Division of Nuclear Medicine and Molecular Imaging, Department of Radiology , Massachusetts General Hospital and Harvard Medical School , Boston , Massachusetts 02114 , United States.
School of Pharmaceutical Science and Technology , Tianjin University , 92 Weijin Road, Nankai District , Tianjin 300072 , China.
J Med Chem. 2018 Mar 22;61(6):2278-2291. doi: 10.1021/acs.jmedchem.7b01400. Epub 2018 Mar 9.
Monoacylglycerol lipase (MAGL) is the principle enzyme for metabolizing endogenous cannabinoid ligand 2-arachidonoyglycerol (2-AG). Blockade of MAGL increases 2-AG levels, resulting in subsequent activation of the endocannabinoid system, and has emerged as a novel therapeutic strategy to treat drug addiction, inflammation, and neurodegenerative diseases. Herein we report a new series of MAGL inhibitors, which were radiolabeled by site-specific labeling technologies, including C-carbonylation and spirocyclic iodonium ylide (SCIDY) radiofluorination. The lead compound [C]10 (MAGL-0519) demonstrated high specific binding and selectivity in vitro and in vivo. We also observed unexpected washout kinetics with these irreversible radiotracers, in which in vivo evidence for turnover of the covalent residue was unveiled between MAGL and azetidine carboxylates. This work may lead to new directions for drug discovery and PET tracer development based on azetidine carboxylate inhibitor scaffold.
单酰基甘油脂肪酶（MAGL）是代谢内源性大麻素配体 2-花生四烯酸甘油（2-AG）的主要酶。MAGL 的阻断会增加 2-AG 水平，从而导致内源性大麻素系统的后续激活，并且已成为治疗药物成瘾、炎症和神经退行性疾病的新的治疗策略。在此，我们报告了一系列新的 MAGL 抑制剂，这些抑制剂通过定点标记技术进行放射性标记，包括 C-羰基化和螺环碘化𬭩叶立德（SCIDY）放射性氟化。先导化合物 [C]10（MAGL-0519）在体外和体内表现出高特异性结合和选择性。我们还观察到这些不可逆示踪剂的意外洗脱动力学，其中揭示了 MAGL 和氮杂环丁烷羧酸酯之间的共价残基的酶促转化的体内证据。这项工作可能为基于氮杂环丁烷羧酸酯抑制剂支架的药物发现和正电子发射断层扫描（PET）示踪剂开发开辟新的方向。
