A novel monoacylglycerol lipase-targeted^(18)F-labeled probe for positron emission tomography imaging of brown adipose tissue in the energy network  

作　　者：Ran Cheng Masayuki Fujinaga Jing Yang Jian Rong Ahmed Haider Daisuke Ogasawara Richard S.Van Tuo Shao Zhen Chen Xiaofei Zhang Erick R.Calderon Leon Yiding Zhang Wakana Mori Katsushi Kumata Tomoteru Yamasaki Lin Xie Shaofa Sun Lu Wang Chongzhao Ran Yihan Shao Benjamin Cravatt Lee Josephson Ming-Rong Zhang Steven H.Liang 

机构地区：[1]Division of Nuclear Medicine and Molecular Imaging,Department of Radiology,Massachusetts General Hospital and Harvard Medical School,Boston,MA 02114,USA [2]School of Medical Imaging,Tianjin Medical University,Tianjin 300203,China [3]Department of Radiopharmaceuticals Development,National Institute of Radiological Sciences,National Institutes for Quantum and Radiological Science and Technology,Chiba 263-8555,Japan [4]Athinoula A.Martinos Center for Biomedical Imaging,Massachusetts General Hospital and Harvard Medical School,Boston,MA 02125,USA [5]The Skaggs Institute for Chemical Biology and Department of Chemical Physiology,The Scripps Research Institute,La Jolla,CA 92037,USA [6]Department of Chemistry and Biochemistry,University of Oklahoma,Norman,OK 73019,USA [7]Hubei Collaborative Innovation Centre for Non-power Nuclear Technology,College of Nuclear Technology&Chemistry and Biology,Hubei University of Science and Technology,Xianning,Hubei Province 437100,China

出　　处：《Acta Pharmacologica Sinica》2022年第11期3002-3010,共9页中国药理学报（英文版）

基　　金：the National Natural Science Foundation of China(No.81801770);the Natural Science Foundation of Tianjin City(19JCQNJC11100).

摘　　要：Monoacylglycerol lipase(MAGL)constitutes a serine hydrolase that orchestrates endocannabinoid homeostasis and exerts its function by catalyzing the degradation of 2-arachidonoylglycerol(2-AG)to arachidonic acid(AA).As such,selective inhibition of MAGL represents a potential therapeutic and diagnostic approach to various pathologies including neurodegenerative disorders,metabolic diseases and cancers.Based on a unique 4-piperidinyl azetidine diamide scaffold,we developed a reversible and peripheral-specific radiofluorinated MAGL PET ligand[^(18)F]FEPAD.Pharmacokinetics and binding studies on[^(18)F]FEPAD revealed its outstanding specificity and selectivity towards MAGL in brown adipose tissue(BAT)–a tissue that is known to be metabolically active.We employed[^(18)F]FEPAD in PET studies to assess the abundancy of MAGL in BAT deposits of mice and found a remarkable degree of specific tracer binding in the BAT,which was confirmed by post-mortem tissue analysis.Given the negative regulation of endocannabinoids on the metabolic BAT activity,our study supports the concept that dysregulation of MAGL is likely linked to metabolic disorders.Further,we now provide a suitable imaging tool that allows non-invasive assessment of MAGL in BAT deposits,thereby paving the way for detailed mechanistic studies on the role of BAT in endocannabinoid system(ECS)-related pathologies.

关 键 词：monoacylglycerol lipase(MAGL) positron emission tomography(PET) diagnostic imaging FLUORINE-18 brown adipose tissue(BAT) 

分 类 号：R589.2[医药卫生—内分泌]