CEA, I2BM, Service Hospitalier Frédéric Joliot, Orsay 91401, France.
Pharm Res. 2012 Sep;29(9):2468-76. doi: 10.1007/s11095-012-0776-7. Epub 2012 May 30.
Several in vivo studies have found that the 5-HT(1A) PET radioligand (18)F-MPPF is a substrate of rodent P-glycoprotein (P-gp). However, in vitro assays suggest that MPPF is not a substrate of human P-gp. We have now tested the influence of inhibiting P-gp on the brain kinetics of (18)F-MPPF in mice and non-human primates.
We measured the peripheral kinetics (arterial input function, metabolism, free fraction in plasma (f(P))) during (18)F-MPPF brain PET scanning in baboons with or without cyclosporine A (CsA) infusion. We measured (3)H-MPPF transport at the mouse BBB using in situ brain perfusion in P-gp/Bcrp deficient mice and after inhibiting P-gp with PSC833.
There was an unexpected 1.9-fold increase in brain area under the curve in CsA-treated baboons (n = 4), with no change in radiometabolite-corrected arterial input. However, total volume of distribution corrected for f(P) (V(T)/f(P)) remained unchanged. In situ brain perfusion showed that P-gp restricted the permeability of the mouse BBB to (3)H-MPPF while Bcrp did not.
These and previous in vitro results suggest that P-gp may not influence the permeability of human BBB to (18)F-MPPF. However, CsA treatment increased (18)F-MPPF free fraction, which is responsible for a misleading, P-gp unrelated enhanced brain uptake.
几项体内研究发现，5-HT(1A) PET 放射性配体（18）F-MPPF 是啮齿动物 P 糖蛋白（P-gp）的底物。然而，体外测定表明 MPPF 不是人 P-gp 的底物。我们现在已经测试了抑制 P-gp 对（18）F-MPPF 在小鼠和非人类灵长类动物脑中动力学的影响。
我们在给予环孢菌素 A（CsA）输注或不给予 CsA 输注的狒狒中，测量（18）F-MPPF 脑 PET 扫描期间的外周动力学（动脉输入函数、代谢、血浆中游离分数（f(P)））。我们使用 P-gp/Bcrp 缺陷型小鼠的原位脑灌注和 PSC833 抑制 P-gp 来测量（3）H-MPPF 在小鼠 BBB 中的转运。
在 CsA 处理的狒狒（n = 4）中，脑区曲线下面积出乎意料地增加了 1.9 倍，放射性代谢产物校正的动脉输入没有变化。然而，校正 f(P)的总分布容积（V(T)/f(P)）保持不变。原位脑灌注表明 P-gp 限制了（3）H-MPPF 通过小鼠 BBB 的通透性，而 Bcrp 则没有。
这些和以前的体外结果表明，P-gp 可能不会影响（18）F-MPPF 通过人 BBB 的通透性。然而，CsA 处理增加了（18）F-MPPF 游离分数，这导致了一种误导性的、与 P-gp 无关的增强的脑摄取。
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