TARGETED METAL CHELATORS FOR DIAGNOSTIC IMAGING

有相当大的兴趣和在医学上的应用， 金属镓、铟和钆。 镓的放射性同位素， 铟广泛用于医学成像，而钆 作为顺磁性造影剂与核造影剂联合使用， 磁共振成像 在本提案中，计划设计， 合成和研究新的，改进的螯合剂，用于络合 这些金属离子。 设计镓和铟的螯合剂 通过与供体基团的配体一起使用具有最大的热力学稳定性 对这些三价金属离子具有高度选择性，并且通过将这些 基团形成大环。 螯合物的位点方向为 通过调节它们的脂溶性和膜渗透性来实现 具有烷基和其它取代基。 螯合基团将是 用几种类型的键官能化，以实现位点 通过共价连接到抗体的特异性。 磁共振 将用Fe（III）和Gd（III）的配体开发造影剂 虽然设计的最大稳定性将允许协调 内球水通过省略一个或多个配体供体基团， 用于这些金属离子的标准配体。 的稳定常数 这些新的配体将被测定， 蛋白质测量 这样，平衡和动力学稳定性 将确定这些配体的络合物。 的生物分布 将在大鼠、仓鼠中测定标记化合物的含量， 灵长类动物 有前途的配体将连接到单克隆抗体上， 在体外和体内模型中评估。 钆配合物 将在体外和体内进行研究，作为顺磁NMR的潜在用途 造影剂。 本论文将进行合成、表征和物理化学研究 在德克萨斯A&M大学用非放射性同位素在体外 并进行药物制剂的体内评价 在华盛顿大学。

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.