Exploring Bioinspired Ln³⁺ Complexes for Cu²⁺ Detection: Design and Efficacy as MRI Contrast Agents

Abstract Imaging extracellular Cu 2+ in vivo is important due to its role in physiological and pathological processes. Magnetic resonance imaging is a promising modality for this purpose but developing contrast agents selective for Cu 2+ over abundant Zn 2+ ions remains a challenge. We synthesized and characterized two novel ligands, DO3A‐picG and DO3A‐picGH, containing a macrocycle and a pendant arm for Cu 2+ complexation inspired from the ATCUN site of human serum albumin. The corresponding Ln 3+ complexes were studied in the presence and in the absence of Cu 2+ through UV‐visible, fluorescence and EPR spectroscopies, as well as relaxivity measurements. These studies show that Gd‐DO3A‐picG and Gd‐DO3A‐picGH are non‐hydrated complexes, in which the pyridine‐amide moiety remains coordinated to Ln 3+ even in the presence of Cu 2+ . While Gd‐DO3A‐picG does not respond to Cu 2+ , a sizeable relaxivity increase is observed for Gd‐DO3A‐picGH. This increase is attributed to an increased second‐sphere contribution to the relaxivity, i. e. a higher number of H 2 O molecules retained in close proximity to Gd 3+ through H‐bonding. Finally, we show that Gd‐DO3A‐picGH binds Cu 2+ with a μM affinity, and is selective for Cu 2+ vs Zn 2+ .