Purpose: P-glycoprotein (Pgp) is an efflux protein found amongst other locations in the blood-brain barrier. It is important to investigate the effect of Pgp modulation on clinically used brain tracers, because brain uptake of the tracer can be altered by blocking of the Pgp efflux transporter. The function of Pgp can be blocked with cyclosporin A.
Methods: We investigated the effect of cyclosporin A administration on the biodistribution of [(123)I]R91150 in rodents, and the effect of Pgp blocking on the quality of multipinhole muSPECT imaging with [(123)I]R91150. The influence of increasing doses of cyclosporin A on the brain uptake of [(123)I]R91150 was investigated in NMRI mice. A biodistribution study with [(123)I]R91150 was performed in male Sprague-Dawley rats pretreated with cyclosporin A and not pretreated. Brain uptake of [(123)I]R91150 after cyclosporin A injection was compared to the brain uptake in untreated animals, and a displacement study with ketanserin was performed in both groups. A multipinhole muSPECT brain imaging study was also performed using a Milabs U-SPECT-II camera in male Sprague-Dawley rats. To exclude the effect of possible metabolites, a metabolite study was also performed.
Results: At the highest cyclosporin A dose (50 mg/kg), a sevenfold increase in brain radioactivity concentration was observed in NMRI mice. Also, a dose-response relationship was established between the dose of cyclosporin A and the brain uptake of [(123)I]R91150 in mice. Compared to the control group, a five-fold increase in [(123)I]R91150 radioactivity concentration was observed in the brain of Sprague-Dawley rats after cyclosporin A treatment (50 mg/kg). Radioactivity concentration in the frontal cortex increased from 0.24+/-0.0092 to 1.58+/-0.097% injected dose per gram of tissue after treatment with cyclosporin A (at the 1-h time-point). Blood radioactivity concentrations did not increase to the same extent. The cortical activity was displaced by administration of ketanserin. A metabolite study confirmed that there was no increased metabolism of [(123)I]R91150 due to cyclosporin A. The visual quality of multipinhole muSPECT images with [(123)I]R91150 in Sprague-Dawley rats improved markedly after cyclosporin A pretreatment.
Conclusion: From the results obtained in the biodistribution studies, it can be concluded that [(123)I]R91150 is a substrate for Pgp in rodents. A relationship between the administered dose of cyclosporin A and the increase in [(123)I]R91150 brain radioactivity concentration was established. The overall quality of our multipinhole muSPECT images with [(123)I]R91150 in rats improved markedly after pretreatment of the animals with cyclosporin A.