Desferrithiocin Analogue Actinide Decorporation Agents

建议项目的具体目标是加快去铁硫蛋白的整体发展- 用于放射性核素脱孔的基络合剂。过去的系统结构-活性研究已经 允许设计和合成类似物和衍生物，保留了特殊的铁螯合作用 去铁硫蛋白(DFT)的活性，同时消除其不良影响。这项研究背后的假设 方案是可以采用类似的方法来利用DFT平台来设计 会有效地去除放线元素的孔洞。根据过去的经验，铁的广泛研究结果 啮齿动物和灵长类动物的螯合作用，以及对现有科学文献的广泛审查，一种配体 选择了包括一些已被证明用于脱孔铀的络合剂的碱组来代表铀。 重新推荐目前U(VI)，Th(IV)[Pu(IV)的代替者]的最佳可用候选人 和EU(11)[Am(11)的代理人]。对啮齿动物的系统调查(包括剂量反应、药物和 COLOGIC、毒理学和组织病理学研究)将确定配体基组中的DFT手性因子 对U(VI)、Th(IV)和Eu(111)的修饰效果最好，毒性最小。一种创新的新方法-- 用核磁共振研究一种选择性的螯合剂对Eu(111)在啮齿动物体内的分布和消除的作用 还将接受检查。最终，最有希望的候选螯合剂将在灵长类动物身上进行评估 模型，以提供对人类有效的最佳可用证据。 因此，拟议的研究将确定领先的DFT螯合剂(S)，以进入进一步的产品开发- 开发并提供关键数据，用于设计前瞻性评估动物和 人类的安全。

The specific goal of the proposed project is to accelerate the overall development of desferrithiocin- based chelating agents for decorporation of radionuclides. Past systematic structure-activity studies have allowed the design and synthesis of analoguesand derivatives which retain the exceptional iron-chelating activity of desferrithiocin (DFT) while eliminating its adverse effects. The hypothesis underlying the research program is that a similar approach can be adopted to utilize the DFT platform for the design of ligands that will effectively decorporate actinides. On the basis of past experience, the results of extensive studies of iron chelation in rodents and primates, and a wide-ranging review of the available scientific literature, a ligand basis set which includes a number of chelators already shown to decorporate uranium was selected to rep- resent the best available candidates at presentfor the decorporationof U(VI), Th(IV) [a surrogate for Pu(IV)] and Eu(lll) [a surrogate for Am(lll)]. Systematic investigations in rodents (including dose-response, pharma- cologic, toxicologic and histopathologic studies) will identify the DFT chela'tors in the ligand basis set that are most effective and least toxic for decorporationof U(VI), Th(IV) and Eu(lll). An innovative new approach us- ing MRI to characterize the action of a selected chelator on distribution and elimination of Eu(lll) in rodents will also be examined. Ultimately, the most promising candidate chelators will be evaluated in a primate model to provide the best available evidence for efficacy in humans. Accordingly, the proposed research will identify the lead DFT chelator(s) to enter further product devel- opment and provide critical data for the design of studies to prospectively assess efficacy in animals and safety in humans.