PET Imaging of Fatty Acid Amide Hydrolase with [¹⁸F]DOPP in Nonhuman 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 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 [18F]DOPP binding is specific for FAAH, consistent with previous rodent data.

11CO bonds made easily for positron emission tomography radiopharmaceuticals

“…It was found that a linear N -alkyl substituent leads to increased potency over cyclic isomers and that the presence of a dihydrooxazole confers faster and greater brain uptake with lower nonspecific binding. These insights lead directly to the design of two fluorine-18 labeled FAAH radiotracers: [ 18 F]DOPP 75,76 and [ 18 F]FCHC. 77 Both show greater brain uptake in vivo and sensitivity to FAAH activity in vitro than [ 11 C]CURB.…”

Fluorine-18 labelled building blocks for PET tracer synthesis

“…8). 146,198,200,201,205 The radiofluorination reaction was carried out using the purified (distilled) fluorine-18 labelled building block, but also successful one-pot three step reactions including [ 18 F]fluorination and deprotection of the amine have been reported. In most syntheses, the carbamate formation was carried out at room temperature without additives.…”

“…One-pot reaction at 80 1C with 2-[ 18 F]fluoroethyl azide-derived [ 18 F]fluoroethylamine under basic conditions (TEA) gave GABA A tracer 277 in 46% decay-corrected radiochemical yield (calculated from 2-[ 18 F]fluoroethyl azide). 205 Since 2010 the synthesis of two fluorine-18 labelled urea derivatives has been reported. In the procedure described by Majo et al, the potential PET ligand for mTOR 278 was synthesised from an amine precursor, which was pre-treated with trisphosgene and TEA in dichloromethane.…”

Development of an In Vivo Method to Estimate Effective Drug Doses and Quantify Fatty Acid Amide Hydrolase in Rodent Brain using Positron Emission Tomography Tracer [11C]DFMC

“…Several FAAH inhibitors, classified as urea, carbamate, and keto-heterocycle derivatives, have been developed (Seierstad and Breitenbucher, 2008) and progressed to clinical trials to treat inflammatory pain, cannabis dependence, and schizophrenia (Kathuria et al, 2003;Li et al, 2012). Subsequently, to further understand the function of FAAH and to research JPET # 263772 drug kinetics in vivo, several positron emission tomography (PET) tracers for FAAH were synthesized based on the inhibitors (Shimoda et al, 2016;Kumata et al, 2015;Shimoda et al, 2015;Rotstein et al, 2014;Wilson et al, 2011) (Fig. 1).…”