Novel Reversible-Binding PET Ligands for Imaging Monoacylglycerol Lipase Based on the Piperazinyl Azetidine Scaffold

Monoacylglycerol lipase (MAGL) is a 33 kDa serine protease primarily
responsible for hydrolyzing 2-arachidonoylglycerol into the proinflammatory
eicosanoid precursor arachidonic acid in the central nervous system.
Inhibition of MAGL constitutes an attractive therapeutic concept for
treating psychiatric disorders and neurodegenerative diseases. Herein,
we present the design and synthesis of multiple reversible MAGL inhibitor
candidates based on a piperazinyl azetidine scaffold. Compounds 10 and 15 were identified as the best-performing
reversible MAGL inhibitors by pharmacological evaluations, thus channeling
their radiolabeling with fluorine-18 in high radiochemical yields
and favorable molar activity. Furthermore, evaluation of [18F]10 and [18F]15 ([18F]­MAGL-2102) by autoradiography and positron emission tomography
(PET) imaging in rodents and nonhuman primates demonstrated favorable
brain uptakes, heterogeneous radioactivity distribution, good specific
binding, and adequate brain kinetics, and [18F]15 demonstrated a better performance. In conclusion, [18F]15 was found to be a suitable PET radioligand for
the visualization of MAGL, harboring potential for the successful
translation into humans.