Thiosemicarbazone‐Based Responsive MRI Contrast Agents Activated Through a Change in Cu II Binding Site on Albumin

The development of copper‐responsive magnetic resonance imaging (MRI) probes remains limited by the scarcity of robust strategies capable of operating under physiological conditions and within complex biological environments. Here we report Cu II ‐responsive MRI contrast agents (CAs) which are able to extract Cu II from human serum albumin (HSA) and subsequently form ternary adducts. The CAs combine a Gd III ‐DO3A‐monoamide complex linked to α‐pyridyl thiosemicarbazone (pyrTSC) ligands, introduced here as innovative Cu II binding units. The TSC units display strong Cu II affinity and form ternary TSC–Cu II– HSA adducts at a site distinct from the canonical ATCUN motif. Using UV‐visible and EPR spectroscopies, we show that the Cu II extraction and ternary adduct formation remain possible even in the presence of the Gd‐binding moiety. The formation of ternary complexes enhances the rotational correlation time ( τ R ), leading to measurable increases in relaxivity for the various complexes. This work introduces a new strategy in which Cu II ‐triggered protein binding is exploited to activate responsive MRI CAs, thereby broadening their chemical space.