Gadolinium(III) complex formation with a β-cyclodextrin ligand: an XAS study of a potential MRI contrast agent

In the search for improved and safer gadolinium-based magnetic resonance imaging (MRI) contrast agents, macrocyclic cyclodextrins (CDs) attract great interest. Our group previously synthesized a cyclodextrin-based ligand with 1,2,3-triazolmethyl residues conjugated to β-CD, called β-CD(A), which efficiently chelates Gd(III) ions. To probe the local structure around the Gd(III) ion in the 1:1 Gd(III): β-CD(A) complex in aqueous solution (pH 5.5), we used extended X-ray absorption fine structure (EXAFS) spectroscopy. Least-squares curve fitting of the Gd L₃-edge EXAFS spectrum revealed 5 Gd-O (4 COO^- and 1 H₂O) and 4 Gd-N (from two imino and two 1,2,3-triazole groups) bonds around the Gd(III) ion with average distances 2.36 and 2.56 ± 0.02 Å, respectively. A similar EXAFS spectrum was obtained from an aqueous solution of the clinically used MRI contrast agent Na[Gd(DOTA)(H₂O)], also 9-coordinated in its first shell. Careful analysis revealed that the mean Gd-N distance is shorter in the Gd(III): β-CD(A) (1:1) complex, indicating stronger Gd-N bonding and stronger Gd(III) complex formation than with the DOTA^4- ligand. This is consistent with the lower free Gd³⁺ concentration found previously for the Gd(III): β-CD(A) (1:1) complex than for the [Gd(DOTA)(H₂O)]^- complex, and shows its potential as an MRI probe. EXAFS spectroscopy revealed a similar Gd(III) 9-coordination although slightly stronger for a modified β-cyclodextrin: Gd(III) 1:1 complex, [Gd(LH₄)]^7-, in aqueous solution than for the clinically used MRI contrast agent Na[Gd(DOTA)(H₂O)].