Andrew Horti

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David Seamon

Kansas State University

Franco Barchiesi

Ohio State University

Jan A Kozák

Charles University, Prague

Janet Cherry

Nelson Mandela Metropolitan University

François-Xavier Fauvelle

Collège de France

rudolph bauer

Washington Center for Consciousness Studies

David Sharp

Imperial College London

Nicolas A Karakatsanis

Weill Cornell Medicine

Stefka G Eriksen

University of Oslo

Damian Valdés Santiago

Universidad de la Habana

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Abstract 4533: Synthesis and biodistribution of225Ac-substance P for intracavitary radiopharmaceutical therapy of high-grade recurrent glioma

Cancer Research, Apr 1, 2013

Glioblastoma (GB) is the most common malignant brain tumor in adults and prognosis of patients re... more Glioblastoma (GB) is the most common malignant brain tumor in adults and prognosis of patients remains poor with median survival of only 14.6 months. The majority of patients recur with tumor growth beyond the margin of the surgical cavity. The failure to significantly impact overall survival with current treatments is mainly due to the aggressive invasiveness of GB cells and their resistance to radiation and chemotherapy. High linear energy transfer (LET) alpha particle radiation offers an attractive approach to overcome resistance of GB and improve survival. We propose to treat GB patients with intracavitary injected alpha particle emitter 225Ac delivered on a synthetic peptide, substance P of the tachykinin neuropeptide family (NK1 receptor), which can readily penetrate brain parenchyma and target widely disseminated GB cells. Importantly, increased expression of NK-1 receptors is correlated with glioma malignancy and is thought to be responsible for tumor progression. A recent clinical study evaluating alpha particle emitter 213Bi labeled substance P for treatment of high grade gliomas demonstrated tolerable toxicity and efficacy. The pharmacokinetic and SPECT/CT imaging studies of 111In-substance P revealed large variability among patients in the rate of clearance from the tumor cavity. These observations suggest that better treatment planning with patient specific pre-therapy imaging based dosimetry can optimize the absorbed doses delivered to the tumor cavity while limiting toxicity to normal tissues. Based on this hypothesis, we evaluated radiochemical property and biodistribution of 225Ac-substance P in vitro and in mice. Both 225Ac and 111In were readily labeled to substance P-DOTA at 95 °C in an acetate buffer. After purification with reverse phase HPLC, the purities of both radio-peptides were around 99%. Binding affinity (Kd) of radiolabeled substance P was found to be 20 nM with Scatchard analysis. In vitro cell kill assay showed that cytotoxicity of 225Ac-substance P (A0=6.3nCi) significantly increased in NK-1 expressing U251 cells compared to non-specific 225Ac-Rituximab (A0=15.4nCi). Biodistribution studies following intracranial (right side of the midline) injection of 225Ac- or 111In- substance P showed that 111In- and 225Ac cleared from right brain (injection side) in tumor free mice with similar half-lives (11.2 hr vs. 16.5 hr) and penetrated into left side of the brain with a similar peak uptake of 31.0 and 33.8 %ID/g at 4 hours after injection. Moreover, both 111In- and 225Ac-substance P was cleared quickly from the kidneys with a peak uptake of 2.5% and 2.2 %ID/g at 4 hrs after injection. No significant accumulation in other normal organs was observed. These data suggest that intracavitary 225Ac-substance P might be a viable treatment option and pre-treatment dosimetry planning based on 111In-substance P imaging is feasible. Citation Format: Hong Song, Hugo Guerrero-Cazares, Andrew Horti, Richard L. Wahl, Alfredo Quinones-Hinojosa, George Sgouros. Synthesis and biodistribution of 225Ac-substance P for intracavitary radiopharmaceutical therapy of high-grade recurrent glioma. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 4533. doi:10.1158/1538-7445.AM2013-4533

Microwave-assisted radiosynthesis of [18F]ASEM, a radiolabeledα7-nicotinic acetylcholine receptor antagonist

Journal of Labelled Compounds and Radiopharmaceuticals, Feb 26, 2015

An improvement of the original radiochemical synthesis of [ 18 F]ASEM, an α7-nicotinic acetylchol... more An improvement of the original radiochemical synthesis of [ 18 F]ASEM, an α7-nicotinic acetylcholinergic receptor radioligand, is reported. The new procedure utilizes microwave-assisted radiofluorination. In addition, a new preparative HPLC method was developed to eliminate a chemical impurity in the final product. Quality control procedures were also enhanced to improve detection of product with enhanced resolution of potential impurities. [ 18 F]ASEM was produced in 20.1 ± 8.9% non-decay corrected (NDC) yield with an average synthesis time of 57 min and an average specific radioactivity of 856 ± 332 GBq/μmol (23 ± 9 Ci/μmol).

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