title: Radiosynthesis and evaluation of [¹¹C-carbonyl]-labeled carbamates as fatty acid amide hydrolase radiotracers for positron emission tomography.
abstract: Fatty acid amide hydrolase (FAAH) plays a key role in regulating the tone of the endocannabinoid system. Radiotracers are required to image and quantify FAAH activity in vivo. We have synthesized a series of potent FAAH inhibitors encompassing two classes of N-alkyl-O-arylcarbamates and radiolabeled eight of them with carbon-11. The [¹¹C-carbonyl]-radiotracers were evaluated in vitro and ex vivo in rats as potential FAAH imaging agents for positron emission tomography (PET). Both sets of [¹¹C]O-arylcarbamates showed good to excellent brain penetration and an appropriate regional distribution. Pretreatments with a FAAH inhibitor demonstrated that 80-95% of brain uptake of radioactivity constituted binding of the radiotracers to FAAH. Brain extraction measurements showed that binding to FAAH was irreversible and kinetically different for the two classes of carbamates. These promising results are discussed in terms of the requirements of a suitable radiotracer for the in vivo imaging of FAAH using PET.
authors.affiliation: Research Imaging Centre, Centre for Addiction and Mental Health, Toronto, Ontario M5T 1R8, Canada. alan.wilson@camhpet.ca
authors.forename: Alan A
authors.initials: AA
authors.lastname: Wilson
authors.forename: Justin W
authors.initials: JW
authors.lastname: Hicks
authors.forename: Oleg
authors.initials: O
authors.lastname: Sadovski
authors.forename: Jun
authors.initials: J
authors.lastname: Parkes
authors.forename: Junchao
authors.initials: J
authors.lastname: Tong
authors.forename: Sylvain
authors.initials: S
authors.lastname: Houle
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: Fowler
authors.forename: Neil
authors.initials: N
authors.lastname: Vasdev
mesh_terms: D000581:Amidohydrolases / Q000378:metabolism*; D000818:Animals; D001921:Brain / Q000000981:diagnostic imaging / Q000201:enzymology*; D002219:Carbamates / Q000138:chemical synthesis* / Q000737:chemistry / Q000493:pharmacokinetics; D002250:Carbon Radioisotopes; D006801:Humans; D007553:Isotope Labeling; D049268:Positron-Emission Tomography; D011485:Protein Binding; D051381:Rats; D013329:Structure-Activity Relationship; D014018:Tissue Distribution; D000099252:Fatty Acid Amide Hydrolases
chemical_list: D000581:Amidohydrolases; D002219:Carbamates; D002250:Carbon Radioisotopes; D000099252:Fatty Acid Amide Hydrolases