title: Synthesis and preliminary evaluation of N-(16-18F-fluorohexadecanoyl)ethanolamine (18F-FHEA) as a PET probe of N-acylethanolamine metabolism in mouse brain.
abstract: N-Acylethanolamines are lipid signaling molecules found throughout the plant and animal kingdoms. The best-known mammalian compound of this class is anandamide, N-arachidonoylethanolamine, one of the endogenous ligands of cannabinoid CB1 and CB2 receptors. Signaling by N-acylethanolamines is terminated by release of the ethanolamine moiety by hydrolyzing enzymes such as fatty acid amide hydrolase (FAAH) and N-acylethanolamine-hydrolyzing amidase (NAAA). Herein, we report the design and synthesis of N-(16-(18)F-fluorohexadecanoyl)ethanolamine ((18)F-FHEA) as a positron emission tomography (PET) probe for imaging the activity of N-acylethanolamine hydrolyzing enzymes in the brain. Following intravenous administration of (18)F-FHEA in Swiss Webster mice, (18)F-FHEA was extracted from blood by the brain and underwent hydrolysis at the amide bond and incorporation of the resultant (18)F-fluorofatty acid into complex lipid pools. Pretreatment of mice with the FAAH inhibitor URB-597 (1 mg/kg IP) resulted in significantly slower (18)F-FHEA incorporation into lipid pools, but overall (18)F concentrations in brain regions were not altered. Likewise, pretreatment with a NAAA inhibitor, (S)-N-(2-oxo-3-oxytanyl)biphenyl-4-carboxamide (30 mg/kg IV), did not significantly affect the uptake of (18)F-FHEA in the brain. Although evidence was found that (18)F-FHEA behaves as a substrate of FAAH in the brain, the lack of sensitivity of brain uptake kinetics to FAAH inhibition discourages its use as a metabolically trapped PET probe of N-acylethanolamine hydrolyzing enzyme activity.
authors.affiliation: Division of Nuclear Medicine, Department of Radiology, and ‡Division of Biomedical Statistics and Informatics, Mayo Clinic , Rochester, Minnesota 55905, United States.
authors.forename: Mukesh K
authors.initials: MK
authors.lastname: Pandey
authors.forename: Timothy R
authors.initials: TR
authors.lastname: DeGrado
authors.forename: Kun
authors.initials: K
authors.lastname: Qian
authors.forename: Mark S
authors.initials: MS
authors.lastname: Jacobson
authors.forename: Clinton E
authors.initials: CE
authors.lastname: Hagen
authors.forename: Richard I
authors.initials: RI
authors.lastname: Duclos
authors.forename: S John
authors.initials: SJ
authors.lastname: Gatley
mesh_terms: D000818:Animals; D001095:Arachidonic Acids; D001921:Brain / Q000000981:diagnostic imaging / Q000378:metabolism*; D063388:Endocannabinoids / Q000378:metabolism*; D004983:Ethanolamines / Q000737:chemistry* / Q000378:metabolism*; D005462:Fluorine Radioisotopes / Q000378:metabolism*; D051379:Mice; D053284:Polyunsaturated Alkamides; D049268:Positron-Emission Tomography
chemical_list: D001095:Arachidonic Acids; D063388:Endocannabinoids; D004983:Ethanolamines; D005462:Fluorine Radioisotopes; C022203:N-acylethanolamines; D053284:Polyunsaturated Alkamides; C078814:anandamide
keywords: 18F-FHEA; Endocannabinoids; N-(16-18F-fluorohexadecanoyl)ethanolamine; N-acylethanolamines; PET