Development of a novel 18F-labeled reversible-binding radioligand for imaging monoacylglycerol lipase with positron emission tomography

作者：Jian Rong, Chunyu Zhao, Ahmad Chaudhary, Tim Ware, Richard Van, Yinlong Li, Erick R. Calderon Leon, Vivi Dang, Jiahui Chen, Zhiwei Xiao, Xin Zhou, Wei Zhang, Chunyang Bi, Kuo Zhang, Jimmy S. Patel, Yihan Shao, Chongzhao Ran, Ludovic Collin, Ahmed Haider, Benjamin F. Cravatt, Steven H. Liang · 发表于：Acta Pharmaceutica Sinica B · 年份：2025 · DOI：10.1016/j.apsb.2025.05.041 · 被引用次数：3 · 研究领域：Cannabis and Cannabinoid Research、Alcohol Consumption and Health Effects、Diet, Metabolism, and Disease

Monoacylglycerol lipase (MAGL) constitutes a crucial serine hydrolase within the endocannabinoid system, which has been suggested as a potential therapeutic target for the treatment of various neurodegenerative disorders. While MAGL inhibitors have entered the clinical arena, a highly selective and MAGL-specific positron emission tomography (PET) ligand holds promise to significantly facilitate clinical drug development by allowing the quantification of MAGL levels and the assessment of target occupancy in patients. Accordingly, this study aimed to develop a new series of reversible MAGL inhibitor candidates, based on a piperazinyl azetidine diamide scaffold. Compound 3 demonstrated the most promising performance characteristics in pharmacological evaluations compared to other MAGL inhibitor candidates. Subsequently, it was labeled with fluorine-18 and further assessed through autoradiography and PET imaging, as well as ex vivo biodistribution and metabolite analysis experiments in rodents. Compound 3 exhibited a heterogeneous radioactivity distribution, favorable brain uptake, and excellent in vivo binding specificity. The target occupancy study with a therapeutic MAGL inhibitor demonstrated a dose-dependent PET signal reduction of [ 18 F] 3 in rat brains. In conclusion, [ 18 F] 3 ([ 18 F]MAGL-2011) has the potential to serve as an effective MAGL PET ligand.