https://doi.org/10.1016/j.apsb.2025.05.041
This new article publication from Acta Pharmaceutica Sinica B , discusses the development of a novel 18F-labeled reversible-binding radioligand for imaging monoacylglycerol lipase with positron emission tomography.
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. Target occupancy studies 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.
Keywords: Monoacylglycerol lipase, MAGL, Serine hydrolase, PET
Graphical Abstract: available https://ars.els-cdn.com/content/image/1-s2.0-S221138352500379X-ga1_lrg.jpg
A highly potent reversible MAGL PET ligand [ 18 F] 3 ([ 18 F]MAGL-2011) was developed with promising in vitro and in vivo characteristics, including heterogeneous radioactivity distribution, favorable brain uptake, and excellent binding specificity.
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The Journal of the Institute of Materia Medica, the Chinese Academy of Medical Sciences and the Chinese Pharmaceutical Association .
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CiteScore: 24.3
Impact Factor: 14.6 (Top 6 journal in the category of Pharmacology and pharmacy)
JIF without self-citation: 13.8
ISSN 2211-3835
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Jian Rong, Chunyu Zhao, Ahmad F. Chaudhary, Tim Ware, Richard S. 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, Achi Haider, Benjamin F. Cravatt, Steven H. Liang, Development of a novel 18F-labeled reversible-binding radioligand for imaging monoacylglycerol lipase with positron emission tomography, Acta Pharmaceutica Sinica B, Volume 15, Issue 12, 2025, Pages 6714-6726, ISSN 2211-3835, https://doi.org/10.1016/j.apsb.2025.05.041
Acta Pharmaceutica Sinica B