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

该项目的目标是合成不仅对铅(II)和铋(III)都具有高亲和力，而且在动力学和热力学上都是惰性的螯合剂。这主要是通过硫给体原子的存在来实现的，尽管可以设想使用其他杂原子给体基团。然后，这些配体的化学也必须服从于引入适合于将配体与蛋白质或多肽结合的反应官能团。二硫代丁二酸(DMSA)等简单的硫酸盐配体形成了高稳定性的络合物(1：2的铋[DMSA]络合物的K^f>为log43.87)，但目前还没有合适的多齿螯合剂用于连接单抗。因此，系统地探索将多个硫醇给体基团结合到现有的和新型的大环络合剂中的化学方法。正在使用适当的前体分子来测试和发展引入这种给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多氮杂羧酸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。最初的一系列这些配体现在正在进行中，这些配体的铅(II)配合物的制备和表征是一项持续的努力。存在这样一种可能性，即铅(II)络合物稳定性的显著增强，再加上硫醇在铅-212的β衰变事件(T^1/2=10.6h)期间调节短暂的高能态的能力，将导致这种放射性核素作为体内发生器用于传递治疗性剂量的α发射体Bi-212。因此，随着每一种新的络合剂被合成，其相应的单独的铅(II)和铋(III)络合物被发现是动力学惰性的，通过衰变事件来评估稳定性继续被研究。此外，这种基本设计的配体具有足够的配位位置和给体性质，可以作为潜在的螯合剂在-211处用于α粒子发射体。虽然传统上认为由于它在元素周期表中的位置而具有卤素化学的特征，但大量的文献报告清楚地表明这种元素具有相当大的金属行为。因此，随着新的铅(II)配体的开发，这些配体继续被建议作为AT-211的螯合剂进行评估。-金属络合物、单抗、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,