Discovery of N-{(1S,2S)-2-(3-Cyanophenyl)-3-[4-(2-[18F]fluoroethoxy)phenyl]-1-methylpropyl}-2-methyl-2-[(5-methylpyridin-2-yl)oxy]propanamide, a cannabinoid-1 receptor positron emission tomography tracer suitable for clinical use

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 F-18 to the molecule was developed. Further optimization focused on reducing the lipophilicity and increasing the CB1R affinity. These efforts led to the identification of [F-18]-16 that exhibited good brain uptake and an excellent signal-to-noise ratio in rhesus monkeys.