Synthesis of [11C]carbonyl-labeled cyclohexyl (5-(2-acetamidobenzo[d]thiazol-6-yl)-2-methylpyridin-3-yl)carbamate ([11C-carbonyl]PK68) as a potential PET tracer for receptor-interacting protein 1 kinase

Abstract

BackgroundReceptor-interacting protein 1 kinase (RIPK1) is a key enzyme in the regulation of cellular necroptosis. Recently, cyclohexyl (5-(2-acetamidobenzo[d]thiazol-6-yl)-2-methylpyridin-3-yl)carbamate (PK68, 5) has been developed as a potent inhibitor of RIPK1. Herein, we synthesized [11C]carbonyl-labeled PK68 ([11C-carbonyl]PK68, [11C]PK68) as a potential PET tracer for imaging RIPK1 and evaluated its brain uptake in vivo.ResultsWe synthesized [11C]PK68 by reacting amine precursor 14 with [11C]acetyl chloride. At the end of synthesis, we obtained [11C]PK68 of 1200–1790 MBq with a radiochemical yield of 9.1 ± 5.9% (n = 10, decay-corrected to the end of irradiation) and radiochemical purity of > 99%, and a molar activity of 37–99 GBq/μmol starting from 18–33 GBq of [11C]CO2. The fully automated synthesis took 30 min from the end of irradiation. In a small-animal PET study, [11C]PK68 was rapidly distributed in the liver and kidneys of healthy mice after injection, and subsequently cleared from their bodies via hepatobiliary excretion and the intestinal reuptake pathway. Although there was no obvious specific binding of RIPK1 in the PET study, [11C]PK68 demonstrated relatively high stability in vivo and provided useful structural information further candidate development.ConclusionsIn the present study, we successfully radiosynthesized [11C]PK68 as a potential PET tracer and evaluated its brain uptake. We are planning to optimize the chemical structure of [11C]PK68 and conduct further PET studies on it using pathological models.