Design, Synthesis, and Evaluation of Reversible and Irreversible Monoacylglycerol Lipase Positron Emission Tomography (PET) Tracers Using a “Tail Switching” Strategy on a Piperazinyl Azetidine Skeleton

Monoacylglycerol
lipase (MAGL) is a serine hydrolase that degrades
2-arachidonoylglycerol (2-AG) in the endocannabinoid system (eCB).
Selective inhibition of MAGL has emerged as a potential therapeutic
approach for the treatment of diverse pathological conditions, including
chronic pain, inflammation, cancer, and neurodegeneration. Herein,
we disclose a novel array of reversible and irreversible MAGL inhibitors
by means of “tail switching” on a piperazinyl azetidine
scaffold. We developed a lead irreversible-binding MAGL inhibitor 8 and reversible-binding compounds 17 and 37, which are amenable for radiolabeling with 11C or 18F. [11C]8 ([11C]­MAGL-2-11) exhibited high brain uptake and excellent binding specificity
in the brain toward MAGL. Reversible radioligands [11C]17 ([11C]­PAD) and [18F]37 ([18F]­MAGL-4-11) also demonstrated excellent in vivo
binding specificity toward MAGL in peripheral organs. This work may
pave the way for the development of MAGL-targeted positron emission
tomography tracers with tunability in reversible and irreversible
binding mechanisms.