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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


Correspondence to: S.J. Finnema, Department of Clinical Neuroscience, Karolinska Institutet, Karolinska University Hospital, Center for Psychiatric Research, Building R5:02, SE-17176 Stockholm, Sweden. E-mail:


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. Synapse 67:586–595, 2013. © 2013 Wiley Periodicals, Inc.