[3C]SCH39166, a D1 dopamine receptor antagonist : binding characteristics and localization

Schering-Plough Research has developed a new, more specific analogue of SCH23390. This compound, SCH39166, has been shown to be a potent, specific, D1 receptor antagonist with several features which are advantageous over its predecessor. In this report, the binding characteristics of [3H]SCH39166 are described by in vitro analysis in rat brain tissues. The binding was shown to be of high affinity (Kd in the low nM range), saturable, and specific (readily displaceable with SCH23390, but not with the D2 receptor antagonists sulpiride or haloperidol). The binding of SCH39166 is more selective for binding to D1 receptors than SCH23390 with regard to overlap of the latter compound onto 5HT2 and 5HT1C receptors. Autoradiographic localization of D1 receptor sites labeled with [3H]SCH39166 showed a very specific distribution in areas known to contain high quantities of D1 receptors. These regions included the deepest layer of the cerebral cortex, the caudate-putamen, nucleus accumbens, olfactory tubercle, entopeduncular nucleus, and substantia nigra-pars reticulata, as well as less dense binding in a few other areas. At the concentration of ligand used (1 nM), there was a noticeable paucity of labeling in lamina IV of the cerebral cortex and in the choroid plexus, regions of high 5HT2 and 5HT1C receptor binding, respectively. Thus, SCH39166 represents a new D1 receptor antagonist which shows a greater specificity for the D1 receptor than its predecessor SCH23390. As previously shown, another distinct advantage of this compound is its stability in primates which should allow the determination of the effects and utility of D1 receptor antagonism in vivo.