Carbon-11-NNC 112: A radioligand for PET examination of striatal and neocortical D-1-dopamine receptors

The aim of this work was to explore the potential of a selective D-1-dopami ne receptor antagonist as a new radioligand for PET examination of striatal and neocortical D-1-dopamine receptors. Methods: The active (+)- and inact ive (-)-enantiomers of [C-11]NNC 112 were radiolabeted using the N-methylat ion approach and were examined by PET in cynomolgus monkeys and healthy men . Metabolite levels in plasma were measured by gradient high-performance li quid chromatography (HPLC). Results: N-methylation of the corresponding des methyl precursors with [C-11]methyl triflate gave high total radiochemical yield (50%-60%) and specific radioactivity (110 GBq/mu mol). (+)-[C-11]NNC 112 binding in cynomolgus monkeys was 5.77 +/- 0.31 and 2.36 +/- 0.14 times higher in the striatum and neocortex, respectively, than in the cerebellum at a transient equilibrium that appeared 40-50 min after injection. The bi nding of (+)-[C-11]NNC 112 is stereoselective, because the brain distributi on of the inactive (-)-enantiomer was on an equally low level for all brain regions, Displacement and pretreatment experiments using unlabeled SCH 233 90 and ketanserin confirms that (+)-[C-11]NNC 112 binds specifically and re versibly to D-1-dopamine receptors. The radioactivity ratios of the striatu m, frontal cortex and nucleus accumbens to the cerebellum were 3.8-4.0, 1.7 -2.0 and 2.8-3.1, respectively, at a transient equilibrium that appeared 40 -50 min after injection in four healthy human subjects. Linear graphical an alysis gave distribution volume ratios of 3.9 and 1.5 in the putamen and fr ontal cortex, respectively, The fraction of the total radioactivity in huma n plasma representing unchanged (+)-[C-11]NNC 112 was 85% at 5 min and 25% at 75 min after injection. Conclusion: (+)-[C-11]NNC 112 should be a useful PET radioligand for quantitative examination of not only striatal but neoc ortical D-1-dopamine receptors in man.