The novel metal ion chemistry described in this proposal is designed to provide new types of bifunctional chelation reagents for the conjugation of beta--emitting radiometals (90Y, 186Re, 105Rh, 67Cu, 59Fe and others) with monoclonal antibodies (MAbs). Three distinctly different types of metal-binding processes and reagents are to be employed. (1) A new and synthetically simplified modification of the well known bifunctional polyaminocarboxylate reagents suitable for 90Y+3 and 67Cu+2 conjugation with MAbs. (2) Bifunctional metal cluster species (radiometallacarboranes) of demonstrated utility (Venus Flytrap Clusters) specifically designed for the available radioisotopes of transition metals (59Fe, 186Re, 67Cu and others). (3) An entirely new class of bifunctional and general metal chelators (oxochelates) specifically designed for oxophilic metals of all types which are based upon the preorganized presentation of an octahedral array of nucleophilic and pi- donating oxygen atoms to the sequestered radiometal ion (90Y+3, 186Re+3, 67Cu+2, 105Rh+3 and others). All metal-binding substructures of the bifunctional reagents which comprise the three types described above are constructed from inorganic components. This design feature should eliminate or seriously impede catabolic decomposition of the radiometal chelates thereby allowing their excretion prior to in vivo redistribution of the radiometal.
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