Development of a highly-specific 18F-labeled irreversible positron emission tomography tracer for monoacylglycerol lipase mapping

• 作者: 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
• 来源期刊: 药学学报（英文版）
• 年，卷（期）: 2021,（6）
• 所属期刊栏目: Short communication
• 页码范围: 1686-1695
• 页数: 10页
• 语种: 英文

摘要

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 forma-tion 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 treat-ment of these conditions,and a MAGL positron emission tomography (PET) probe would greatly facil-itate 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 can-didates by activity-based protein profiling identified 14 as a lead compound,which was then radiolabeled with fluorine-18 via a facile SNAr reaction to form 2-[18F]fluoropyridine scaffold.Good blood-brain bar-rier permeability and high in vivo specific binding was demonstrated for radioligand[18F]14 (also named as[18F]MAGL-1902).This work may serve as a roadmap for clinical translation and further design of potent 18F-labeled MAGL PET tracers.