在非人类灵长类动物血脑屏障中 P-糖蛋白功能的发育变化：使用 R-11C-维拉帕米和 11C-奥司他韦的 PET 研究。
Developmental changes in P-glycoprotein function in the blood-brain barrier of nonhuman primates: PET study with R-11C-verapamil and 11C-oseltamivir.
机构信息
RIKEN Center for Molecular Imaging Science, Chuo-ku, Kobe, Japan.
出版信息
J Nucl Med. 2011 Jun;52(6):950-7. doi: 10.2967/jnumed.110.083949. Epub 2011 May 13.
UNLABELLED
P-glycoprotein (P-gp) plays a pivotal role in limiting the penetration of xenobiotic compounds into the brain at the blood-brain barrier (BBB), where its expression increases with maturation in rats. We investigated developmental changes in P-gp function in the BBB of nonhuman primates using PET with R-(11)C-verapamil, a PET radiotracer useful for evaluating P-gp function. In addition, developmental changes in the brain penetration of (11)C-oseltamivir, a substrate for P-gp, was investigated as practical examples.
METHODS
PET studies in infant (age, 9 mo), adolescent (age, 24-27 mo), and adult (age, 5.6-6.6 y) rhesus monkeys (Macaca mulatta) were performed with R-(11)C-verapamil and also with (11)C-oseltamivir. Arterial blood samples and PET images were obtained at frequent intervals up to 60 min after administration of the PET tracer. Dynamic imaging data were evaluated by integration plots using data collected within the first 2.5 min after tracer administration.
RESULTS
R-(11)C-verapamil rapidly penetrated the brain, whereas the blood concentration of intact R-(11)C-verapamil decreased rapidly in all subjects. The maximum brain uptake in infant (0.033% ± 0.007% dose/g of brain) and adolescent (0.020% ± 0.002% dose/g) monkeys was 4.1- and 2.5-fold greater, respectively, than uptake in adults (0.0082% ± 0.0007% dose/g). The clearance of brain R-(11)C-verapamil uptake in adult monkeys was 0.056 ± 0.010 mL/min/g, significantly lower than that in infants (0.11 ± 0.04 mL/min/g) and adolescents (0.075 ± 0.023 mL/min/g). (11)C-oseltamivir showed little brain penetration in adult monkeys, with a clearance of R-(11)C-verapamil uptake of 0.0072 and 0.0079 mL/min/g, slightly lower than that in infant (0.0097 and 0.0104 mL/min/g) and adolescent (0.0097 and 0.0098 mL/min/g) monkeys.
CONCLUSION
These results suggest that P-gp function in the BBB changes with development in rhesus monkeys, and this change may be closely related to the observed difference in drug responses in the brains of children and adult humans.
目的
使用正电子发射断层扫描（PET）与 R-[11]C-维拉帕米（一种评估 P-糖蛋白功能的 PET 示踪剂）研究非人类灵长类动物血脑屏障（BBB）中 P-糖蛋白功能的发育变化。此外，还研究了 P-糖蛋白底物 [11]C-奥司他韦在脑内的穿透情况，作为实际示例。
方法
对 9 月龄（婴儿）、24-27 月龄（青少年）和 5.6-6.6 岁（成人）恒河猴进行 R-[11]C-维拉帕米和 [11]C-奥司他韦的 PET 研究。在给予 PET 示踪剂后 60 分钟内频繁采集动脉血样和 PET 图像。通过整合图评估动态成像数据，使用给药后最初 2.5 分钟内收集的数据进行评估。
结果
R-[11]C-维拉帕米迅速穿透大脑，而所有受试者的完整 R-[11]C-维拉帕米血浓度迅速下降。婴儿（0.033%±0.007%剂量/g 脑）和青少年（0.020%±0.002%剂量/g 脑）猴子的最大脑摄取量分别是成人（0.0082%±0.0007%剂量/g 脑）的 4.1 倍和 2.5 倍。成人猴子大脑中 R-[11]C-维拉帕米摄取的清除率为 0.056±0.010 mL/min/g，明显低于婴儿（0.11±0.04 mL/min/g）和青少年（0.075±0.023 mL/min/g）。[11]C-奥司他韦在成年猴子的脑内穿透性较小，R-[11]C-维拉帕米摄取的清除率为 0.0072 和 0.0079 mL/min/g，略低于婴儿（0.0097 和 0.0104 mL/min/g）和青少年（0.0097 和 0.0098 mL/min/g）。
结论
这些结果表明，在恒河猴中，BBB 中的 P-糖蛋白功能随发育而变化，这种变化可能与儿童和成人大脑中观察到的药物反应差异密切相关。
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