Bis(amido)bis(oxinate)diamine ligands for theranostic radiometals

With the interest in radiometal-containing diagnostic and therapeutic pharmaceuticals burgeoning, appropriate ligands to coordinate completely and stably said radiometals is essential. Reported here are two novel, bis(amido)bis(oxinate)diamine ligands, H2amidohox and H2amidoC3hox, that combine two 8-hydroxyquinoline with two amide donor groups and differ by one carbon in their 1,2-ethylenediaminevs. 1,3-diaminopropane backbones, respectively. Both ligands have been thoroughly studied via metal complexation, solution thermodynamics and radiolabeling with three radiometal ions: [nat/64Cu]Cu2+,
[nat/111In]In3+, and [nat/203Pb]Pb2+. X-ray crystallography determined the structures of the hexacoordinated Cu2+-ligand complexes, indicating a better fit of Cu2+ to the H2amidohox binding pocket. Concentration dependent radiolabeling with [64Cu]Cu2+ was quantitative as low as 1 μM with H2amidohox and 10 μM
with H2amidoC3hox within 5 minutes at room temperature. However, [64Cu][Cu(amidohox)] maintained higher kinetic inertness against a superoxide dismutase enzyme-challenge assay and ligand challengescompared to the [64Cu][Cu(amidoC3hox)] counterpart. Similarly, H2amidohox had significantly higher
radiochemical conversion with both [111In]In3+ (97% at 1 μM) and [203Pb]Pb2+ (97% at 100 μM) under mild conditions compared to H2amidoC3hox (76% with [111In]In3+ at 1 μM and 0% with [203Pb]Pb2+). By studying non-radioactive and radioactive complexation with both ligands, a comprehensive understanding of the coordination differences between two- and three-carbon diamine backbones is discussed. Overall, the ethylenediamine backbone of H2amidohox proves to be superior with rapid radiolabeling and kinetic inertness towards competing ligands and proteins.