TARGETED METAL CHELATORS FOR DIAGNOSTIC IMAGING

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There is considerable interest in the application in medicine of the metals gallium, indium, gadolinium, and technetium. Radioisotopes of gallium, indium, and technetium are widely used in medical imaging, while gadolinium has been proposed for use as a paramagnetic contrast agent in conjunction with nuclear magnetic resonance imaging. In this proposal it is planned to synthesize new low molecular weight ligands capable of binding gallium, indium, gadolinium, and in some cases, technetium with high stability constants. The structure of the ligands will be designed such that both hydrophilic and lipophilic complexes with the metals will be produced and also so that complexes with positive and negative charges can be formed. The stability constants of the new ligands wit the four metals will be determined and the rate of exchange with plasma proteins measured. In this way both the equilibrium and kinetic stability of the complexes of these ligands will be calclulated. The biodistribution of the labeled compounds will be determined initially in rats and, in some cases, in dogs and primates. Promising ligands will be attached to monoclonal antibodies and the monoclonal antibodies labeled with gallium, indium, or technetium. These labeled antibodies will then be compared in vivo with antibodies labeled using current technology. The gadolinium complexes will be studied in vivo and in vitro for potential use as paramagnetic NMR contrast agents. In this case as macroscopic amounts of the complex will be administered, detailed studies on the stability of these complexes will be carried out.