In Vitro and in Vivo Evaluation of (11)C-Labeled Azetidinecarboxylates for Imaging Monoacylglycerol Lipase by PET Imaging Studies.
In Vitro and in Vivo Evaluation of (11)C-Labeled Azetidinecarboxylates for Imaging Monoacylglycerol Lipase by PET Imaging Studies.
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DOI：
10.1021/acs.jmedchem.7b01400
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发表时间：
2018-03-22
影响因子：
7.3
通讯作者：
Liang SH
中科院分区：
文献类型：
--
作者：
Cheng R;Mori W;Ma L;Alhouayek M;Hatori A;Zhang Y;Ogasawara D;Yuan G;Chen Z;Zhang X;Shi H;Yamasaki T;Xie L;Kumata K;Fujinaga M;Nagai Y;Minamimoto T;Svensson M;Wang L;Du Y;Ondrechen MJ;Vasdev N;Cravatt BF;Fowler C;Zhang MR;Liang SH
单酰甘油脂肪酶（MAGL）是代谢内源性大麻素配体2-花生四烯酸酰甘油（2-AG）的主要酶。MAGL的阻断增加2-AG水平，导致内源性大麻素系统的随后激活，并且已经成为治疗药物成瘾、炎症和神经退行性疾病的新型治疗策略。本文报道了一系列新的MAGL抑制剂，它们通过位点特异性标记技术进行放射性标记，包括11 C-羰基化和螺环碘鎓叶立德（SCIDY）放射性标记。先导化合物[11 C]10（MAGL-0519）在体外和体内均表现出较高的特异性结合和选择性。我们还观察到这些不可逆放射性示踪剂的意外洗脱动力学，其中在MAGL和氮杂环丁烷羧酸酯之间揭示了共价残基周转的体内证据。这项工作可能会导致新的方向，药物发现和PET示踪剂开发的基础上氮杂环丁烷羧酸抑制剂支架。
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 11C-carbonylation and spirocyclic iodonium ylide (SCIDY) radiofluorination. The lead compound [11C]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.
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影响因子：
56.9
作者：
FOWLER, JS;MACGREGOR, RR;LANGSTROM, B
通讯作者：
LANGSTROM, B
影响因子：
7.3
作者：
Bjorklund, E.;Noren, E.;Fowler, C. J.
通讯作者：
Fowler, C. J.
影响因子：
--
作者：
Blankman, Jacqueline L.;Simon, Gabriel M.;Cravatt, Benjamin F.
通讯作者：
Cravatt, Benjamin F.
影响因子：
64.8
作者：
通讯作者：
--
影响因子：
7.3
作者：
Friesner, Richard A.;Murphy, Robert B.;Mainz, Daniel T.
通讯作者：
Mainz, Daniel T.