Research & Teaching Faculty

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

TitleBis(amido)bis(oxinate)diamine Ligands for theranostic radiometals
Publication TypeJournal Article
Year of Publication2022
AuthorsSouthcott, L, Whetter, JN, Wharton, L, Patrick, BO, Zarschler, K, Kubeil, M, Stephan, H, Jaraquemada-Peláez, Mde Guadalu, Orvig, C
JournalJ. Inorg. Biochem.
Pagination111789. Invited for Special Issue in Memory of Ademir Neves
Date Published03/2022
KeywordsCOORDINATION CHEMISTRY, Theranostics, [In]In [Cu]Cu [Pb]Pb solution thermodynamic studies

With the interest in radiometal-containing diagnostic and therapeutic pharmaceuticals increasing rapidly, appropriate ligands to coordinate completely and stably said radiometals is essential. Reported here are two novel, bis(amido)bis(oxinate)diamine ligands, H2amidohox (2,2′-(ethane-1,2-diylbis(((8-hydroxyquinolin-2-yl)methyl)azanediyl))diacetamide) and H2amidoC3hox (2,2′-(propane-1,3-diylbis(((8-hydroxyquinolin-2-yl)methyl)azanediyl))diacetamide), that combine two 8-hydroxyquinoline and amide donor groups and differ by one carbon in their 1,2-ethylenediamine vs. 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 successfully quantitative as low as 1 μM with H2amidohox and 10 μM with H2amidoC3hox within 5 min at room temperature. However, [64Cu][Cu(amidohox)] maintained higher kinetic inertness against a superoxide dismutase enzyme-challenge assay and ligand challenges compared 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 in rapid, mild radiolabeling and kinetic inertness towards competing ligands and proteins.

Refereed DesignationRefereed