Evaluation of [¹⁸F]DOPP in nonhuman primates for imaging FAAH

Objectives Fatty acid amide hydrolase (FAAH) regulates endocannabinoid signaling. [¹¹C]CURB has been developed for clinical FAAH imaging and [¹⁸F]DOPP was identified as a promising ¹⁸F-labeled analog in rodents. The goal of this work is to evaluate [¹⁸F]DOPP in nonhuman primates to determine dose response and to support its clinical translation.

Methods High specific activity [¹⁸F]DOPP (5-6 Ci/µmol) was injected iv in baboons (3F, 3-4 yr) and imaged over 2 h with a Biograph mMR PET/MR. Pretreatment studies dosed the selective FAAH inhibitor URB597 at 0.2 or 0.3 mg/kg iv, 10 min prior to [¹⁸F]DOPP administration. Rapid arterial blood sampling for the first 3 minutes followed by interval sampling with metabolite analysis provided a parent radiotracer input function. Regional brain distribution and saturability of binding were determined and TACs of ROIs in the brain were generated. Data was analyzed with 1-, 2-, and 3-tissue compartment models (TCM) with and without irreversible trapping. The composite parameter λk₃ was used to evaluate whole brain (WB) and regional binding of [¹⁸F]DOPP.

Results Rapid brain uptake of [¹⁸F]DOPP was observed, with an initial WB activity peak at 45 s and reached a maximum of 2 SUV beginning at 55 min. Parent plasma fraction data shows ~95% metabolism at 1 h. Regional brain distribution ranged from peak SUV of 2.9 in putamen to 2.4 in occipital frontal cortex. The irreversible 2TCM was found to provide the best fit for modeling the data in all regions. Pretreatment studies showed dose dependent inhibition of λk₃ across all brain regions (WB baseline: 0.112; 0.3 mg/kg URB597: 0.058 mL/cm³/min) suggesting that [¹⁸F]DOPP binding is specific for FAAH, consistent with previous rodent data.

Conclusions [¹⁸F]DOPP is a suitable radiotracer for imaging FAAH, likely through an irreversible binding mechanism. Human studies with [¹⁸F]DOPP are planned.

Research Support NIH Grant #1R21MH094424 (AAW), NSERC Postdoctoral Fellowship (BHR)