The proposed project will continue to investigate the radiopharmacokinetic modeling of receptor-specific radiotracers. This new class of radiopharmaceutical, which accumulates at a target tissue by virtue of its affinity for a specific receptor molecule, offers an opportunity for the noninvasive study of in vivo receptor biochemistry. Interpretation of the tracer data into information concerning the receptor chemistry will require a kinetic model. We have tested a kinetic model for the hepatic uptake of Tc-99m galactosyl-neoglycoalbumin (TcNGA) in healthy pigs, and found the model estimates of receptor concentration and affinity, and hepatic blood flow to agree with the actual values which were measured independently by established techniques. We will modify the kinetic model to incorporate the following conditions: 1) receptor recycling, 2) elevated serum concentration of endogenous ligand, 3) fibrinogenesis, which impedes the diffusion of macromolecules across the hepatic sinusoids within cirrhotic livers, and 4) regional heterogeneity of flow and receptor function. After appropriate modifications to the model, the above will be investigated in the following manner: 1) Use a hepatocyte perifusion circuit to model cell uptake with (37 degrees C) and without receptor recycling (4 degrees C). 2) Assay serum for endogenous ligand during TcNGA uptake. 3) Study cirrhotic dogs with labeled ligands of differing molecular weights. 4) Study the current model and an axial distributed model using regional kinetic data obtained from PET imaging of Gallium-68-deferoxamine-NGA. Model candidates will be tested for validity (goodness-of-fit, plausibility, identifiability). Answers to these questions will permit us to develop a model that will be valid for a wide spectrum of pathophysiology. Development of a positron-labeled NGA will allow us to develop and validate a model for the regional measurement of liver blood flow and receptor biochemistry. Based on our past work we know that the TcNGA model is testable, and as a result, offers an opportunity to extensively study the behavior of a radiopharmacokinetic system in healthy and diseased tissue. Thus, this project will advance the technique of functional imaging via physiologic modeling.
