AMPHIPATHIC ORAL CHELATORS AND RADIONUCLIDE CONTAMINATION

描述（由申请人提供）：本申请是响应RFA-A1-06-030，辐射/核紧急情况的放射性核素修饰剂：生物盾项目（ROl）。我们建议进一步开发一系列两亲性口服多氨基羧酸螯合剂。这些都是基于三乙烯四胺六乙酸（TT），并与二乙烯三胺五乙酸（DTPA）有关。口服两亲性TT螯合剂对消除全身沉积的镅、钚和一些过渡金属非常有效。它们还对一系列潜在有毒金属具有广泛的化学结合亲和力。我们提出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、代谢和排泄作为其两亲性的功能。C-14标记的化合物将使用既定的PK方法合成和测试。这些数据将有助于优化螯合剂的设计和剂量范围。2)确定对一系列金属的结合稳定性，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。这些数据将有助于在体内研究中优化各种金属螯合剂的设计。3)测定口服TT螯合剂促进内源性金属排泄的能力。将使用与研究2中使用的相同的金属（U, Co, Sr, Ce），这些金属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），它们的放射性同位素是放射性分散装置的潜在组成部分。注射DTPA的有效剂量将作为对照。进一步的发展可能包括具体的放射性核素功效研究，也许包括不同途径的暴露（例如吸入、伤口）。应进行符合法规的毒性和安全性研究。由于对DTPA和EDTA等PACA螯合剂的药理学和毒理学的了解比较充分，相关tt基螯合剂的开发途径可能会迅速进行。

DESCRIPTION (provided by applicant): This application is in response to RFA-A1-06-030, Radionuclide Decorporation Agents for Radiation/Nuclear Emergencies: Project BioShield (ROl). 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 plutoniurn) 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 studies, 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.