Synthesis and preclinical evaluation of [¹⁸F]FCHC for neuroimaging of fatty acid amide hydrolase.

Abstract

Fatty acid amide hydrolase (FAAH), a catabolic enzyme which regulates lipid transmitters in the endocannabinoid system, is an avidly sought therapeutic and positron emission tomography (PET) imaging target for studies involving addiction and neurological disorders. We report the synthesis of a new fluorine-18-labeled FAAH inhibitor, trans-3-(4, 5-dihydrooxazol-2-yl)phenyl-4-[(18)F]fluorocyclohexylcarbamate ([(18)F]FCHC), and its evaluation in rat brain. The synthesis of [(18)F]FCHC was conducted via a 3-step, 1-pot reaction, resulting in uncorrected radiochemical yields between 10 and 20% (n = 5) relative to [(18)F]fluoride, with specific activities of >5 Ci/μmol at the end of the synthesis. The radiosynthesis was seamlessly automated using a commercial radiofluorination apparatus. Ex vivo biodistribution and preliminary PET imaging studies were carried out in male Sprague-Dawley rats. Rat brain biodistribution at 2 min post-injection showed a standard uptake value of 4.6 ± 0.1 in the cortex, which increased to 7.8 ± 0.1 at 40 min. Pretreatment with the selective FAAH inhibitor URB597 reduced uptake of radioactivity in all brain regions by >90%, with 98 % blockade in the FAAH-rich cortex. PET imaging was consistent with biodistribution studies. [(18)F]FCHC appears to be a highly sensitive (18)F-labeled radiotracer for imaging FAAH in the central nervous system, and these results warrant further imaging in nonhuman primates.