PET Imaging of Fatty Acid Amide Hydrolase with [18F]DOPP in Nonhuman Primates

• Type of Material: Article
• Authors: Benjamin H. Rotstein, Massachusetts General Hospital; Hsiao-Ying Wey, Massachusetts General Hospital; Timothy M. Shoup, Massachusetts General Hospital; Alan A. Wilson, University of Toronto; Steven Huan Liang, Emory University; Jacob M. Hooker, Harvard Medical School; Neil Vasdev, Massachusetts General Hospital
• Language: English
• Date: 2014-11-03
• Publisher: American Chemical Society
• Publication Version: Final Published Version
• Copyright Statement: © 2014 American Chemical Society
• Final Published Version (URL): http://dx.doi.org/10.1021/mp500316h
• Title of Journal or Parent Work: Molecular Pharmaceutics
• Volume: 11
• Issue: 11
• Start Page: 3832
• End Page: 3838
• Grant/Funding Information: B.H.R. is a Natural Sciences and Engineering Research Council of Canada (NSERC) Postdoctoral Fellow. H.-Y.W. is supported by the Harvard/MGH Nuclear Medicine Training Program from the Department of Energy (DE-SC0008430). This work was supported in part by NIH Grants: 1R21MH094424 (A.A.W.) and 1K01DA038000-01 (S.H.L.).
• Keywords: Blood-Brain Barrier; fatty acid amide hydrolase; Magnetic Resonance Imaging; Brain; Endocannabinoids; Tissue Distribution; Amidohydrolases; Fluorine Radioisotopes; kinetic modeling; positron emission tomography; Oxazoles; Carbamates; Animals; [18F]DOPP; PET; Benzamides; Models, Chemical; Positron-Emission Tomography; FAAH; Primates; Papio
• Research Categories: Chemistry, Biochemistry; Biology, Neuroscience

Abstract

Fatty acid amide hydrolase (FAAH) regulates endocannabinoid signaling. [C]CURB, an irreversibly binding FAAH inhibitor, has been developed for clinical research imaging with PET. However, no fluorine-18 labeled radiotracer for FAAH has yet advanced to human studies. [18F]DOPP ([18F]3-(4,5-dihydrooxazol-2-yl)phenyl (5-fluoropentyl)carbamate) has been identified as a promising 18F-labeled analogue based on rodent studies. The goal of this work is to evaluate [18F]DOPP in nonhuman primates to support its clinical translation. High specific activity [18F]DOPP (5-6 Ci·μmol-1) was administered intravenously (iv) to three baboons (2M/1F, 3-4 years old). The distribution and pharmacokinetics were quantified following a 2 h dynamic imaging session using a simultaneous PET/MR scanner. Pretreatment with the FAAH-selective inhibitor, URB597, was carried out at 200 or 300 μg/kg iv, 10 min prior to [18F]DOPP administration. Rapid arterial blood sampling for the first 3 min was followed by interval sampling with metabolite analysis to provide a parent radiotracer plasma input function that indicated ∼95% baseline metabolism at 60 min and a reduced rate of metabolism after pretreatment with URB597. Regional distribution data were analyzed with 1-, 2-, and 3-tissue compartment models (TCMs), with and without irreversible trapping since [18F]DOPP covalently links to the active site of FAAH. Consistent with previous findings for [11C]CURB, the 2TCM with irreversible binding was found to provide the best fit for modeling the data in all regions. The composite parameter λk3 was therefore used to evaluate whole brain (WB) and regional binding of [18F]DOPP. Pretreatment studies showed inhibition of λk3 across all brain regions (WB baseline: 0.112 mL/cm3/min; 300 μg/kg URB597: 0.058 mL/cm3/min), suggesting that [F]DOPP binding is specific for FAAH, consistent with previous rodent data.