Discovery of N{(lS,2S)-2-(3-Cyanophenyl)-3-[4-(2-[~(18)F]fluoroethoxy)phenyl]-l-methylpropyI}-2-methyl-2-[(5-methylpyridin-2-yl)oxy]propan-amide, a Cannabinoid-1 Receptor Positron Emission Tomography Tracer Suitable for Clinical Use

摘要

The discovery of a structurally distinct cannabinoid-1 receptor (CB1R) positron emission tomography tracer is described. Starting from an acyclic amide CB1R inverse agonist (1) as the lead compound, an efficient route to introduce ~(18)F to the molecule was developed. Further optimization focused on reducing the lipophilicity and increasing the CB1R affinity. These efforts led to the identification of [~(18)F]-16 that exhibited good brain uptake and an excellent signal-to-noise ratio in rhesus monkeys.