Journal Article Radiosynthesis and evaluation of N-(3,4-dimethylisoxazol-5-yl)piperazine-4-[4-(4- fluorophenyl)thiazol-2-yl]-1-[11C]carboxamide for in vivo positron emission tomography imaging of fatty acid amide hydrolase in brain

Shimoda, Yoko  ,  Yui, Joji  ,  Zhang, Yiding  ,  Hatori, Akiko  ,  Ogawa, Masanao  ,  Fujinaga, Masayuki  ,  Yamasaki, Tomoteru  ,  Xie, Lin  ,  Kumata, Katsushi  ,  Ming-Rong, Zhang

5pp.106122 - 106127 , 2015-12
We developed a novel positron emission tomography (PET) radiotracer N-(3,4-dimethylisoxazol-5-yl)piperazine-4-[4-(4-fluorophenyl)thiazol-2-yl]-1-[11C]carboxamide ([11C]DPFC, [11C]1) for in vivo imagingof fatty acid amide hydrolase (FAAH) in rat brain. Compound 1 showed a high binding affinity for FAAH(IC50: 3.3 nM). [11C]1 was synthesized by reaction of 5-amino-3,4-dimethylisoxazole (2) with [11C]phosgene ([11C]COCl2), followed by reaction with 4-(4-fluorophenyl)-2-(piperazin-1-yl)thiazole (3), witha 9 4% radiochemical yield (decay-corrected, n ¼ 9) based on [11C]CO2. A biodistribution study inmice showed a high uptake of radioactivity in FAAH-rich organs, including the lung, liver, and kidney.PET summation images of rat brains showed high radioactivity (>2 SUV) in the cerebellar nuclei andfrontal cortex. This pattern was consistent with the known regional distribution pattern of FAAH in therodent brain. Pretreatment with the FAAH-selective inhibitor URB597 significantly reduced the wholebrain uptake of [11C]1. At 30 min after the radiotracer injection, more than 95% of the total radioactivitywas found to be irreversible in the brain homogenate of rats. Our results indicate that [11C]1 isa promising PET tracer for in vivo visualization of FAAH in living brains.

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