Electrochemical evaluation of Cu(II)/Cu(I) redox behavior and coordination stability in copper radiopharmaceuticals: recent progress

Abstract Copper radionuclides connect coordination chemistry with diagnostic and therapeutic nuclear medicine. The 12.7 h half-life of 64 Cu and the therapeutic emissions of 67 Cu make radiocopper attractive for peptides, antibodies, prostate-specific membrane antigen (PSMA) ligands, bombesin analogues, hypoxia tracers, and theranostic pairs, although limited 67 Cu access and the low positron-emission probability of 64 Cu constrain translation. The same chemistry creates a stability problem because Cu(II) and Cu(I) prefer different donor environments and geometries. Reduction, proton-assisted decomplexation, and transchelation can therefore alter biodistribution even when release radiochemical purity is high. This review summarizes recent progress in electrochemical evaluation of Cu(II)/Cu(I) redox behavior and coordination stability in copper radiopharmaceuticals, with emphasis on quantitative redox, acid stability, serum stability, radiolabeling, and translational performance data. Non-radioactive copper complexes are discussed as mechanistic models when they clarify redox and coordination behavior relevant to 64 Cu and 67 Cu. The evidence indicates that reduction potential alone is not a reliable stability ranking. Predictive evaluation requires the combination of voltammetric reversibility, ligand geometry, kinetic inertness, biological challenge assays, and vector-specific pharmacokinetics.