title: The dopamine D₁ receptor agonist (S)-[¹¹C]N-methyl-NNC 01-0259 is not sensitive to changes in dopamine concentration--a positron emission tomography examination in the monkey brain.
abstract: Dopamine D₂ receptor positron emission tomography (PET) radioligands have proven useful for indirect assessment of the endogenous dopamine concentration in the living brain. On the contrary, dopamine D₁ receptor antagonist radioligands have shown no sensitivity to changes in the dopamine concentration. A recent approach to enhance the sensitivity of radioligands to the dopamine concentration has been the development of dopamine D₂ receptor agonist radioligands. The aim of this study was to evaluate the dopamine sensitivity of a dopamine D₁ receptor agonist radioligand. For this purpose, we developed (S)-[¹¹C]N-methyl-NNC 01-0259 ((S)-[¹¹C]1) and characterized the receptor binding of (S)-[¹¹C]1 using in vitro receptor binding assays and in vivo PET measurements in monkeys. In vitro, both enantiomers of 1 were partial dopamine D₁ receptor agonists, with (S)-1 having a 10-50 times higher affinity than (R)-1. PET studies in monkey confirmed the stereoselectivity of [¹¹C]1 in vivo. In monkey, administration of the dopamine D₁-like receptor antagonist (R)-(+)-SCH 23390 decreased the striatal binding potential of (S)-[¹¹C]1 by 97%, but administration of the dopamine concentration enhancer d-amphetamine did not affect (S)-[¹¹C]1 binding. We conclude that the agonist (S)-[¹¹C]1 provides specific binding to dopamine D₁-like receptors, possibly representing binding to the high-affinity state of the receptors. The partial dopamine D₁ receptor agonist radioligand has, however, no enhanced sensitivity to endogenous dopamine concentrations in comparison with antagonist radioligands.
authors.affiliation: Translational Science Center at Karolinska Institutet, AstraZeneca, Stockholm, Sweden. sjoerd.finnema@ki.se
authors.forename: S J
authors.initials: SJ
authors.lastname: Finnema
authors.forename: B
authors.initials: B
authors.lastname: Bang-Andersen
authors.forename: M
authors.initials: M
authors.lastname: Jørgensen
authors.forename: C T
authors.initials: CT
authors.lastname: Christoffersen
authors.forename: B
authors.initials: B
authors.lastname: Gulyás
authors.forename: H V
authors.initials: HV
authors.lastname: Wikström
authors.forename: L
authors.initials: L
authors.lastname: Farde
authors.forename: C
authors.initials: C
authors.lastname: Halldin
mesh_terms: D000818:Animals; D001552:Benzazepines / Q000494:pharmacology*; D001572:Benzofurans / Q000494:pharmacology*; D001921:Brain / Q000000981:diagnostic imaging*; D016466:CHO Cells; D006224:Cricetinae; D003412:Cricetulus; D004298:Dopamine / Q000378:metabolism*; D018491:Dopamine Agonists / Q000494:pharmacology*; D006801:Humans; D008252:Macaca fascicularis; D049268:Positron-Emission Tomography; D011485:Protein Binding; D019275:Radiopharmaceuticals / Q000494:pharmacology*; D017447:Receptors, Dopamine D1 / Q000819:agonists* / Q000378:metabolism
chemical_list: D001552:Benzazepines; D001572:Benzofurans; D018491:Dopamine Agonists; C586312:N-methyl-NNC 01-0259; D019275:Radiopharmaceuticals; D017447:Receptors, Dopamine D1; C534628:SCH 23390; C077123:NNC 112; D004298:Dopamine
keywords: MDL-100907; catecholamines; d-amphetamine; neurotransmitter; nonhuman primates