Blanckaert P, Burvenich I, Staelens S, De Bruyne S, Moerman L, Wyffels L, De Vos F
Laboratory for Radiopharmacy, Faculty of Pharmaceutical Sciences, Ghent University, Harelbekestraat 72, 9000 Gent, Belgium.
Eur J Nucl Med Mol Imaging. 2009 Mar;36(3):446-53. doi: 10.1007/s00259-008-0968-x. Epub 2008 Nov 5.
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.
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.
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.
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.
P-糖蛋白（Pgp）是一种外排蛋白，存在于血脑屏障等部位。研究Pgp调节对临床使用的脑显像剂的影响很重要，因为阻断Pgp外排转运体可改变显像剂在脑内的摄取。环孢素A可阻断Pgp的功能。
我们研究了给予环孢素A对[(123)I]R91150在啮齿动物体内生物分布的影响，以及阻断Pgp对[(123)I]R91150多针孔微单光子发射计算机断层显像（muSPECT）成像质量的影响。在NMRI小鼠中研究了不同剂量环孢素A对[(123)I]R91150脑摄取的影响。对用环孢素A预处理和未预处理的雄性斯普拉格-道利大鼠进行了[(123)I]R91150的生物分布研究。将注射环孢素A后[(123)I]R91150的脑摄取与未处理动物的脑摄取进行比较，并在两组中进行了酮色林的置换研究。还使用Milabs U-SPECT-II相机对雄性斯普拉格-道利大鼠进行了多针孔muSPECT脑显像研究。为排除可能代谢物的影响，还进行了代谢物研究。
在NMRI小鼠中，给予最高剂量的环孢素A（50 mg/kg）时，脑放射性浓度增加了7倍。此外，在小鼠中建立了环孢素A剂量与[(123)I]R91150脑摄取之间的剂量反应关系。与对照组相比，环孢素A处理（50 mg/kg）后，斯普拉格-道利大鼠脑内[(123)I]R91150放射性浓度增加了5倍。环孢素A处理后（在1小时时间点），额叶皮质每克组织的放射性浓度从0.24±0.0092%注射剂量增加到1.58±0.097%注射剂量。血液放射性浓度没有增加到相同程度。给予酮色林后皮质活性被置换。代谢物研究证实，环孢素A不会增加[(123)I]R91150的代谢。环孢素A预处理后，[(123)I]R91150在斯普拉格-道利大鼠中的多针孔muSPECT图像视觉质量明显改善。
从生物分布研究结果可以得出结论，[(123)I]R91150在啮齿动物中是Pgp的底物。建立了环孢素A给药剂量与[(123)I]R91150脑放射性浓度增加之间的关系。用环孢素A对动物进行预处理后，我们用[(123)I]R91150在大鼠中进行的多针孔muSPECT图像的整体质量明显改善。
