European Journal of Inorganic Chemistry

Abstract

Imaging extracellular Cu²⁺ 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 Cu²⁺ over abundant Zn²⁺ ions remains a challenge. We synthesized and characterized two novel ligands, DO3A-picG and DO3A-picGH, containing a macrocycle and a pendant arm for Cu²⁺ complexation inspired from the ATCUN site of human serum albumin. The corresponding Ln³⁺ complexes were studied in the presence and in the absence of Cu²⁺ 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 Ln³⁺ even in the presence of Cu²⁺. While Gd-DO3A-picG does not respond to Cu²⁺, 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 H₂O molecules retained in close proximity to Gd³⁺ through H-bonding. Finally, we show that Gd-DO3A-picGH binds Cu²⁺ with a μM affinity, and is selective for Cu²⁺ vs Zn²⁺.

Graphical Abstract

Gd³⁺ complexes bearing a bioinspired Cu²⁺-binding site derived from ATCUN are studied as MRI contrast agents. The presence of two amino acids (GH) is necessary to bind Cu²⁺ and trigger a relaxivity increase. This is due to a higher number of H₂O retained close to Gd³⁺ through H-bonding with Cu²⁺. Remarkably, the system remains selective for Cu²⁺ vs Zn²⁺.