THIOL CONTAINING LIGANDS FOR PB(II) AND BI(III)

PB(II) 和 BI(III) 的含硫醇配体

• 批准号: 6290751
• 负责人: MARTIN W BRECHBIEL
• 金额: --
• 依托单位: DIVISION OF CLINICAL SCIENCES - NCI
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/6290751
• 关键词: bismuth; chelating agents; chemical synthesis; lead; ligands; metal complex; sulfur; thiols

The goal of the project is to synthesize chelating agents which not only have high affinities for both Pb(II) and Bi(III), but also are both kinetically and thermodynamically inert. This is to be accomplished principally by virtue of the presence of sulfur donor atoms, although use of other heteroatom donor groups is envisioned. The chemistry of these ligands then must also be amenable to introduction of a reactive functionality suitable for conjugating the ligand to proteins or peptides. Simple thiolate ligands such as dimercaptosuccinic acid (DMSA) form complexes of high stability (K<SUB>f</SUB> for the 1:2 Bi[DMSA] complex is log 43.87), yet appropriate multidentate chelating agents suitable for linkage to monoclonal antibodies are not yet available. As such, systematic exploration of the chemistry to incorporate multiple thiol donor groups into both existing and novel macrocyclic chelating agents proceeds. Appropriate precursor molecules readily available for testing and developing the general chemistry necessary for the introduction of such donor atom character are being employed. Of particular interest are target macrocyclic ligands that incorporate poly(2-mercaptoethylene) elements into the structure analogous to macrocyclic polyazacarboxylate ligands, such as 1,4,7,10-tetraazacyclododecane tetraacetic acid (DOTA) and homologs thereof. An initial series of these ligands is now in hand, and preparation and characterization of the Pb(II) complexes of these ligands is an ongoing effort. The possibility exists that significant enhancement of the Pb(II) complex stability coupled with the ability of the thiols to moderate a transitory high energy state during the beta decay event of Pb-212 (T<SUB>1/2</SUB>=10.6h) would lead to the clinical use of this radionuclide as an in vivo generator for delivery of therapeutic doses of the alpha-emitter Bi-212. Thus, as each new chelating agent is synthesized and its corresponding individual Pb(II) and Bi(III) complexes are found to be kinetically inert, evaluation of stability through the decay event continues to be studied. Additionally, ligands of this fundamental design possess adequate coordination sites and donor character to be evaluated as potential chelating agents for the alpha-particle emitter At-211. While traditionally assumed to possess characteristics of halogen chemistry due to its location in the periodic table, substantial literature reports clearly indicate considerable metallic behavior to this element. Therefore, as new ligands are developed for Pb(II), these ligands continue to be proposed for evaluation as chelating agents for At-211. - metal chelates, monoclonal antibodies, radiation, radioimmunotherapy,

该项目的目标是合成不仅对 Pb(II) 和 Bi(III) 具有高亲和力，而且在动力学和热力学上均呈惰性的螯合剂。这主要通过硫供体原子的存在来实现，尽管设想使用其他杂原子供体基团。这些配体的化学性质还必须适合于引入适合于将配体与蛋白质或肽缀合的反应性官能团。简单的硫醇配体如二巯基丁二酸 (DMSA) 形成高稳定性复合物（1:2 Bi[DMSA] 复合物的 K<SUB>f</SUB> 为 log 43.87），但适合连接单克隆抗体的适当多齿螯合剂目前还没有抗体。因此，将多个硫醇供体基团纳入现有和新型大环螯合剂的化学系统探索正在进行。正在使用易于用于测试和开发引入这种供体原子特征所需的一般化学的适当前体分子。特别感兴趣的是目标大环配体，其将聚(2-巯基乙烯)元素并入类似于大环多氮杂羧酸酯配体的结构中，例如1,4,7,10-四氮杂环十二烷四乙酸(DOTA)及其同系物。这些配体的初始系列现已在手，并且这些配体的 Pb(II) 配合物的制备和表征正在进行中。存在这样的可能性：Pb(II)络合物的稳定性显着增强，并且硫醇能够在 Pb-212 的 β 衰变事件期间调节短暂的高能态 (T<SUB>1/2</SUB>= 10.6h）将导致这种放射性核素作为体内发生器用于递送治疗剂量的α发射体Bi-212的临床应用。因此，随着每种新螯合剂的合成，并且发现其相应的单独 Pb(II) 和 Bi(III) 配合物具有动力学惰性，因此通过衰变事件评估稳定性的研究仍在继续。此外，这种基本设计的配体具有足够的配位位点和供体特征，可作为 α 粒子发射体 At-211 的潜在螯合剂进行评估。虽然传统上认为由于其在元素周期表中的位置而具有卤素化学特性，但大量文献报告清楚地表明该元素具有相当大的金属行为。因此，随着新的 Pb(II) 配体的开发，这些配体继续被提议作为 At-211 的螯合剂进行评估。 - 金属螯合物、单克隆抗体、放射线、放射免疫疗法、