesis, biological evaluation and primate brain images of S-[11C]methyl-Lthiocitrulline ([11C]MTICU). Methods: The two-step synthesis of [11C]MTICU consisted of the S-alkylation of a-N-Boc-L-thiocitrulline t-butyl ester with [11C]Mel followed by TFA hydrolysis and HPLC purification. The final product was obtained within 50 min (yield = 9.1%-12.5%, based on [11C]Mel SA=27-680 Ci/mmol at end of synthesis). The lipophilicity of [11C]MTICU was determined by octa nol/water partition coefficient (LogP). Blood stability of this tracer in vitro and in vivo was measured by HPLC analysis. Biodistribution using female Sprague-Dawley rats was performed, including exam
Mitomycin Biosynthesis by Streptomyces verticillatus Sir : The mitomycins (I, mitomycin B; 11, mi... more Mitomycin Biosynthesis by Streptomyces verticillatus Sir : The mitomycins (I, mitomycin B; 11, mitomycin C) are a group of anticancer antibiotics which contain a unique carbon-nitrogen ring skeleton' and which are produced by Streptomyces verticillatus and other strains of Streptomyces. Previous studies on their biosynthesis have shown that L-[methyl-14C]methionine provides 0and N-methyl groups but not the C-methyl that L-[guanidino-14C]arginine labels the carbamoyl group,l that label from ~-g l u c o s e~ and from ~-r i b o s e~ appears in the methylbenzoquinone moiety, and that D-[ 1-14C,6-3H, 15N]glucosamine is incorporated in a manner suggesting its utilization as an intact unit.4j6 To further examine the intact incorporation of this amino sugar, D-[ 1-I3C, 15N]glucosamine was prepared from D-arabinose, [ 15N]benzylamine (99 atom I5N), and HI3CN (90 atom % 13C).' Fifty milligrams of
Journal of Cerebral Blood Flow and Metabolism, 1998
Few data regarding early developmental changes in cerebral (blood-to-brain) glucose transport (CT... more Few data regarding early developmental changes in cerebral (blood-to-brain) glucose transport (CTXglc) and CMRglc are available for humans. We measured CBF, CTXglc, and CMRglc with positron emission tomography at 4 to 7 days of life in six preterm human infants whose estimated gestational age was 25 to 34 weeks. The Michaelis-Menten constants Kt and Tmax were estimated from CTXglc and
relation between p320 and mammalian high molecular weight MAPs is suggested by the observation th... more relation between p320 and mammalian high molecular weight MAPs is suggested by the observation that antibody against hog brain MAP 2 reacts weakly with trypanosomal p320, and vice versa (20). The only MAP whose complete sequence has been published so far is the tau protein of mouse brain (29). No similarity between p320 and tau primary sequence is observed. However, the tau sequence also contains three repetitive stretches of 18 amino acids. This, together with proteolysis experiments with mammalian MAP 3 (30) and direct prot9in sequencing of a 180-kD MAP from the spindle apparatus (31) suggest that a repetitive motive may be a common feature in MAP architecture.
Lactate is a key myocardial energy source. Lactate metabolism is altered in a variety of conditio... more Lactate is a key myocardial energy source. Lactate metabolism is altered in a variety of conditions, such as exercise and diabetes mellitus. However, to our knowledge, noninvasive quantitative measurements of myocardial lactate metabolism have never been performed ...
The aim of this study was to investigate whether compartmental modeling of 1-11 C-glucose PET kin... more The aim of this study was to investigate whether compartmental modeling of 1-11 C-glucose PET kinetics can be used for noninvasive measurements of myocardial glucose metabolism beyond its initial extraction. Methods: 1-11 C-Glucose and U-13 C-glucose were injected ...
The ligands currently used for PET studies of the dopamine receptor are fluorine-18-labeled spipe... more The ligands currently used for PET studies of the dopamine receptor are fluorine-18-labeled spiperone (FSp) and carbon-11 or fluorine-18-labeled N-methyl-spiperone. All three of these ligands have drawbacks in either their chemical preparation or their biological behavior. ...
International journal of radiation applications and instrumentation. Part B, Nuclear medicine and biology, 1991
Two 18F-labeled analogues of dexetimides, 2-[18F]fluorodexetimide (2-FDEX) and 4-[18F]fluorodexet... more Two 18F-labeled analogues of dexetimides, 2-[18F]fluorodexetimide (2-FDEX) and 4-[18F]fluorodexetimide (4-FDEX), were prepared and evaluated in vivo as possible agents for the study of the muscarinic acetylcholine receptor (mAChR) with PET. Two synthetic approaches, a 2-step reductive alkylation procedure and a 4-step alkylation approach, were investigated. The alkylation approach with higher overall radiochemical yields was used to prepare 2- and 4-FDEX for biodistribution studies. The overall synthesis time for both compounds was 2.5 h and the overall radiochemical yield at end-of-synthesis was 12%. The specific activity was found to be greater than 600 mCi/mumol. Biodistribution studies of 2-FDEX in rats produced striatum-to-cerebellum and cortex-to-cerebellum ratios of 8.6 +/- 1.1 and 8.4 +/- 1.0 at 1 h after injection, and 12.1 +/- 2.1 and 10.7 +/- 2.2 at 3 h, respectively. Substantial radioactivity detected in bone indicated the in vivo defluorination of 2-FDEX. The striatum-t...
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