Presentation Evaluation of kinetics of acetovanillone in the brain by PET

Okamura, Toshimitsu  ,  Okada, Maki  ,  Kikuchi, Tatsuya  ,  Wakizaka, Hidekatsu  ,  Ming-Rong, Zhang

Objectives: NADPH oxidase produces reactive oxygen species (ROS) in physiological processes, but overproduction of ROS by this enzyme leads to oxidative stress, which contributes to the pathogenesis of various brain diseases. Acetovanillone is considered an anti-inflammatory and antioxidant agent, mainly due to blocking NADPH oxidase, and has thus been examined in many animal models of brain diseases. In such studies, understanding the brain kinetics would be important for interpreting the efficacy of acetovanillone in vivo. However, very limited work has been done on in vivo kinetics of acetovanillone in the brain. In this study, we therefore examined the brain kinetics of acetovanillone using [11C]acetovanillone and PET.Methods: [11C]acetovanillone was synthesized by the reaction of 3',4'-dihydroxyacetophenone with [11C]methyl iodide in dimethylformamide. In vivo PET studies were performed on mice, which received intraperitoneal (i.p.) administration of [11C]acetovanillone. The brain tissue of mice received i.p. administration of [11C]acetovanillone was analyzed by HPLC for the chemical form. Whether acetovanillone is converted into the glucuronide conjugate was examined by comparing brain samples treated with or without -glucuronidase. The doses of acetovanillone used in this study ranged from 1.5 g/kg to 100 mg/kg.Results: The radiochemical yield of isolated [11C]acetovanillone was 9  4% (decay corrected to the end of bombardment), and the radiochemical purity was greater than 98%. Brain radioactivity was extremely low at doses of less than 10 mg/kg; low radioactivity was observed in the brain a few minutes after the administration at doses of 25 and 50 mg/kg, and rapidly decreased thereafter. At a dose of 100 mg/kg, [11C]acetovanillone showed the moderate radioactivity uptake followed by gradual reduction. An unknown metabolite was observed in the HPLC chromatogram of brain samples for all doses, and the fraction of the unchanged form increased with increasing the doses of acetovanillone. -Glucuronidase treatment caused the disappearance of the unknown peak and increased the fraction of acetovanillone. This result demonstrated that the metabolite generated in the brain was its glucuronide conjugate. Acetovanillone has been reported to be oxidized to a dimmer (active metabolite) in vitro. In our study, however, the dimer was not observed in the brain at any doses.Conclusions: These data are useful for the evaluation of the efficacy of acetovanillone as a neuroprotective agent.
22nd International symposium on radiopharmaceutical science (ISRS)

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