AMPHIPATHIC ORAL CHELATORS AND RADIONUCLIDE CONTAMINATION

本申请是对RFA-A1-06-030《用于辐射/核的放射性核素去腐剂》的响应 紧急情况：生物盾牌项目(R01)。我们建议进一步开发一系列两亲性、口服型 给药，多氨基羧酸(PACA)螯合剂。它们是基于三亚乙四胺六乙酸乙酯 酸(TT)，与二乙烯三胺-五乙酸(DTPA)有关。口服给药 两亲性TT螯合剂对消除全身Am和Am沉积非常有效 钚)和一些过渡金属。它们还对一系列化合物具有广泛的化学结合亲和力 潜在的有毒金属。我们提出了3项研究。1)进行药代动力学(PK)研究以确定 TT螯合剂的吸收、分布、代谢和排泄与其两亲性的关系 属性。将合成C-14标记化合物，并使用已建立的PK方法进行测试。这些 数据。将有助于优化螯合剂设计和剂量范围分布。2)确定一种类型的 并测定两亲性TT螯合剂在体外提取这些金属的能力。。。 肝脏和红细胞分析将确定金属的结合和提取，包括铀、钴、 锶和铈。这些数据将有助于优化体内各种金属的螯合剂设计。 学习。3)测定口服TT螯合剂促进体内排泄的能力。 联合金属公司。将使用研究2中使用的相同金属(U、Co、Sr、Ce)，这些金属代表 不同类别的化学物质(例如，鳗系元素、过渡金属、碱土金属和镧系元素)及其 放射性同位素是放射性弥散装置的潜在组件。注射有效剂量 DTPA将用作比较对照。进一步的研究可能包括特定的放射性核素功效。 Jtudy，也许包括通过不同途径接触(例如吸入、伤口)。合规 应进行毒性和安全性研究。因为PACA的药理和毒理学 目前对DTPA和EDTA等螯合剂的研究很多，相关的TT-2的发展途径。 基络合剂的进展可能很快。

This application is in response to RFA-A1-06-030, Radionuclide Decoproration Agents for Radiation/Nuclear Emergencies: Project BioShield (R01). We propose to further develop a series of amphipathic, orally administered, polyaminocarboxylic (PACA) chelators. These are based on triethylenetetraminehexaacetic acid (TT) and are related to diethylenetriamine-pentaacetic acid (DTPA). The orally administered amphipathic TT chelators are very effective for the elimination of systemic deposits of americium and plutonium)and some transition metals. They also have broad chemical binding affinities for a range of potentially toxic metals. We propose 3 studies. 1) To perform pharmacokinetic (PK) studies to determine the absorption, distribution, metabolism and excretion of the TT chelators as a function of their amphipathic properties. C-14 labeled compounds will be synthesized and tested using established PK methods. These data.will help optimize chelator design and dose range profiles. 2) To determine the binding stabilities for a range of metals and determine the ability of the amphipathic TT chelators to extract these metals in vitro. .. Liver and erythrocyte assays will determine the binding and extraction of metals to include uranium, cobalt, strontium and cerium. These data will help optimize chelator design for various metals for the in vivo studies. 3) To determine the ability of the orally administered TT chelators, to promote excretion of internally incorporated metals. The same metals as used in study 2 will be used (U, Co, Sr, Ce) and these represent different chemical classes (e.g. actinide, transition metal, alkaline earth metal and lanthanide) and their radioactive isotopes are potential components of a radiological dispersion device. Effective doses of injected DTPA will be used as a comparison control. Further development may include specific radionuclide efficacy Jtudies, perhaps to include exposures by different routes (e.g. inhalation, wounds). Regulatory compliant toxicity and safety studies should to be conducted. Because the pharmacology and toxicology of PACA chelators, such as DTPA and EDTA, are quite well understood, the development pathway of the related TT- based chelators may proceed rapidly.