title: Development and characterization of a promising fluorine-18 labelled radiopharmaceutical for in vivo imaging of fatty acid amide hydrolase.
abstract: Fatty acid amide hydrolase (FAAH), the enzyme responsible for terminating signaling by the endocannabinoid anandamide, plays an important role in the endocannabinoid system, and FAAH inhibitors are attractive drugs for pain, addiction, and neurological disorders. The synthesis, radiosynthesis, and evaluation, in vitro and ex vivo in rat, of an (18)F-radiotracer designed to image FAAH using positron emission tomography (PET) is described. Fluorine-18 labelled 3-(4,5-dihydrooxazol-2-yl)phenyl (5-fluoropentyl)carbamate, [(18)F]5, was synthesized at high specific activity in a one-pot three step reaction using a commercial module with a radiochemical yield of 17-22% (from [(18)F]fluoride). In vitro assay using rat brain homogenates showed that 5 inhibited FAAH in a time-dependent manner, with an IC50 value of 0.82nM after a preincubation of 60min. Ex vivo biodistribution studies and ex vivo autoradiography in rat brain demonstrated that [(18)F]5 had high brain penetration with standard uptake values of up to 4.6 and had a regional distribution which correlated with reported regional FAAH enzyme activity. Specificity of binding to FAAH with [(18)F]5 was high (>90%) as demonstrated by pharmacological challenges with potent and selective FAAH inhibitors and was irreversible as demonstrated by radioactivity measurements on homogenized brain tissue extracts. We infer from these results that [(18)F]5 is a highly promising candidate radiotracer with which to image FAAH in human subjects using PET and clinical studies are proceeding.
authors.affiliation: Research Imaging Centre, Centre for Addiction and Mental Health, 250 College St., Toronto, ON M5T 1R8, Canada.
authors.forename: Oleg
authors.initials: O
authors.lastname: Sadovski
authors.forename: Justin W
authors.initials: JW
authors.lastname: Hicks
authors.forename: Jun
authors.initials: J
authors.lastname: Parkes
authors.forename: Roger
authors.initials: R
authors.lastname: Raymond
authors.forename: José
authors.initials: J
authors.lastname: Nobrega
authors.forename: Sylvain
authors.initials: S
authors.lastname: Houle
authors.forename: Mariateresa
authors.initials: M
authors.lastname: Cipriano
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: Fowler
authors.forename: Neil
authors.initials: N
authors.lastname: Vasdev
authors.forename: Alan A
authors.initials: AA
authors.lastname: Wilson
mesh_terms: D000581:Amidohydrolases / Q000037:antagonists & inhibitors* / Q000737:chemistry*; D000818:Animals; D001921:Brain / Q000000981:diagnostic imaging*; D002219:Carbamates / Q000138:chemical synthesis* / Q000737:chemistry; D002851:Chromatography, High Pressure Liquid; D005462:Fluorine Radioisotopes / Q000737:chemistry*; D006801:Humans; D015394:Molecular Structure; D010080:Oxazoles / Q000138:chemical synthesis* / Q000737:chemistry; D011877:Radionuclide Imaging; D019275:Radiopharmaceuticals / Q000138:chemical synthesis* / Q000737:chemistry; D051381:Rats; D014018:Tissue Distribution; D000099252:Fatty Acid Amide Hydrolases
chemical_list: D000581:Amidohydrolases; D002219:Carbamates; D005462:Fluorine Radioisotopes; D010080:Oxazoles; D019275:Radiopharmaceuticals; D000099252:Fatty Acid Amide Hydrolases; C585738:3-(4,5-dihydrooxazol-2-yl)phenyl (5-fluoropentyl)carbamate