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[18F]FEPAD.Pharmacokinetics and binding studies on[18F]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[18F]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.

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

Division of Nuclear Medicine and Molecular Imaging,Department of Radiology,Massachusetts General Hospital and Harvard Medical School,Boston,MA 02114,USA;School of Medical Imaging,Tianjin Medical University,Tianjin 300203,China;Department of Radiopharmaceuticals Development,National Institute of Radiological Sciences,National Institutes for Quantum and Radiological Science and Technology,Chiba 263-8555,Japan;Athinoula A.Martinos Center for Biomedical Imaging,Massachusetts General Hospital and Harvard Medical School,Boston,MA 02125,USA;The Skaggs Institute for Chemical Biology and Department of Chemical Physiology,The Scripps Research Institute,La Jolla,CA 92037,USA;Department of Chemistry and Biochemistry,University of Oklahoma,Norman,OK 73019,USA;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

中国药理学报（英文版）

[1]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-.A novel monoacylglycerol lipase-targeted 18F-labeled probe for positron emission tomography imaging of brown adipose tissue in the energy network)[J].中国药理学报（英文版）,2022(11):3002-3010

Monoacylglycerol,arachidonoylglycerol,piperidinyl,azetidine,diamide,radiofluorinated,FEPAD,endocannabinoids

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