Identification and Development of an Irreversible Monoacylglycerol Lipase (MAGL) Positron Emission Tomography (PET) Radioligand with High Specificity

Monoacylglycerol lipase (MAGL), a
serine hydrolase extensively
expressed throughout the brain, serves as a key gatekeeper regulating
the tone of endocannabinoid signaling. Preclinically, inhibition of
MAGL is known to provide therapeutic benefits for a number of neurological
disorders. The availability of a MAGL-specific positron emission tomography
(PET) ligand would considerably facilitate the development and clinical
characterization of MAGL inhibitors via noninvasive and quantitative
PET imaging. Herein, we report the identification of the potent and
selective irreversible MAGL inhibitor 7 (PF-06809247)
as a suitable radioligand lead, which upon radiolabeling was found
to exhibit a high level of MAGL specificity; this enabled cross-species
measurement of MAGL brain expression (Bmax), assessment of in vivo binding in the rat, and nonhuman primate
PET imaging.