title: Synthesis, in vitro and in vivo evaluation, and radiolabeling of aryl anandamide analogues as candidate radioligands for in vivo imaging of fatty acid amide hydrolase in the brain.
abstract: Fatty acid amide hydrolyase (FAAH) is one of the main enzymes responsible for terminating the signaling of endocannabinoids in the brain. Imaging FAAH in vivo using PET or SPECT is important to deeper understanding of its role in neuropsychiatric disorders. However, at present, no radioligand is available for mapping the enzyme in vivo. Here, we synthesized 18 aryl analogues of anandamide, FAAH's endogenous substrate, and in vitro evaluated their potential as metabolic trapping tracers. Interaction studies with recombinant FAAH revealed good to very good interaction of the methoxy substituted aryl anandamide analogues 17, 18, 19, and 20 with FAAH and they were identified as competing substrates. Compounds 17 and 18 did not display significant binding to CB1 and CB2 cannabinoid receptors and stand out as potential candidate metabolic trapping tracers. They were successfully labeled with 11C in good yields and high radiochemical purity and displayed brain uptake in C57BL/6J mice. Radioligands [11C]-17 and [11C]-18 merit further investigation in vivo.
authors.affiliation: Department of Radiopharmacy, Ghent University, Harelbekestraat 72, B-9000 Ghent, Belgium.
authors.forename: Leonie
authors.initials: L
authors.lastname: Wyffels
authors.forename: Giulio G
authors.initials: GG
authors.lastname: Muccioli
authors.forename: Sylvie
authors.initials: S
authors.lastname: De Bruyne
authors.forename: Lieselotte
authors.initials: L
authors.lastname: Moerman
authors.forename: Johan
authors.initials: J
authors.lastname: Sambre
authors.forename: Didier M
authors.initials: DM
authors.lastname: Lambert
authors.forename: Filip
authors.initials: F
authors.lastname: De Vos
mesh_terms: D000581:Amidohydrolases / Q000032:analysis* / Q000378:metabolism; D000818:Animals; D001095:Arachidonic Acids / Q000138:chemical synthesis / Q000378:metabolism*; D001921:Brain / Q000201:enzymology*; D016466:CHO Cells; D002250:Carbon Radioisotopes; D006224:Cricetinae; D003412:Cricetulus; D063388:Endocannabinoids; D007553:Isotope Labeling; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D053284:Polyunsaturated Alkamides / Q000138:chemical synthesis / Q000378:metabolism*; D011869:Radioligand Assay; D043884:Receptor, Cannabinoid, CB1 / Q000378:metabolism; D013329:Structure-Activity Relationship; D000099252:Fatty Acid Amide Hydrolases
chemical_list: D000581:Amidohydrolases; D001095:Arachidonic Acids; D002250:Carbon Radioisotopes; D063388:Endocannabinoids; D053284:Polyunsaturated Alkamides; D043884:Receptor, Cannabinoid, CB1; D000099252:Fatty Acid Amide Hydrolases; C078814:anandamide