Pirro J P, Di Rocco R J, Narra R K, Nunn A D
Bristol-Myers Squibb Pharmaceutical Research Institute, Princeton, New Jersey 08543-4000.
J Nucl Med. 1994 Sep;35(9):1514-9.
In vitro transendothelial permeability was compared to in vivo rat single-pass cerebral extractions to evaluate which method would best estimate the blood-brain barrier (BBB) permeability of several SPECT imaging agents.
Six 99mTc complexes and seven non-Tc complexes were tested in vitro using monolayers of primary bovine brain microvessel endothelial cells and in vivo using the rat single-pass cerebral extraction model. In vitro transendothelial permeability indices (PI) were determined by measuring the average percent of radioactivity traversing the monolayers as a function of time. In vivo single-pass cerebral extractions were determined using an indicator fractionation method.
A positive correlation between extraction and PI was found for the non-Tc complexes (r2 = 0.96). The CBF imaging agents 99mTc-ECD and 99mTc-PnAO have high values for E and PI, demonstrating that these agents penetrate the BBB and have a high membrane permeability, while the heart imaging agent 99mTc-sestamibi had low values for both E and PI. The low PI and E values for 99mTc-sestamibi are consistent with a low brain uptake for this agent, except in cases of disruption of the BBB. In contrast to 99mTc-ECD, 99mTc-PnAO and 99mTc-sestamibi, which had concordant values for E and PI, two highly lipophilic boronic acid adducts of technetium dioxime (BATOs), 99mTc-teboroxime and 99mTcCl(DMG)3(2)MP, had low negative values for PI, but high values for E. In addition, after 3 hr of incubation, the monolayer-to-medium concentration ratio of the BATOs was 642:1 and 744:1, respectively. This compares with values of 89:1 (99mTc-PnAO), 25:1 (99mTc-ECD) and 34:1 (99mTc-sestamibi).
These data suggest that the high in vivo single-pass extraction of the BATOs may be explained by a hydrophobic interaction with the luminal surface of the capillary endothelial cell plasma membrane. We conclude that a high single-pass extraction cannot necessarily be used to infer high BBB or membrane permeability.
将体外跨内皮通透性与体内大鼠单次通过脑摄取进行比较，以评估哪种方法能最佳估计几种SPECT成像剂的血脑屏障（BBB）通透性。
使用原代牛脑微血管内皮细胞单层在体外对6种99mTc配合物和7种非Tc配合物进行测试，并使用大鼠单次通过脑摄取模型在体内进行测试。通过测量放射性穿过单层的平均百分比随时间的变化来确定体外跨内皮通透性指数（PI）。使用指示剂分馏法确定体内单次通过脑摄取。
发现非Tc配合物的摄取与PI之间存在正相关（r2 = 0.96）。脑血流量成像剂99mTc-ECD和99mTc-PnAO的E和PI值较高，表明这些药剂可穿透血脑屏障并具有高膜通透性，而心脏成像剂99mTc-司他比的E和PI值均较低。99mTc-司他比的低PI和E值与该药剂的低脑摄取一致，除非血脑屏障被破坏。与99mTc-ECD、99mTc-PnAO和99mTc-司他比的E和PI值一致相反，两种高亲脂性的二肟锝硼酸加合物（BATOs），99mTc-替硼肟和99mTcCl(DMG)3(2)MP，PI值为低负值，但E值较高。此外，孵育3小时后，BATOs的单层与培养基浓度比分别为642:1和744:1。与之相比，99mTc-PnAO为89:1、99mTc-ECD为25:1、99mTc-司他比为34:1。
这些数据表明，BATOs在体内的高单次通过摄取可能是由于与毛细血管内皮细胞质膜腔表面的疏水相互作用所致。我们得出结论，高单次通过摄取不一定能用于推断高血脑屏障或膜通透性。
