A hybrid pyridine-thioether macrocycle to chelate theranostic copper and silver radioisotopes

Coinage radiometals such as Cu-64/67 and Ag-103/111 offer unique opportunities for cancer theranostics, providing matched diagnostic and therapeutic radionuclides within the same chemical family. However, their clinical translation is limited by the lack of robust chelators for Ag-103/111 and by the redox-induced instability of Cu-64/67 complexes. To address these chelation challenges, we developed DO2S2Py, a sulfur-containing cyclen (cy)-based macrocycle incorporating pyridine (py) donors, introduced to create a protected coordination environment for silver and copper ions. DO2S2Py rapidly forms highly thermodynamically stable and kinetically inert 1 : 1 metal-to-ligand complexes with both Cu2+ and Ag+. Structural investigations reveal distinct yet strongly stabilized coordination environments for Cu2+ (4N(cy)2N(py)) and Ag+ (4N(cy)1N(py)1S and 4N(cy)2N(py)), underscoring the crucial contribution of the pyridine donors. Under highly diluted radiochemical conditions and mild labeling protocols, DO2S2Py efficiently binds Cu-64 and Ag-111. The Cu-64 complex demonstrates exceptional stability in PBS and human serum (>95% intact complex after 24 h), while the Ag-111 analogue, though somewhat less stable (75% intact after 24 h), outperforms the current gold-standard chelator. These findings validate the incorporation of pyridine donors as an effective strategy toward unified chelation of theranostic coinage radiometals.