Development of a highly-specific

Zhen Chen; Wakana Mori; Jian Rong; Michael A Schafroth; Tuo Shao; Richard S Van; Daisuke Ogasawara; Tomoteru Yamasaki; Atsuto Hiraishi; Akiko Hatori; Jiahui Chen; Yiding Zhang; Kuan HU; Masayuki Fujinaga; Jiyun Sun; Qingzhen YU; Thomas L Collier; Yihan Shao; Benjamin F Cravatt; Lee Josephson; Ming-rong Zhang; Steven H Liang

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Development of a highly-specific

Author: Zhen CHEN ¹ ; Wakana MORI ² ; Jian RONG ¹ ; Michael A SCHAFROTH ³ ; Tuo SHAO ¹ ; Richard S VAN ⁴ ; Daisuke OGASAWARA ³ ; Tomoteru YAMASAKI ² ; Atsuto HIRAISHI ² ; Akiko HATORI ² ; Jiahui CHEN ¹ ; Yiding ZHANG ² ; Kuan HU ² ; Masayuki FUJINAGA ² ; Jiyun SUN ¹ ; Qingzhen YU ¹ ; Thomas L COLLIER ¹ ; Yihan SHAO ⁴ ; Benjamin F CRAVATT ³ ; Lee JOSEPHSON ¹ ; Ming-Rong ZHANG ² ; Steven H LIANG ¹
Author Information

1. Division of Nuclear Medicine and Molecular Imaging, Massachusetts General Hospital & Department of Radiology, Harvard Medical School, Boston, MA 02114, USA.
2. Department of Advanced Nuclear Medicine Sciences, National Institute of Radiological Sciences, National Institutes for Quantum and Radiological Science and Technology, Chiba 263-8555, Japan.
3. The Skaggs Institute for Chemical Biology and Department of Chemical Physiology, The Scripps Research Institute, La Jolla, CA 92037, USA.
4. Department of Chemistry and Biochemistry, University of Oklahoma, Norman, OK 73019, USA.
Publication Type:Journal Article
Keywords: 2-Arachidonylglycerol (2-AG); Arachidonic acid (AA); Central nervous system (CNS); Fluorine-18; Monoacylglycerol lipase (MAGL); Positron emission tomography (PET)
From: Acta Pharmaceutica Sinica B 2021;11(6):1686-1695
CountryChina
Language:English
Abstract: As a serine hydrolase, monoacylglycerol lipase (MAGL) is principally responsible for the metabolism of 2-arachidonoylglycerol (2-AG) in the central nervous system (CNS), leading to the formation of arachidonic acid (AA). Dysfunction of MAGL has been associated with multiple CNS disorders and symptoms, including neuroinflammation, cognitive impairment, epileptogenesis, nociception and neurodegenerative diseases. Inhibition of MAGL provides a promising therapeutic direction for the treatment of these conditions, and a MAGL positron emission tomography (PET) probe would greatly facilitate preclinical and clinical development of MAGL inhibitors. Herein, we design and synthesize a small library of fluoropyridyl-containing MAGL inhibitor candidates. Pharmacological evaluation of these candidates by activity-based protein profiling identified