2014 Jul 8. [Epub ahead of print]
PET Imaging of Fatty Acid Amide Hydrolase with [18F]DOPP in Non-Human Primates.
Abstract
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 analog based on rodent studies. The goal of this work is to evaluate [18F]DOPP in non-human primates to support its clinical translation. High specific activity [18F]DOPP (5 – 6 Ci•µmol-1) was administered intravenously (i.v.) to three baboons (2M/1F, 3 – 4 yr). 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 i.v., 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 is believed to covalently link 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 [18F]DOPP binding is specific for FAAH, consistent with previous rodent data.
- PMID:
25004399
[PubMed – as supplied by publisher]
