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.

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.