SYNTHESIS OF [C-11-METHYL]-(-)-OSU6162, ITS REGIONAL BRAIN DISTRIBUTION AND SOME PHARMACOLOGICAL EFFECTS OF (-)-OSU6162 ON THE DOPAMINERGICSYSTEM STUDIED IN THE RHESUS-MONKEY BY POSITRON EMISSION TOMOGRAPHY

The labelling of the presynaptic dopamine receptor antagonist (-)-OSU6 162, -)-3-(3-(methylsulfonyl)phenyl)-1-propylpiperdine) was performed by an alkylation with [C-11]methyl iodide of the thio anion (-)-OSU128 1, followed by a selective oxidation to the corresponding methyl sulfo ne, [C-11-methyl]-(-)-OSU6162, The total radiochemical yield calculate d from the produced [C-11]carbon dioxide to final product was about 25 % and the time of synthesis was in the range of 40 min from end of bom bardment, The synthesis of the precursor, (-)-OSU1281, was performed f rom (-)-3PPP in a three step synthesis, The regional brain distributio n of (-)-OSU6162 radiolabelled with C-11 was studied in rhesus monkeys by means of positron emission tomography, PET. [C-11-Methyl]-(-)-OSU6 162 was rapidly and uniformly distributed to gray matters of the brain , and no decrease of radioactivity uptake in the brain was seen after pretreatment with 1 to 3 mg/kg/h of (-)-OSU6162. The effect of doses o f 1 to 3 mg/kg/h of (-)-OSU6162 on the dopamine binding was studied by PET using [C-11-methyl]raclopride. Radioactivity in the striatum was significantly and dose-dependently decreased by (-)-OSU6162 (r = 0.88) , supporting competition with dopamine for selective binding to dopami ne receptors. (C) 1997 Elsevier Science Inc.