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

[C-11]PHNO is a recently introduced agonist to image DA D-2-like receptors with Positron Emission Tomography (PET). In cats and humans, [C-11]PHNO revealed an atypical distribution compared to radiolabeled D-2-like antagonists (such as [C-11]raclopride) or other D-2-like agonists (such as [C-11]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 [C-11]PHNO in the GP in nonhuman primates. As previously reported in humans, [C-11]PHNO equilibrium specific to nonspecific equilibrium partition coefficients (V-3) 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 [C-11]raclopride (1.48 +/- 0.41 in GP, 2.56 +/- 0.91 in DST) and [C-11]NPA (0.87 +/- 0.19 in GP, 1.02 +/- 0.13 in DST). Administration of unlabeled raclopride resulted in similar reductions of [11C] PHNO V-3 and [C-11]raclopride V-3 in both the GP and the DST. This observation demonstrated that the [C-11]PHNO binding in the GP was specific to D-2-like receptors. To evaluate the respective contribution of D-3 and D-2 receptors to the binding potential (BP) of [C-11]PHNO and [C-11]raclopride, experiments were carried out with the selective D-3 partial agonist 1-(4(2-Napthoylamino)butyl)-4-(2-methoxyphenyl)-1A-piperazine HCL (BP897). BP897 reduced [C-11]raclopride V-3 by 29% +/- 9%, 19% +/- 8%, and 10% +/- 7% in GP, VST, and DST, respectively, a result consistent with expectation from postmortem studies (D-3/D-2 ratio in GP > VST > DST). BP897 reduced [C-11]PHNO V-3 by 57% +/- 11%, 30% +/- 11%. and 13% +/- 8% in GP, VST, and DST, respectively, indicating that the D-3 receptor contribution to [C-11]PHNO signal is higher than that of [C-11]raclopride. From these experiments we conclude that [C-11]PHNO is a D3 preferring agonist, and that this property explains the high GP signal not observed with [C-11]raclopride or [C-11]NPA. This property might contribute to its higher vulnerability to endogenous DA compared to [C-11]raclopride and [C-11]NPA. (c) 2006 Wiley-Liss, Inc.