Dopamine (D2/3) receptor agonist positron emission tomography radiotracer [11C]-(+)-PHNO is a D3 receptor preferring agonist in vivo

[11C]PHNO is a recently introduced agonist to image DA D2‐like receptors with Positron Emission Tomography (PET). In cats and humans, [11C]PHNO revealed an atypical distribution compared to radiolabeled D2‐like antagonists (such as [11C]raclopride) or other D2‐like agonists (such as [11C]NPA), as it displayed unusual high binding in the globus pallidus (GP). The goal of this study was to assess the pharmacological nature of the binding of [11C]PHNO in the GP in nonhuman primates. As previously reported in humans, [11C]PHNO equilibrium specific to nonspecific equilibrium partition coefficients (V3″) in baboons was much higher in GP (3.88 ± 1.15) than in the dorsal striatum (DST, 2.07 ± 0.43), whereas the reverse was true for [11C]raclopride (1.48 ± 0.41 in GP, 2.56 ± 0.91 in DST) and [11C]NPA (0.87 ± 0.19 in GP, 1.02 ± 0.13 in DST). Administration of unlabeled raclopride resulted in similar reductions of [11C] PHNO V3″ and [11C]raclopride V3″ in both the GP and the DST. This observation demonstrated that the [11C]PHNO binding in the GP was specific to D2‐like receptors. To evaluate the respective contribution of D3 and D2 receptors to the binding potential (BP) of [11C]PHNO and [11C]raclopride, experiments were carried out with the selective D3 partial agonist 1‐(4(2‐Napthoylamino)butyl)‐4‐(2‐methoxyphenyl)‐1A‐piperazine HCL (BP897). BP897 reduced [11C]raclopride V3″ by 29% ± 9%, 19% ± 8%, and 10% ± 7% in GP, VST, and DST, respectively, a result consistent with expectation from postmortem studies (D3/D2 ratio in GP > VST > DST). BP897 reduced [11C]PHNO V3″ by 57% ± 11%, 30% ± 11%, and 13% ± 8% in GP, VST, and DST, respectively, indicating that the D3 receptor contribution to [11C]PHNO signal is higher than that of [11C]raclopride. From these experiments we conclude that [11C]PHNO is a D3 preferring agonist, and that this property explains the high GP signal not observed with [11C]raclopride or [11C]NPA. This property might contribute to its higher vulnerability to endogenous DA compared to [11C]raclopride and [11C]NPA. Synapse 60:485–495, 2006. © 2006 Wiley‐Liss, Inc.