title: Lack of effect of reserpine-induced dopamine depletion on the binding of the dopamine-D3 selective radioligand, [11C]RGH-1756.
abstract: The effect of reserpine induced dopamine depletion on the binding of the putative dopamine-D3 receptor ligand, [(11)C]RGH-1756 was examined in the monkey brain with positron emission tomography (PET). In a previous series of experiments, we have made an attempt to selectively label D3 receptors in the monkey brain using [(11)C]RGH-1756. Despite high selectivity and affinity of RGH-1756 in vitro, [(11)C]RGH-1756 displayed only low specific binding to D3 receptors in vivo. The aim of the present study was to examine whether low specific binding of [(11)C]RGH-1756 is caused by insufficient in vivo affinity of the ligand, or by high physiological occupancy of D3 receptors by endogenous dopamine (DA). PET experiments were performed in three monkeys under baseline conditions and after administration of reserpine (0.5 mg/kg). The results of the baseline measurements corresponded well to our earlier observations with [(11)C]RGH-1756. Reserpine caused no evident change in the regional distribution of [(11)C]RGH-1756 in the monkey brain, and no conspicuous regional accumulation of activity could be observed. After reserpine treatment there was no evident increase of specific binding and binding potential (BP) of [(11)C]RGH-1756. The lack of increased [(11)C]RGH-1756 binding after reserpine treatment indicates that competition with endogenous DA is not the predominant reason for the failure of the radioligand to label D3 receptors. Therefore, the low binding of [(11)C]RGH-1756 could largely be explained by the need for very high affinity of radioligand for D3 receptors in vivo, to obtain a suitable signal for the minute densities of D3 receptors expressed in the primate brain.
authors.affiliation: Karolinska Institutet, Department of Clinical Neuroscience, Psychiatry Section, SE-171 76 Stockholm, Sweden.
authors.forename: Judit
authors.initials: J
authors.lastname: Sóvágó
authors.forename: Lars
authors.initials: L
authors.lastname: Farde
authors.forename: Christer
authors.initials: C
authors.lastname: Halldin
authors.forename: Evgenij
authors.initials: E
authors.lastname: Schukin
authors.forename: Magnus
authors.initials: M
authors.lastname: Schou
authors.forename: István
authors.initials: I
authors.lastname: Laszlovszky
authors.forename: Béla
authors.initials: B
authors.lastname: Kiss
authors.forename: Balázs
authors.initials: B
authors.lastname: Gulyás
mesh_terms: D018759:Adrenergic Uptake Inhibitors / Q000494:pharmacology*; D000818:Animals; D001667:Binding, Competitive / Q000187:drug effects*; D001921:Brain / Q000000981:diagnostic imaging* / Q000187:drug effects / Q000378:metabolism; D002247:Carbon Isotopes / Q000493:pharmacokinetics; D004298:Dopamine / Q000378:metabolism*; D005260:Female; D008252:Macaca fascicularis; D010879:Piperazines / Q000493:pharmacokinetics*; D049268:Positron-Emission Tomography / Q000379:methods; D011485:Protein Binding / Q000187:drug effects; D012110:Reserpine / Q000494:pharmacology*; D013844:Thiazoles / Q000493:pharmacokinetics*; D013997:Time Factors
chemical_list: C427703:1-(2-methoxy-phenyl)-4-(4-(4-(6-imidazol(2,1-b) thiazolyl)-phenoxy)-butyl-4-(14)C)-piperazine dimethane; D018759:Adrenergic Uptake Inhibitors; D002247:Carbon Isotopes; D010879:Piperazines; D013844:Thiazoles; D012110:Reserpine; D004298:Dopamine