Effects of the substituted (S)-3-phenylpiperidine (-)-OSU6162 on PET measurements of [C-11]SCH23390 and [C-11]raclopride binding in primate brains

The substituted (S)-3-phenylpiperidine (-)-OSU6162 belongs to a novel class of functional modulators of dopaminergic systems. In vivo, (-)-OSU6162 has a unique stabilising profile on dopaminergic functions. In vitro this comp ound exhibits low affinity for the dopamine D2 receptor, but due to its sim ilarity to neuroleptics on brain dopaminergic neurochemistry and different postsynaptic effects it has been characterised as a preferential dopamine a utoreceptor antagonist. To further clarify the effects of(-)-OSU6162 on the postjunctional nigrostriatal dopaminergic system, dopamine receptor bindin g was measured in rhesus monkeys (Macaca mulatta) by positron emission tomo graphy (PET) using the D1 and D2 dopamine receptor radioligands [C-11]SCH23 390 and [C-11]raclopride respectively, before and during continuous intrave nous infusions of(-)-OSU6162. Additionally, the test-retest variability of sequential [C-11]SCH23390 scans was estimated. Following the administration of(-)-OSU6162, [C-11]raclopride binding in striatum was dose-dependently d ecreased with a 76% reduction occurring after 3.0 mg/kg per h continuous in fusion. Whereas (-)-OSU6162 in the lower doses had no effect on [C-11]SCH23 390 binding, the highest dose, 3.0 mg/kg per h, increased [C-11]SCH23390 bi nding, which may indicate a potentiating effect on D1 dopamine receptor med iated functions. Thus, in contrast to the conditions in vitro, (-)-OSU6162 produces a high displacement of raclopride from D2 receptors in vivo. (C) 1 999 Elsevier Science Ltd. All rights reserved.