N-(3, 4- Dimethylisoxazol -5-yl) piperazine-4-[4-(2-fluoro-4-[11C] methylphenyl) thiazol-2-yl] -1-carboxamide: a promising positron emission tomography ligand for fatty acid amide hydrolase

Publication: Bioorg Med Chem


To visualize fatty acid amide hydrolase (FAAH) in brain in vivo, we developed a novel positron emission tomography (PET) ligand N-(3,4-dimethylisoxazol-5-yl)piperazine-4-[4-(2-fluoro-4-[11C]methylphenyl)thiazol-2-yl]-1-carboxamide ([11C]DFMC, [11C]1). DFMC (1) was shown to have high binding affinity (IC50: 6.1 nM) for FAAH. [11C]1 was synthesized by C11C coupling reaction of arylboronic ester 2 with [11C]methyl iodide in the presence of Pd catalyst. At the end of synthesis, [11C]1 was obtained with a radiochemical yield of 20 ± 10% (based on [11C]CO2, decay-corrected, n = 5) and specific activity of 48–166 GBq/μmol. After the injection of [11C]1 in mice, high uptake of radioactivity (>2% ID/g) was distributed in the lung, liver, kidney, and brain, organs with high FAAH expression. PET images of rat brains for [11C]1revealed high uptakes in the cerebellar nucleus (SUV = 2.4) and frontal cortex (SUV = 2.0), two known brain regions with high FAAH expression. Pretreatment with the FAAH-selective inhibitor URB597 reduced the brain uptake. Higher than 90% of the total radioactivity in the rat brain was irreversible at 30 min after the radioligand injection. The present results indicate that [11C]1 is a promising PET ligand for imaging of FAAH in living brain.