Bifeprunox and aripiprazole are two novel antipsychotics presenting partial agonistic activity for the D(2) and D(3) dopamine (DA) receptors. Using in vivo electrophysiological paradigms in anaesthetized rats, we have previously shown that both drugs independently inhibit the spontaneous firing and bursting activity of ventral tegmental area (VTA) dopaminergic neurons and partially reverse the suppressing effect of the full DA receptor agonist apomorphine. Moreover, we have also shown that the D(2/3) receptor antagonist haloperidol prevents the inhibitory effects of these antipsychotics, confirming their partial D(2)-like agonistic activities [L. Dahan, H. Husum, O. Mnie-Filali, J. Arnt, P. Hertel, N. Haddjeri, Effects of bifeprunox and aripiprazole on rat serotonin and dopamine neuronal activity and anxiolytic behaviour, J. Psychopharmacol. (2009)]. In the present electrophysiological study, selective antagonists of D(2) and D(3) receptors were used to further characterize the inhibitory role of bifeprunox and aripiprazole on the D(2) and D(3) receptors in vivo. Administration of bifeprunox (250 microg/kg, i.v.) or aripiprazole (300 microg/kg, i.v.) reduced the firing activity of VTA DA neurons by 40-50%. The bursting activity was reduced by 95% and 77% by bifeprunox and aripiprazole, respectively. Systemic administration of the preferential D(3) receptor antagonist GR218,231 (200 microg/kg, i.v.) did not modify the inhibitory effect of bifeprunox or aripiprazole, either on the firing or on the bursting activity. On the other hand, the preferential D(2) receptor antagonist L741,626 (500 microg/kg, i.v.) completely blocked the inhibitory effect of both bifeprunox and aripiprazole on the VTA DA neuronal activity. The present study shows that bifeprunox and aripiprazole behave as partial D(2), but not D(3), receptor agonists in vivo, inhibiting the firing activity (preferentially the phasic activity) of VTA DA cells.

01 Aug 2005·Journal of nuclear medicine : official publication, Society of Nuclear Medicine

Synthesis and evaluation of dopamine D3 receptor antagonist 11C-GR218231 as PET tracer for P-glycoprotein.

Article

Author: de Vries, Erik F J ; Elsinga, Philip H ; Vaalburg, Willem ; Kortekaas, Rudie ; van Waarde, Aren ; Dijkstra, Durk

While searching for a PET method to determine the density and occupancy of the dopamine D(3) receptor, we found evidence that suggested that the dopamine D(3) antagonist GR218231 could be a substrate of the P-glycoprotein efflux pump. P-glycoprotein protects the brain against toxic substances and xenobiotics, but it also hampers the delivery of various drugs into the brain. In this study, we aimed to explore whether radiolabeled GR218231 could be applied as a PET tracer for monitoring P-glycoprotein activity in the blood-brain barrier. Such an imaging technique could be useful for the development of new drugs and novel strategies to deliver drugs to the brain and for identification of undesirable drug-drug interactions.METHODSAs a potential PET tracer, GR218231 was labeled with (11)C by reaction of the newly synthesized desmethyl precursor with (11)C-methyl triflate. The biodistribution of (11)C-GR218231 was determined in rats. To assess specific binding to the dopamine D(3) receptor, blocking experiments with unlabeled GR218231 (0.2 and 2.5 mg/kg) were performed. To demonstrate the influence of P-glycoprotein on cerebral uptake of (11)C-GR218231, the efflux pump was modulated with 50 mg/kg cyclosporine A. The sensitivity of (11)C-GR218231 for P-glycoprotein modulation was assessed in dose-response studies, using escalating cyclosporine A dosages.RESULTS(11)C-GR218231 was prepared in 53% +/- 8% decay-corrected radiochemical yield and had a specific activity of 15 +/- 10 GBq/micromol (mean +/- SD). Biodistribution studies in rats revealed a low and homogeneous uptake in the brain. Pretreatment of the animals with unlabeled GR218231 did not demonstrate any specific binding. Modulation of P-glycoprotein with cyclosporine A caused a 12-fold higher (11)C-GR218231 uptake in the brain, indicating that the low cerebral tracer uptake was caused by the P-glycoprotein efflux pump in the blood-brain barrier. Cyclosporine A dose-escalation studies showed a dose-dependent sigmoidal increase in (11)C-GR218231 uptake in brain and spleen (median effective dose [ED(50)], 23.3 +/- 0.6 and 38.4 +/- 2.4 mg/kg, respectively), whereas a dose-dependent decrease was observed in the pancreas (ED(50), 36.0 +/- 4.4 mg/kg).CONCLUSIONAlthough (11)C-GR218231 is unsuited for dopamine D(3) receptor imaging with PET, it appears to be an attractive PET tracer for visualization and quantification of P-glycoprotein activity in the blood-brain barrier.

