AMPHIPATHIC ORAL CHELATORS AND RADIONUCLIDE CONTAMINATION

本申请是对RFA-A1-06-030《辐射/核用放射性核素脱色剂》的回应 紧急情况：BioShield项目（R 01）。我们建议进一步开发一系列的两亲性，口服 施用的聚氨基羧酸（PACA）螯合剂。这些是基于三亚乙基四胺六乙酸 酸（TT），与二亚乙基三胺五乙酸（DTPA）有关。口服给药 两亲性TT螯合剂对于消除镅的系统性沉积非常有效， 钚）和一些过渡金属。它们还具有广泛的化学结合亲和性，可用于一系列 潜在的有毒金属我们提出了三项研究。1)进行药代动力学（PK）研究，以确定 TT螯合剂的吸收、分布、代谢和排泄作为其两亲性的函数， 特性.将合成C-14标记的化合物，并使用已建立的PK方法进行检测。这些 将有助于优化螯合剂设计和剂量范围分布。2)对象的绑定稳定性 范围的金属，并确定两亲性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各种金属的螯合剂设计，用于体内 问题研究3)确定口服TT螯合剂促进体内 加入金属。将使用与研究2中使用的相同的金属（U、Co、Sr、Ce），并且这些代表 不同的化学类别（例如锕系元素、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部件。注射的有效剂量 DTPA将用作比较对照。进一步的发展可能包括特定的放射性核素功效 可能包括通过不同途径（如吸入、伤口）接触。符合法规 应进行毒性和安全性研究。因为PACA的药理学和毒理学 螯合剂，如DTPA和EDTA，是相当好理解的，相关TT- 基螯合剂可以快速进行。

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.