Abstract
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 CuII-responsive MRI contrast agents (CAs) which are able to extract CuII from human serum albumin (HSA) and subsequently form ternary adducts. The CAs combine a GdIII-DO3A-monoamide complex linked to α-pyridyl thiosemicarbazone (pyrTSC) ligands, introduced here as innovative CuII binding units. The TSC units display strong CuII affinity and form ternary TSC–CuII–HSA adducts at a site distinct from the canonical ATCUN motif. Using UV-visible and EPR spectroscopies, we show that the CuII 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 (τR), leading to measurable increases in relaxivity for the various complexes. This work introduces a new strategy in which CuII-triggered protein binding is exploited to activate responsive MRI CAs, thereby broadening their chemical space.
Graphical Abstract
A τR-based CuII-responsive MRI contrast agent containing a thiosemicarbazone unit as a CuII-selective chelator has been designed, synthesized and evaluated. This work demonstrates that the agent can efficiently withdraw CuII from its native binding site in HSA and form CuII-bridged ternary complexes. This strategy allows a marked increase in relaxivity and provides a new strategy for CuII-responsive agents based on metal redistribution within biological macromolecules.
