Effects of the substituted (S)-3-phenylpiperidine (-)-OSU6162 on PET measurements in subhuman primates: evidence for tone-dependent normalization of striatal dopaminergic activity.
(-)-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.
Tedroff
J
J
Department of Neurology, University Hospital, Uppsala University, Sweden. Joakim.Tedroff@PET.uu.se
Torstenson
R
R
Hartvig
P
P
Sonesson
C
C
Waters
N
N
Carlsson
A
A
Neu
H
H
Fasth
K J
KJ
Långström
B
B
D000818:Animals; D001708:Biopterins / Q000031:analogs & derivatives / Q000494:pharmacology; D003342:Corpus Striatum / Q000000981:diagnostic imaging / Q000187:drug effects* / Q000378:metabolism*; D004298:Dopamine / Q000378:metabolism*; D015259:Dopamine Agents / Q000378:metabolism; D018492:Dopamine Antagonists / Q000494:pharmacology*; D005260:Female; D007980:Levodopa / Q000378:metabolism; D008253:Macaca mulatta; D010880:Piperidines / Q000494:pharmacology*; D012016:Reference Values; D014055:Tomography, Emission-Computed; D014443:Tyrosine / Q000494:pharmacology
D015259:Dopamine Agents; D018492:Dopamine Antagonists; D010880:Piperidines; C109513:OSU 6162; D001708:Biopterins; D014443:Tyrosine; D007980:Levodopa; C003402:sapropterin; D004298:Dopamine