Relationship between in vitro transendothelial permeability and in vivo single-pass brain extraction
- Bristol-Myers Squibb Pharmaceutical Research Institute, Princeton, NJ (United States); and others
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 {sup 99m}Tc 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 (r{sup 2} = 0.96). The CBF imaging agents {sup 99m}Tc-ECD and {sup 99m}Tc-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 {sup 99m}Tc-sestamibi had low values for both E and PI. The low PI and E values for {sup 99m}Tc-sestamibi are consistent with a low brain uptake for this agent, except in cases of disruption of the BBB. In contrast to {sup 99m}Tc-ECD, {sup 99m}Tc-PnAO and {sup 99m}Tc-sestamibi, which had concordant values for E and PI, two highly lipophilic boronic acid adducts of technetium dioxime (BATOs), {sup 99m}Tc-teboroxime and {sup 99m}Tc-ECD, {sup 99m}Tc-Cl(DMG){sub 3}2MP, 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 ({sup 99m}Tc-PnAO), 25:1 ({sup 99m}Tc-ECD) and 34:1 ({sup 99m}Tc-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.
- OSTI ID:
- 114866
- Journal Information:
- Journal of Nuclear Medicine, Vol. 35, Issue 9; Other Information: PBD: Sep 1994
- Country of Publication:
- United States
- Language:
- English
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