Development of High Brain-Penetrant and Reversible Monoacylglycerol Lipase PET Tracers for Neuroimaging

Monoacylglycerol lipase (MAGL) is
one of the key enzymes in the
endocannabinoid system. Inhibition of MAGL has been proposed as an
attractive approach for the treatment of various diseases. In this
study, we designed and successfully synthesized two series of piperazinyl
pyrrolidin-2-one derivatives as novel reversible MAGL inhibitors.
(R)-[18F]13 was identified
through the preliminary evaluation of two carbon-11-labeled racemic
structures [11C]11 and [11C]16. In dynamic positron-emission tomography (PET) scans, (R)-[18F]13 showed a heterogeneous
distribution and matched the MAGL expression pattern in the mouse
brain. High brain uptake and brain-to-blood ratio were achieved by
(R)-[18F]13 in comparison
with previously reported reversible MAGL PET radiotracers. Target
occupancy studies with a therapeutic MAGL inhibitor revealed a dose-dependent
reduction of (R)-[18F]13 accumulation
in the mouse brain. These findings indicate that (R)-[18F]13 ([18F]­YH149) is a highly
promising PET probe for visualizing MAGL non-invasively in
vivo and holds great potential to support drug development.