In vivo Binding Behavior of Dopamine Receptor Agonist (+)−PD 128907 and Implications for the “Ceiling Effect” in Endogenous Competition Studies with [11C]Raclopride—a Positron Emission Tomography Study in Macaca mulatta

• Published in: Journal of cerebral blood flow and metabolism 2004-05, Vol.24 (5), p.531-535
• Main Authors: Kortekaas, Rudie, Maguire, R. Paul, Cremers, Thomas I., Dijkstra, Durk, van Waarde, Aren, Leenders, Klaus L.
• Format: Article
• Language: English
• Subjects: Animals; Benzopyrans - metabolism; Biological and medical sciences; Dopamine Agonists - metabolism; Dopamine Antagonists - metabolism; Dose-Response Relationship, Drug; Macaca mulatta; Male; Medical sciences; Neurology; Oxazines - metabolism; Raclopride - metabolism; Receptors, Dopamine D2 - metabolism; Tomography, Emission-Computed; Vascular diseases and vascular malformations of the nervous system
• ISSN: 0271-678X; 1559-7016
• DOI: 10.1097/00004647-200405000-00007

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 [11C]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.