Imaging dopamine D₃ receptors in the human brain with positron emission tomography, [¹¹C]PHNO, and a selective D₃ receptor antagonist

Background: Dopamine D₃ receptors are involved in the pathophysiology of several neuropsychiatric conditions. [¹¹C]-(+)- PHNO is a radiolabeled D₂ and D₃ agonist, suitable for imaging the agonist binding sites (denoted D_2HIGH and D₃) of these receptors with positron emission tomography (PET). PET studies in nonhuman primates documented that, in vivo, [¹¹C]-(+)-PHNO displays a relative selectivity for D₃ compared with D_2HIGH receptor sites and that the [¹¹C]-(+)-PHNO signal is enriched in D ₃ contribution compared with conventional ligands such as [ ¹¹C] raclopride. Methods: To define the D₃ contribution (fPHNOD3) to [¹¹C]-(+)-PHNO binding potential (BP_ND) in healthy humans, 52 PET scans were obtained in 19 healthy volunteers at baseline and following oral administration of various doses of the selective D ₃ receptor antagonist, GSK598809. Results: The impact of GSK598809 on [¹¹C]-(+)-PHNO was regionally selective. In dorsal regions of the striatum, GSK598809 did not significantly affect [¹¹C]-(+)-PHNO BP_ND (fPHNOD3 ≈ 0%). Conversely, in the substantia nigra, GSK598809 dose-dependently reduced [¹¹C]-(+)-PHNO binding to nonspecific level (fPHNOD3 ≈ 100%). In ventral striatum (VST), globus pallidus and thalamus (THA), [¹¹C]-(+)-PHNO BP_ND was attributable to a combination of D_2HIGH and D₃ receptor sites, with fPHNOD3 of 26%, 67% and 46%, respectively. D₃ receptor binding potential (BPNDD3) was highest in globus pallidus (1.90) and substantial nigra (1.39), with lower levels in VST (.77) and THA (.18) and negligible levels in dorsal striatum. Conclusions: This study elucidated the pharmacologic nature of the [¹¹C]-(+)-PHNO signal in healthy subjects and provided the first quantification of D₃ receptor availability with PET in the living human brain.