title: Blockade of [11C](+)-PHNO binding in human subjects by the dopamine D3 receptor antagonist ABT-925.
abstract: Dopamine D3 receptors are preferentially localized in the limbic system and midbrain, and thus may be involved in the pathophysiology of neuropsychiatry disorders. [11C](+)-PHNO is the first preferential D3 receptor radioligand in humans, yet there are no blockade studies with a D3 receptor antagonist in humans. This study characterized the blockade of [11C](+)-PHNO binding by ABT-925, a D3 receptor antagonist, in healthy male subjects. Sixteen subjects underwent 2-3 positron emission tomography (PET) scans, at baseline and following one or two doses of ABT-925 ranging from 50 mg to 600 mg. Receptor occupancies were estimated for globus pallidus, substantia nigra, caudate, putamen, and ventral striatum. At the 600-mg dose (n=9), ABT-925 receptor occupancy (mean+/-s.d.) was higher in substantia nigra (75+/-10%) and globus pallidus (64+/-22%) than in ventral striatum (44+/-17%), caudate (40+/-18%) and putamen (38+/-17%) (ANOVA: F4,140=15.02, p<0.001). The fractions of [11C](+)-PHNO binding attributable to D3 receptors in D3 receptor-rich regions were 100% (substantia nigra) and 90% (globus pallidus), and in D2 receptor-rich regions were 55% (caudate) and 53% (putamen). The ED50 of ABT-925 was 4.37 microg/ml across regions. Our results demonstrate that [11C](+)-PHNO binding can be blocked by a D3 receptor antagonist and confirm preclinical findings that [11C](+)-PHNO signal in the substantia nigra and globus pallidus is mainly reflective of its binding to D3 receptors. Thus, [11C](+)-PHNO seems a suitable PET radiotracer to estimate D3 receptor occupancy in humans.
authors.affiliation: PET Centre, Centre for Addiction and Mental Health, Toronto, ON, Canada. Ariel_graff@yahoo.com.mx
authors.forename: Ariel
authors.initials: A
authors.lastname: Graff-Guerrero
authors.forename: Laura
authors.initials: L
authors.lastname: Redden
authors.forename: Walid
authors.initials: W
authors.lastname: Abi-Saab
authors.forename: David A
authors.initials: DA
authors.lastname: Katz
authors.forename: Sylvain
authors.initials: S
authors.lastname: Houle
authors.forename: Penny
authors.initials: P
authors.lastname: Barsoum
authors.forename: Anahita
authors.initials: A
authors.lastname: Bhathena
authors.forename: Ramesh
authors.initials: R
authors.lastname: Palaparthy
authors.forename: Mario D
authors.initials: MD
authors.lastname: Saltarelli
authors.forename: Shitij
authors.initials: S
authors.lastname: Kapur
mesh_terms: D000293:Adolescent; D000328:Adult; D001667:Binding, Competitive / Q000187:drug effects; D001921:Brain / Q000000981:diagnostic imaging* / Q000187:drug effects*; D001931:Brain Mapping; D002250:Carbon Radioisotopes / Q000493:pharmacokinetics; D018491:Dopamine Agonists / Q000493:pharmacokinetics*; D018492:Dopamine Antagonists / Q000097:blood / Q000494:pharmacology*; D006801:Humans; D008279:Magnetic Resonance Imaging / Q000379:methods; D008297:Male; D010078:Oxazines / Q000493:pharmacokinetics*; D049268:Positron-Emission Tomography / Q000379:methods; D011485:Protein Binding / Q000187:drug effects; D050637:Receptors, Dopamine D3 / Q000037:antagonists & inhibitors / Q000187:drug effects; D055815:Young Adult
chemical_list: D002250:Carbon Radioisotopes; D018491:Dopamine Agonists; D018492:Dopamine Antagonists; D010078:Oxazines; D050637:Receptors, Dopamine D3; C042631:naxagolide