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

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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,