01 Jul 2004·PsychopharmacologyQ3 · MEDICINE

The role of dopamine D3 compared with D2 receptors in the control of locomotor activity: a combined behavioural and neurochemical analysis with novel, selective antagonists in rats

Q3 · MEDICINE

Article

Author: Gobert, Alain ; Seguin, Laetitia ; Millan, Mark J. ; Brocco, Mauricette ; Cussac, Didier

BACKGROUNDThe role of dopamine D(3)/D(2) receptors in the control of locomotion is poorly understood.OBJECTIVESTo examine the influence of selective antagonists at D(3) or D(2) receptors on locomotion in rats, alone and in interaction with the preferential D(3) versus D(2) receptor agonist, PD128,907.METHODSAffinities of ligands at rat D(2) and cloned, human hD(3), hD(2S), hD(2L) and hD(4) sites were determined by standard procedures. Locomotion was monitored automatically in rats pre-habituated for 30 min to an open-field environment. Extracellular levels of dopamine (DA) were determined by dialysis in the nucleus accumbens and striatum. Drugs were given acutely via the systemic route.RESULTSPD128,907, which preferentially recognised D(3) versus D(2) sites, biphasically reduced and enhanced locomotion at "low" (0.01-0.63 mg/kg) and "high" (2.5-10 mg/kg) doses, respectively. L741,626 and S23199, which behaved as preferential D(2) versus D(3) receptor antagonists, enhanced the reduction in locomotion evoked by the low dose of PD128,907, blocked the increase provoked by the high dose and suppressed spontaneous locomotion alone. Analogous findings were obtained with haloperidol and raclopride which showed equilibrated affinity at D(2) and D(3) receptors. UH232 and AJ76, which showed a mild preference for D(3) versus D(2) sites, did not modify the effect of a low dose of PD128,907, slightly enhanced the hyperlocomotion elicited by the high dose and exerted little influence on locomotion alone. S14297 and U99194, which acted as preferential D(3) versus D(2) receptor antagonists, abolished the reduction in locomotion elicited by a low dose of PD128,907, potentiated the induction of locomotion by a high dose, and failed to influence locomotion alone. The actions of S14297 were stereoselective inasmuch as they were mimicked by the racemic form, S11566, but not by the inactive enantiomer, S17777. In contrast to S14297, S11566 and U99194, however, S33084, SB269,652, GR218,231 and N-[-4-['-(1-naphtyl)piperazine-1-yl]butyl] anthracene-2-carboxamide ("NGB-1"), highly selective D(3) versus D(2) receptor antagonists, were inactive under all conditions. PD128,907 (0.01-10.0 mg/kg) suppressed dialysate levels of DA in the nucleus accumbens and striatum, actions blocked by L741,626 and haloperidol, yet unaffected by S14297 and S33084.CONCLUSIONSThe facilitatory influence of a "high" dose of PD128,907 upon locomotion is mediated by postsynaptic D(2) receptors and, possibly, countered by their D(3) counterparts. Correspondingly, selective blockade of D(2) but not of D(3) receptors alone suppresses motor function. The reduction in locomotion provoked by a "low" dose of PD128,907 may be mediated by D(2) autoreceptors, but a role of postsynaptic D(3) receptors cannot be excluded. Finally, mechanisms underlying the contrasting influence of chemically diverse D(3) receptor antagonists upon locomotion remain to be elucidated.

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Indication	Highest Phase	Country/Location	Organization	Date
Psychotic Disorders	Discovery	GB	Glaxo Group Ltd.	-

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