Dopamine (D_2/3) 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 D ₂-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 (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 [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 V″₃ and [ ¹¹C]raclopride V″₃ 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 V″₃ 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 V″₃ 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.