会議発表用資料 [11C]DPFC: a promising PET tracer for imaging fatty acid amide hydrolase in brain

Shimoda, Yoko  ,  Hatori, Akiko  ,  Zhang, Yiding  ,  Ogawa, Masanao  ,  Nengaki, Nobuki  ,  Fujinaga, Masayuki  ,  Kumata, Katsushi  ,  Xie, Lin  ,  Ming-Rong, Zhang

2017-05-18
内容記述
Objectives: Fatty acid amide hydrolase (FAAH) is an intracellular serine hydrolase that catalyzes the deactivating hydrolysis of several endogenous lipid amides, such as anandamide, an endogenous ligand that activates cannabinoid receptors, and oleamide, an endogenous sleep-inducing agent. It has been reported that FAAH-selective inhibitors exert pharmacological effects on pain, anxiety, addiction, and on some psychiatric disorders. PET imaging of FAAH would simplify the study of its function and may aid in evaluating the treating efficiency of FAAH inhibitors for the related brain diseases. In the present study, we developed N-(3,4-dimethylisoxazol-5-yl)piperazine-4-[4-(4-fluorophenyl)thiazol-2-yl]-1-[11C]carboxamide ([11C]DPFC) as a new radiotracer for PET imaging of FAAH in brain. Here, we describe 1) chemical synthesis and in vitro binding affinity of DPFC for FAAH, 2) radiosynthesis of [11C]DPFC and 3) biodistribution, PET and irreversible binding assay.Methods: We labeled DPFC by reacting two different amines: 5-amino-3,4-dimethylisoazole and 4-(4-fluorophenyl)-2-(piperazin-1-yl)thiazole, with [11C]COCl2, and performed competitive activity-based protein profiling to examine the in vitro binding potency for FAAH. The distribution of radioactivity in mice was measured at different time points after injection of [11C]DPFC. PET scans were performed on rat brains.Results: [11C]COCl2 was synthesized from cyclotron-produced [11C]CO2 via [11C]CH4 and then via [11C]CCl4 using a home-made automated production system. Starting with 18.5–26.6 GBq of [11C]CO2, 0.4–1.1 GBq of [11C]DPFC was obtained at the end of synthesis (n = 9). The average total synthesis time from the end of bombardment was 36 min. The in vitro binding affinity (IC50) of DPFC for FAAH was measured to be 3.3 ± 1.0 nM. The biodistribution study in mice showed high uptakes of radioactivity in FAAH-rich organs, such as the lung, liver, and kidney. PET summation images of rat brains showed high uptakes (> 2 SUV) in the cerebellar nuclei and frontal cortex. This pattern was consistent with the known regional distribution pattern of FAAH in the rodent brain. Pretreatment with the FAAH-selective inhibitor URB597 significantly reduced the whole brain uptake. At 30 min after the radiotracer injection, more than 95% of the total radioactivity was found to be irreversible in the brain homogenate of rats. Conclusion: In this study, we have developed [11C]DPFC as a novel radiotracer for PET imaging of FAAH in brain. PET study showed relatively high radioactivity uptake and specific binding to FAAH in the rat brains. [11C]DPFC is thus a promising radiotracer for visualizing FAAH in the brain.
22nd International symposium on radiopharmaceutical science (ISRS)

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