The dopamine D₁ receptor agonist (S)-[¹¹C]N-methyl-NNC 01-0259 is not sensitive to changes in dopamine...

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.