TARGETED METAL CHELATORS FOR DIAGNOSTIC IMAGING

用于诊断成像的靶向金属螯合剂

• 批准号: 2091013
• 负责人: MICHAEL J. WELCH
• 金额: $ 32.44万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1986
• 资助国家: 美国
• 起止时间: 1986-07-01 至 1997-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2091013
• 关键词: Primates; chelating agents; chemical binding; chemical structure function; chemical synthesis; contrast media; drug design /synthesis /production; gadolinium; gallium; hamsters; heavy metals; indium; laboratory rat; ligands; monoclonal antibody; nuclear magnetic resonance spectroscopy; nuclear medicine; radionuclide imaging /scanning; radionuclides; radiopharmacology; thermodynamics

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.

其在医学上的应用和发展引起了极大的兴趣 金属镓、铟和镓。镓和镓的放射性同位素 铟被广泛用于医学成像，而格拉则一直被 作为顺磁造影剂与核素结合使用 磁共振成像。在这份提案中，它计划设计， 合成和研究用于络合的新型络合剂 这些金属离子。将设计用于镓和铟的络合剂 通过与给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很高的选择性，并通过加入这些 分组成大环环。络合物的位置方向将是 通过调节它们的脂类溶解度和膜通透性来实现 具有烷基和其他取代基。螯合基团将是 具有多种类型的链接以实现站点功能 通过与抗体的共价结合而产生的特异性。磁共振 将开发具有Fe(III)和Gd(III)配体的造影剂 虽然它的设计具有最大的稳定性，但它将允许协调 通过省略一个或多个配体给体基团而得到的内球水 用于这些金属离子的标准配体。分子的稳定常数 这些新的配体将被确定，并与血浆的交换率 测得的蛋白质。这样，平衡态和动态态的稳定性 这些配体的络合物的含量将被确定。生物分布 标记化合物的含量将在大鼠、仓鼠和某些情况下进行测定 灵长类动物。有希望的配体将被连接到单抗上，并 在体外和体内模型中都进行了评估。Gd络合物 将在体外和体内研究作为顺磁核磁共振的潜在用途 造影剂。 将进行合成、表征和物理化学研究。 在德克萨斯农工大学用非放射性同位素进行体外实验 并将对药物制剂进行体内评价 在华盛顿大学。