In vivo vulnerability to competition by endogenous dopamine: Comparison of the D2 receptor agonist radiotracer (–)‐N‐[11C]propyl‐norapomorphine ([11C]NPA) with the D2 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 D2 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 (V3″). [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. Synapse 52:188–208, 2004. © 2004 Wiley‐Liss, Inc.