title: Within-subject comparison of [(11)C]-(+)-PHNO and [(11)C]raclopride sensitivity to acute amphetamine challenge in healthy humans.
abstract: [(11)C]PHNO is a D(2)/D(3) agonist positron emission tomography radiotracer, with higher in vivo affinity for D(3) than for D(2) receptors. As [(11)C]-(+)-PHNO is an agonist, its in vivo binding is expected to be more affected by acute fluctuations in synaptic dopamine than that of antagonist radiotracers such as [(11)C]raclopride. In this study, the authors compared the effects of an oral dose of the dopamine releaser amphetamine (0.3 mg/kg) on in vivo binding of [(11)C]-(+)-PHNO and [(11)C]raclopride in healthy subjects, using a within-subjects, counterbalanced, open-label design. In the dorsal striatum, where the density of D(3) receptors is negligible and both tracers predominantly bind to D(2) receptors, the reduction of [(11)C]-(+)-PHNO binding potential (BP(ND)) was 1.5 times larger than that of [(11)C]raclopride. The gain in sensitivity associated with the agonist [(11)C]-(+)-PHNO implies that ∼65% of D(2) receptors are in the high-affinity state in vivo. In extrastriatal regions, where [(11)C]-(+)-PHNO predominantly binds to D(3) receptors, the amphetamine effect on [(11)C]-(+)-PHNO BP(ND) was even larger, consistent with the higher affinity of dopamine for D(3). This study indicates that [(11)C]-(+)-PHNO is superior to [(11)C]raclopride for studying acute fluctuations in synaptic dopamine in the human striatum. [(11)C]-(+)-PHNO also enables measurement of synaptic dopamine in D(3) regions.
authors: GlaxoSmithKline Clinical Imaging Centre, Hammersmith Hospital, London, UK. P.Shotbolt@imperial.ac.uk
authors: Paul
authors: P
authors: Shotbolt
authors: Andri C
authors: AC
authors: Tziortzi
authors: Graham E
authors: GE
authors: Searle
authors: Alessandro
authors: A
authors: Colasanti
authors: Jasper
authors: J
authors: van der Aart
authors: Sergio
authors: S
authors: Abanades
authors: Christophe
authors: C
authors: Plisson
authors: Sam R
authors: SR
authors: Miller
authors: Mickael
authors: M
authors: Huiban
authors: John D
authors: JD
authors: Beaver
authors: Roger N
authors: RN
authors: Gunn
authors: Marc
authors: M
authors: Laruelle
authors: Eugenii A
authors: EA
authors: Rabiner
mesh_terms: D000328:Adult; D000661:Amphetamine / Q000097:blood / Q000494:pharmacology*; D001667:Binding, Competitive; D001921:Brain / Q000187:drug effects / Q000378:metabolism; D004298:Dopamine / Q000378:metabolism; D018491:Dopamine Agonists / Q000493:pharmacokinetics*; D018492:Dopamine Antagonists / Q000493:pharmacokinetics*; D065127:Dopamine D2 Receptor Antagonists; D006801:Humans; D008024:Ligands; D008297:Male; D008875:Middle Aged; D010078:Oxazines / Q000493:pharmacokinetics*; D049268:Positron-Emission Tomography / Q000379:methods*; D011485:Protein Binding; D020891:Raclopride / Q000493:pharmacokinetics*; D011869:Radioligand Assay; D019275:Radiopharmaceuticals / Q000493:pharmacokinetics; D017448:Receptors, Dopamine D2 / Q000819:agonists; D050637:Receptors, Dopamine D3 / Q000819:agonists / Q000037:antagonists & inhibitors; D012680:Sensitivity and Specificity
chemical_list: D018491:Dopamine Agonists; D018492:Dopamine Antagonists; D065127:Dopamine D2 Receptor Antagonists; D008024:Ligands; D010078:Oxazines; D019275:Radiopharmaceuticals; D017448:Receptors, Dopamine D2; D050637:Receptors, Dopamine D3; C042631:naxagolide; D020891:Raclopride; D000661:Amphetamine; D004298:Dopamine