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.

ABSTRACT: 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. Reversi

SUBMITTER: Chen Z 

PROVIDER: S-EPMC6581563 | biostudies-literature | 2019 Apr

REPOSITORIES: biostudies-literature