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

Fatty acid amide hydrolase (FAAH) regulates endocannabinoid signaling. [¹¹C]­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 <i>λk</i>₃ was therefore used to evaluate whole brain (WB) and regional binding of [¹⁸F]­DOPP. Pretreatment studies showed inhibition of <i>λk</i>₃ across all brain regions (WB baseline: 0.112 mL/cm³/min; 300 μg/kg URB597: 0.058 mL/cm³/min), suggesting that [¹⁸F]­DOPP binding is specific for FAAH, consistent with previous rodent data