Development of a Highly-Specific 18F-Labeled Irreversible Positron Emission Tomography Tracer for Monoacylglycerol Lipase Mapping

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 14 as a lead compound,which was then radiolabeled with fluorine-18 via a facile SNAr reaction to form 2-[ 18 F]fluoropyridine scaffold.Good blood-brain barrier permeability and high in vivo specific binding was demonstrated for radioligand [ 18 F]14(also named as [ 18 F]MAGL-1902).This work may serve as a roadmap for clinical translation and further design of potent 18 F-labeled MAGL PET tracers.