VALIDATION OF A KINETIC MODEL FOR RECEPTOR IMAGING

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The specific aim of this proposal is to validate a kinetic model which analyzes the results of a new nuclear medicine modality. This technique employs a hepatocyte-specific receptor-binding radiopharmaceutical, Tc-99m-galactosyl-neoglycoalbumin (Tc-NGA). Kinetic analysis of Tc-NGA time-activity data yields estimates of model parameters which represent hepatic blood flow, receptor concentration, the forward rate constant of receptor biding, hepatic blood and extra-hepatic blood volumes, and Tc-NGA metabolism. This project will measure each of the above mentioned parameters using established techniques. These measurements will be made during Tc-NGA functional imaging of canine livers. The techniques will include: i)\determination of hepatic blood flow using indocyanine green extraction measurements with hepatic venous sampling; ii) measurement of the number of receptors, and the forward rate constant of binding using an in vitro assay; and iii) measurement of hepatic and extra-hepatic blood volumes using chromium-labeled red blood cells and iodinated albumin. Comparison of each value estimated by the Tc-NGA function imaging study and the actual value will be carried out at different hepatic blood flows, liver mass, and forward binding rate constants. This will be accomplished by: a) imaging dogs of differing bodyweight, b) controlling hepatic blood flow with varying levels of halothane anesthesia or i.v. injections of glucagon; and c) injecting NGAs of differing carbohydrate densities. If the kinetic model is a valid representation of Tc-NGA uptake by the receptor, the parameter estimates of the amount of HPB, hepatic blood flow, and blood volumes will agree with the measured values throughout the range of liver blood flows, hepatic mass, and forward binding rate constants. Current clinical application of Tc-NGA functional imaging uses the parameter estimates as indexes of hepatic function. Validation of the kinetic model will provide a physiochemical basis upon which each parameter may be interpreted. This technique could then be used to study the in vivo biochemistry of the specific receptor, as well as, the influence of disease and pharmacologic agents upon hepatic blood flow.