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

• Published in: Synapse (New York, N.Y.) N.Y.), 1998-04, Vol.28 (4), p.280-287
• Main Authors: Tedroff, J., Torstenson, R., Hartvig, P., Sonesson, C., Waters, N., Carlsson, A., Neu, H., Fasth, K.-J., Långström, B.
• Format: Article
• Language: English
• Subjects: (−)-OSU6162; Animals; Biopterins - analogs & derivatives; Biopterins - pharmacology; Corpus Striatum - diagnostic imaging; Corpus Striatum - drug effects; Corpus Striatum - metabolism; dopamine; Dopamine - metabolism; Dopamine Agents - metabolism; Dopamine Antagonists - pharmacology; Female; L-[11C]DOPA; Levodopa - metabolism; Macaca mulatta; monkey; PET; Piperidines - pharmacology; Reference Values; Tomography, Emission-Computed; Tyrosine - pharmacology
• ISSN: 0887-4476; 1098-2396
• DOI: 10.1002/(SICI)1098-2396(199804)28:4<280::AID-SYN3>3.0.CO;2-5

(−)‐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.