TARGETED METAL CHELATORS FOR DIAGNOSTIC IMAGING

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There is considerable interest and the application in medicine of the metals gallium, indium, and gadolinium. Radioisotopes of gallium and indium are widely used in medical imaging while gadolinium has been utilized as a paramagnetic contrast agent in conjunction with nuclear magnetic resonance imaging. In this proposal it is planned to design, synthesize and study new, improved chelating agents for the complexation of these metal ions. Chelating agents for gallium and indium will be designed with maximum thermodynamic stability by use with ligands of donor groups highly selective for these trivalent metal ions, and by incorporating these groups into macrocyclic rings. Site direction of the chelates will be achieved by moderating their lipid solubility and membrane permeability with alkyl groups and other substituents. The chelating groups will be functionalized with several types of linkages for achieving site specificity by covalent attachment to antibodies. Magnetic resonance contrast agents will be developed with ligands for Fe(III) and Gd(III) which, while designed for maximum stability will allow coordination of inner sphere water by the omission of one or more ligand donor groups from the standard ligands used for these metal ions. The stability constants of these new ligands 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 determined. The biodistribution of labeled compounds will be determined in rats, hamsters and in some case primates. Promising ligands will be attached to monoclonal antibodies and evaluated in both in vitro and in vivo models. The gadolinium complexes will be studied in vitro and in vivo for potential uses as paramagnetic NMR contrast agents. The synthesis, characterization and physicochemical studies will be carried out at Texas A&M University with non-radioactive isotopes while in vitro and in vivo evaluation of the pharmaceutical preparations will be carried out at Washington University.