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

作者：Andersson Jan D^*; Pierson M Edward; Finnema Sjoerd J; Gulyas Balazs; Heys Richard; Elmore Charles S; Farde Lars; Halldin Christer

来源：Nuclear Medicine and Biology, 2011, 38(2): 261-272.

DOI：10.1016/j.nucmedbio.2010.08.006

• Radioligand development
• Positron emission tomography (PET)
• Serotonin
• 5-HT1B

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.

• 出版日期2011-2