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

该项目的目标是合成螯合剂，不仅对Pb（II）和Bi（III）具有高亲和力，而且在动力学和化学上都是惰性的。这主要通过硫供体原子的存在来实现，尽管设想使用其它杂原子供体基团。然后，这些配体的化学性质还必须适合于引入适合于将配体缀合至蛋白质或肽的反应性官能团。简单的硫醇盐配体如二巯基琥珀酸（DMSA）形成高稳定性的络合物（1：2 Bi[DMSA]络合物的K<SUB>f</SUB>为log 43.87），但适合于连接到单克隆抗体的适当的多齿螯合剂还不可用。因此，系统地探索将多个硫醇供体基团并入现有和新型大环螯合剂中的化学过程。目前正在使用易于获得的适当前体分子，用于测试和开发引入这种供体原子特性所需的一般化学。特别感兴趣的是将聚（2-巯基乙烯）元素结合到类似于大环聚氮杂羧酸酯配体的结构中的目标大环配体，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在在手，这些配体的Pb（II）配合物的制备和表征是一个持续的努力。Pb（II）络合物稳定性的显著增强与硫醇在Pb-212的β衰变事件（<SUB>T1/2</SUB>=10.6h）期间缓和瞬时高能量状态的能力相结合的可能性存在，这将导致该放射性核素作为用于递送治疗剂量的α-发射体Bi-212的体内发生器的临床用途。因此，由于合成了每种新的螯合剂，并且发现其相应的单独的Pb（II）和Bi（III）络合物是动力学惰性的，因此继续研究通过衰变事件的稳定性评价。此外，这种基本设计的配体具有足够的配位位点和供体特性，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Pb（II）的新配体的开发，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，放射免疫疗法，

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,