PET EXAMINATION OF [C-11] NNC-687 AND [C-11] NNC-756 AS NEW RADIOLIGANDS FOR THE D-1-DOPAMINE RECEPTOR

The benzazepines NNC 687 and NNC 756 have in animal studies been described as selective D-1-dopamine receptor antagonists. Both compounds have been labeled with C-11 for examination by positron emission tomography (PET). In the present study central receptor binding was studied in monkeys and healthy men. After IV injection of both radioligands in Cynomolgus monkeys radioactivity accumulated markedly in the striatum, a region with a high density of D-1-dopamine receptors. This striatal uptake was displaced by high doses of the selective D-1-antagonist SCH 23390 (2 mg/kg) but not by the 5HT(2)- antagonist ketanserin(l.5 mg/kg) or the selective D-2-antagonist raclopride (3 mg/kg). The cortical uptake after injection of [C-11]NNC 687 was not reduced in displacement experiments with ketanserin. The cortical uptake of [C-11]NNC 756 was reduced in displacement and protection experiments with ketanserin by 24-28% (1.5 mg/kg), whereas no reduction could be demonstrated on striatal uptake. In healthy males both compounds accumulated markedly in the striatum. For [C-11]NNC 687 the ratio of radioactivity in the putamen to cerebellum was about 1.5. For [C-11]NNC 756 the ratio was about 5. This ratio of 5 for [C-11]NNC 756 is the highest obtained so far for PET radioligands for the D-1-dopamine receptor.