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 [F-18]10 and [F-18]15 ([F-18]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 [F-18]15 demonstrated a better performance. In conclusion, [F-18]15 was found to be a suitable PET radioligand for the visualization of MAGL, harboring potential for the successful translation into humans.

Automated summary

Monoacylglycerol lipase (MAGL) is responsible for hydrolyzing 2-arachidonoylglycerol into arachidonic acid in the central nervous system, making it a potential target for treating psychiatric disorders and neurodegenerative diseases. Reversible MAGL inhibitors were designed and synthesized, with compounds 10 and 15 identified as the best performers. Radiolabeling with fluorine-18 and evaluation in rodents and nonhuman primates showed that compound [F-18]15 demonstrated the best performance as a PET radioligand for visualizing MAGL in the brain.