Lanthanide complexes bearing a bioinspired Cu ^II binding site with picomolar affinity: synthesis, structural, relaxometric and luminescence studies

In the pursuit of Cu^II-responsive MRI contrast agents with enhanced Cu^II affinity, we report the synthesis and characterization of two Ln^III-DO3A-C3AmpicGH complexes (Ln^III = Gd^III, Eu^III), featuring a tetradentate Cu^II-binding moiety, along with the corresponding mononuclear Cu^II-C3AmpicGH complex. The chelator coordinates Cu^II through two amide groups, a pyridine and an imidazole ring. The use of a propyl-amide linker between the Ln^III- and Cu^II-binding moieties allowed an increased separation between the two metal centers. As a result, both Ln^III-Cu^II-DO3A-C3AmpicGH and Cu^II-C3AmpicGH complexes exhibit the same Cu^II-affinity (log <i>K</i> = 11-12 at pH 7.4) and good selectivity over competing physiological metal ions, particularly Zn^II (up to at least 500 equivalents). While the Gd^III complex displayed no relaxivity changes upon Cu^II binding, the Eu^III analogue showed a luminescence turn-off response. Spectroscopic analyses as well as density functional theory (DFT) calculations provide insights into the coordination environments of both metal ions, notably confirming the absence of amide coordination to the Ln^III center, even in absence of Cu^II.