AIM: To develop a sensitive method for measuring theputative endocannabinoid 2-arachidonylglycerol (2-AG)in the peripheral and ceatral nervous system.METHODS: A method using atmospheric pressurechemical ionization (AP...AIM: To develop a sensitive method for measuring theputative endocannabinoid 2-arachidonylglycerol (2-AG)in the peripheral and ceatral nervous system.METHODS: A method using atmospheric pressurechemical ionization (APCI) liquid chromatography/mass spectrometry (LC/MS ) was developed todetermine the levels of 2-AG in methanol extracts of therat lumar spinal cord, dorsal root ganglion (DRG),and sciatic nerve. RESULTS: 2-AG was detectedwith high sensitivity and minimal sample preparation.The levels in the tissues analyzed were ≤pmol/mg wetweight. Similar levels were found in the spinal展开更多
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).Dys...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 18F-labeled MAGL PET tracers.展开更多
文摘AIM: To develop a sensitive method for measuring theputative endocannabinoid 2-arachidonylglycerol (2-AG)in the peripheral and ceatral nervous system.METHODS: A method using atmospheric pressurechemical ionization (APCI) liquid chromatography/mass spectrometry (LC/MS ) was developed todetermine the levels of 2-AG in methanol extracts of therat lumar spinal cord, dorsal root ganglion (DRG),and sciatic nerve. RESULTS: 2-AG was detectedwith high sensitivity and minimal sample preparation.The levels in the tissues analyzed were ≤pmol/mg wetweight. Similar levels were found in the spinal
基金the financial support from the NIH grants (DA038000 and DA043507 to S. H. L. and DA033760 to B. F. C.)the Swiss National Science Foundation for a postdoctoral fellowship to Michael A. Schafroth (Grant No. P2EZP3_175137, Switzerland)。
文摘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 18F-labeled MAGL PET tracers.
