RELATIONSHIP BETWEEN IN-VITRO TRANSENDOTHELIAL PERMEABILITY AND IN-VIVO SINGLE-PASS BRAIN EXTRACTION

In vitro transendothelial permeability was compared to in vivo rat sin gle-pass cerebral extractions to evaluate which method would best esti mate the blood-brain barrier (BBB) permeability of several SPECT imagi ng agents. Method: Six Tc-99m complexes and seven non-Tc complexes wer e tested in vitro using monolayers of primary bovine brain microvessel endothelial cells and in vivo using the rat single-pass cerebral extr action model. In vitro transendothelial permeability indices (PI) were determined by measuring the average percent of radioactivity traversi ng the monolayers as a function of time. In vivo single-pass cerebral extractions were determined using an indicator fractionation method. R esults: A positive correlation between extraction and PI was found for the non-Tc complexes (r(2) = 0.96). The CBF imaging agents Tc-99m-ECD and Tc-99m-PnAO have high values for E and PI, demonstrating that the se agents penetrate the BBB and have a high membrane permeability, whi le the heart imaging agent Tc-99m-sestamibi had low values for both E and PI. The low PI and E values for Tc-99m-sestamibi are consistent wi th a low brain uptake for this agent, except in cases of disruption of the BBB. In contrast to Tc-99m-ECD, Tc-99m-PnAO and Tc-99m-sestamibi, which had concordant values for E and Pi, two highly lipophilic boron ic acid adducts of technetium dioxime (BATOs), Tc-99m-teboroxime and ( TcCl)-Tc-99m(DMG)(3)2MP, had low negative values for PI, but high valu es for E. In addition, after 3 hr of incubation, the monolayer-to-medi um concentration ratio of the BATOs was 642:1 and 744:1, respectively This compares with values of 89:1 (Tc-99m-PnAO), 25:1 (Tc-99m-ECD) and 34:1 (Tc-99m-sestamibi). Conclusion: These data suggest that the high in vive single-pass extraction of the BATOs may be explained by a hyd rophobic interaction with the luminal surface of the capillary endothe lial cell plasma membrane. We conclude that a high single-pass extract ion cannot necessarily be used to infer high BBB or membrane permeabil ity.