René Milcent

Synthesis and in vivo studies of a specific monoamine oxidase B inhibitor: 5-[4-(benzyloxy)phenyl]-3-(2-cyanoethyl)- 1,3,4-oxadiazol-[11C]-2(3H)-one.

We report the radiochemical synthesis of a specific MAO B inhibitor, namely 5-[4-(benzyloxy)phenyl]-3-(2-cyanoethyl)-1,3,4-oxadiazol-[11C]-2(3H)-one (2b) (in vitro IC50=4nM and selectivity over 71000 for MAO B), by cyclization of its hydrazide precursor1 with [11C]phosgene. The reaction occurred within 2 min. The product obtained after HPLC purification,2b, had a high specific activity (11.1–22.2 GBq/µmol), allowing its use in experiments as a radiotracer in vivo. Biodistribution of2b in the CNS and in the peripheral organs of the rat, and positron emission tomography (PET) studies in the living baboon brain, pretreated or not withl-deprenyl (1 mg/kg, 1 h), an irreversible MAO B-specific inhibitor, were undertaken. The results showed a good uptake of2b in all organs of the rat, with a rapid clearance from the blood (10 min). Metabolite analyses in plasma and in the diencephalon of the rat showed that2b was the only radioactive compound in brain structure whereas in plasma three other radioactive products appeared. PET experiments show that in thel-deprenyl-pretreated baboon brain, specific binding of2b represents around 70% of total radioactivity, whereas in the blood and plasma the radioactivity cleared rapidly (15 min).