Development of a PET radioligand for the central 5-HT1B receptor: radiosynthesis and characterization in cynomolgus monkeys of eight radiolabeled compounds

Introduction: The serotonin 1B (5-HT1B) receptor has been implicated in several psychiatric disorders and is a potential pharmacological target in the treatment of depression. The aim of this study was to develop a radioligand for positron emission tomography (PET) imaging of the 5-HT1B receptor in the primate brain in vivo. Methods: Eight carboxamide radioligands (1-8) from three different core structures were radiolabeled with carbon-11 employing N-methylation with [C-11]methyl triflate on the piperazine structural moiety. In vivo PET evaluation of each radioligand was performed in cynomolgus monkeys and included analysis of radioactive metabolites measured in plasma using high-performance liquid chromatography. Results: In a total of 12 radiosynthesis of the eight radioligands, the mean decay corrected yield was 11%, and the mean specific radioactivity was 299 CBq/mu mol (8075 Ci/mmol) at time of administration. Of the eight tested candidates, [C-11]6 demonstrated the most promising in vivo characteristics, showing high binding in 5-HT1B receptor-rich regions and low binding in the cerebellum. When inspecting data from all eight compounds, lipophilicity appeared as a physicochemical property that could be related to favorable in vivo imaging characteristics. Conclusion: Candidate [C-11]6, i.e., [C-11]AZ10419369, exhibited high binding potentials in regions known to contain 5-HT1B receptors and was nominated for further preclinical characterization and PET examination in human subjects. (C) 2011 Elsevier Inc. All rights reserved.