title: Dopamine (D2/3) receptor agonist positron emission tomography radiotracer [11C]-(+)-PHNO is a D3 receptor preferring agonist in vivo.
abstract: [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.
authors.affiliation: Department of Psychiatry, Columbia University College of Physicians and Surgeons, New York 10032, USA. narendranr@upmc.edu
authors.forename: Rajesh
authors.initials: R
authors.lastname: Narendran
authors.forename: Mark
authors.initials: M
authors.lastname: Slifstein
authors.forename: Olivier
authors.initials: O
authors.lastname: Guillin
authors.forename: Yuying
authors.initials: Y
authors.lastname: Hwang
authors.forename: Dah-Ren
authors.initials: DR
authors.lastname: Hwang
authors.forename: Erica
authors.initials: E
authors.lastname: Scher
authors.forename: Stephanie
authors.initials: S
authors.lastname: Reeder
authors.forename: Eugenii
authors.initials: E
authors.lastname: Rabiner
authors.forename: Marc
authors.initials: M
authors.lastname: Laruelle
mesh_terms: D000818:Animals; D001667:Binding, Competitive / Q000187:drug effects / Q000502:physiology; D001921:Brain / Q000000981:diagnostic imaging / Q000187:drug effects* / Q000378:metabolism*; D001931:Brain Mapping; D002250:Carbon Radioisotopes; D018491:Dopamine Agonists / Q000378:metabolism* / Q000494:pharmacology; D018492:Dopamine Antagonists / Q000378:metabolism / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D015536:Down-Regulation / Q000187:drug effects / Q000502:physiology; D005260:Female; D005917:Globus Pallidus / Q000000981:diagnostic imaging / Q000187:drug effects / Q000378:metabolism; D008297:Male; D010078:Oxazines / Q000378:metabolism* / Q000494:pharmacology; D048530:Papio anubis; D010879:Piperazines / Q000378:metabolism / Q000494:pharmacology; D049268:Positron-Emission Tomography; D020891:Raclopride / Q000378:metabolism / Q000494:pharmacology; D017448:Receptors, Dopamine D2 / Q000187:drug effects / Q000378:metabolism; D050637:Receptors, Dopamine D3 / Q000187:drug effects* / Q000378:metabolism*; D013045:Species Specificity; D013997:Time Factors
chemical_list: D002250:Carbon Radioisotopes; D018491:Dopamine Agonists; D018492:Dopamine Antagonists; D010078:Oxazines; D010879:Piperazines; D017448:Receptors, Dopamine D2; D050637:Receptors, Dopamine D3; C120565:BP 897; C042631:naxagolide; D020891:Raclopride