Effects of the substituted (S)‐3‐phenylpiperidine (−)‐OSU6162 on PET measurements in subhuman primates: Evidence for tone‐dependent normalization of striatal dopaminergic activity

Abstract

(−)-OSU6162 is a substituted (S)-3-phenylpiperidine derivative which exhibits some affinity to the dopamine D2 receptor family. In vivo, the compound displays a unique normalizing profile on psychomotor activity by an intriguing mixture of stimulatory and inhibitory properties. In the present investigation, some of the effects of (−)-OSU6162 on central dopaminergic function were studied by positron emission tomography (PET) and L-[11C]DOPA in anaesthetized female rhesus monkeys. (−)-OSU6162 displayed a dopaminergic tone-dependent effect with a reduction in the striatal L-[11C]DOPA influx rate in monkeys with high baseline values and an increased striatal L-[11C]DOPA influx rate in animals with low baseline values. Infusion of (−)-OSU6162 for a whole day resulted in a stable effect with no evidence of tolerance. (−)-OSU6162 also stabilized dopaminergic function by attenuating the upregulation of the striatal L-[11C]DOPA influx rate which has previously been shown to occur following 6R-BH4 or 6R-BH4 + L-tyrosine infusions. This “Protean” effect of (−)-OSU6162 on the striatal dopaminergic function corresponds to previous behavioral observations in intact animals and demonstrates a true functional correlation to the measures obtained with L-[11C]DOPA and PET. The normalizing and stabilizing profile of (−)-OSU6162 should be of value in treating a variety of disorders where an underlying dysregulation or disruption of dopaminergic function can be assumed. Synapse 28:280–287, 1998. © 1998 Wiley-Liss, Inc.