In Vivo Vulnerability to Competition by Endogenous Dopamine: Comparison of the D2 Receptor Agonist Radiotracer (-)-N-[ 11C]propyl-norapomorphine ([11C]NPA) with the D 2 Receptor Antagonist Radiotracer [11C]-Raclopride

(-)-N-Propyl-norapomorphine (NPA) is a full dopamine (DA) D2 receptor agonist and [11C]NPA is a suitable radiotracer to image D2 receptors configured in a state of high affinity for agonists with positron emission tomography (PET). In this study the vulnerability of the in vivo binding of [11C]NPA to acute fluctuation in synaptic DA was assessed with PET in baboons and compared to that of the reference D 2 receptor antagonist radiotracer [11C]raclopride. Three male baboons were studied with [11C]raclopride and [ 11C]NPA under baseline conditions and following administration of the potent DA releaser amphetamine (0.3, 0.5, and 1.0 mg kg-1 i.v.). Kinetic modeling with an arterial input function was used to derive the striatal specific-to-nonspecific equilibrium partition coefficient (V 3″). [11C]Raclopride V3″ was reduced by 24 ± 10%, 32 ± 6%, and 44 ± 9% following amphetamine doses of 0.3, 0.5, and 1.0 mg kg-1, respectively. [ 11C]NPA V3″ was reduced by 32 ± 2%, 45 ± 3%, and 53 ± 9% following amphetamine doses of 0.3, 0.5, and 1. 0 mg kg-1, respectively. Thus, endogenous DA was more effective at competing with [11C] NPA binding compared to [ 11C]raclopride binding, a finding consistent with the pharmacology of these tracers (agonist vs. antagonist). These results also suggest that 71% of D2 receptors are configured in a state of high affinity for agonists in vivo. In conclusion, [11C]NPA might provide a superior radiotracer to probe presynaptic DA function with PET in health and disease. © 2004 Wiley-Liss, Inc.