title: In vivo binding behavior of dopamine receptor agonist (+)-PD 128907 and implications for the "ceiling effect" in endogenous competition studies with [(11)C]raclopride-a positron emission tomography study in Macaca mulatta.
abstract: In in vivo positron emission tomography (PET) studies, dopamine that is released secondary to amphetamine administration appears unable to achieve a receptor occupancy that is significantly higher than 50% ("ceiling effect"). Also with exogenous agonists no studies have reported a higher than 50% occupancy. To investigate the feasibility of exceeding 50% occupancy in vivo with a dopamine receptor agonist we administered D2/D3 agonist (+)-PD 128907 over an extensive dose range. Two anesthetised Macaca mulatta males were used in a bolus-infusion protocol for [(11)C]raclopride. (+)-PD 128907 was administered as an intravenous challenge during separate PET scans in a dose range of 10 to 10000 nmol/kg. Occupancy by (+)-PD 128907 was estimated by comparing the binding before and after challenge. In a striatal region of interest, receptor occupancy by (+)-PD 128907 increased in an orderly dose-dependent manner to a maximum of at least 85%. This is the first indication that virtually all dopamine D2/D3 receptors in the striatum are in principle accessible to agonist binding. In the case of dopamine a number of protective mechanisms may be responsible for the ceiling effect.
authors.affiliation: Department of Neurology, University of Groningen, The Netherlands. R.Kortekaas@neuro.aazg.nl
authors.forename: Rudie
authors.initials: R
authors.lastname: Kortekaas
authors.forename: R Paul
authors.initials: RP
authors.lastname: Maguire
authors.forename: Thomas I
authors.initials: TI
authors.lastname: Cremers
authors.forename: Durk
authors.initials: D
authors.lastname: Dijkstra
authors.forename: Aren
authors.initials: A
authors.lastname: van Waarde
authors.forename: Klaus L
authors.initials: KL
authors.lastname: Leenders
mesh_terms: D000818:Animals; D001578:Benzopyrans / Q000378:metabolism*; D018491:Dopamine Agonists / Q000378:metabolism*; D018492:Dopamine Antagonists / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D008253:Macaca mulatta; D008297:Male; D010078:Oxazines / Q000378:metabolism*; D020891:Raclopride / Q000378:metabolism*; D017448:Receptors, Dopamine D2 / Q000378:metabolism*; D014055:Tomography, Emission-Computed
chemical_list: D001578:Benzopyrans; D018491:Dopamine Agonists; D018492:Dopamine Antagonists; D010078:Oxazines; D017448:Receptors, Dopamine D2; C062458:3,4,4a,10b-tetrahydro-4-propyl-2H,5H-(1)benzopyrano(4,3-b)-1,4-oxazin-9-ol; D020891:Raclopride