Vasopressin receptor 1A (V1AR) is a G-protein coupled receptor (GPCR) that is expressed throughout the brain and in peripheral organs such as the liver, kidney and the circulatory vascular system. In the central nervous system (CNS), V1AR mediates water reabsorption, thereby maintaining cardiovascular homeostasis and modulating blood pressure. In the CNS, however, V1AR regulates social and emotional behavior as well as cognitive functions. Accordingly, dysfunction of V1AR has been implicated in autism spectrum disorder (ASD) – a complex developmental condition that involves persistent challenges in social interaction, communication and behavior. Given the emerging role in ASD, various V1AR antagonists are in the clinical pipeline. To facilitate the development of V1AR antagonists, we sought to develop a suitable V1AR PET radioligand for non-invasive receptor mapping and target engagement studies. In a multistep synthesis, the recently reported triazolobenzodiazepine derivative, PF-184563 (IC50 V1A = 5.5 nM), and the respective desmethyl precursor for carbon-11 labeling were successfully synthesized using an optimized synthetic approach that involved benzodiazepine ring-closure via intramolecular amide formation, followed by thiation of the carbonyl moiety. Of note, triazole formation was performed in the final synthetic step and was used to link the benzodiazepine core to a pyridine-bearing piperidine moiety. Carbon-11 labeling was accomplished via N-alkylation of the secondary amine, yielding [11C]PF-184563 in high radiochemical purities and molar activities. Biological evaluation of [11C]PF-184563 by in vitro autoradiography, metabolite studies, ex vivo biodistribution and PET imaging experiments is currently ongoing.

Discovery of a triazolobenzodiazepine-based PET radioligand for vasopressin receptor 1A-targeted PET imaging

ACS Spring Meeting 2021

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