Interaction of Gd-DTPA with phosphate and phosphite: toward the reaction intermediate in nephrogenic systemic fibrosis

Abstract

Direct reactions of the MRI contrast agent K₂[Gd(DTPA)(H₂O)]·5H₂O (1) (H₅DTPA = diethylenetriaminepentaacetic acid) with dipotassium hydrogen phosphate (K₂HPO₄) or phosphite (K₂HPO₃) result in the isolation of well-defined Gd-DTPA phosphite K₆[Gd₂(DTPA)₂(HPO₃)]·7H₂O (2) or phosphate K₆[Gd₂(DTPA)₂(HPO₄)]·10H₂O (3), respectively. Their lanthanum analogs K₄[La₂(DTPA)₂(H₂O)]·8H₂O (4), K₆[La₂(DTPA)₂(HPO₃)]·7H₂O (5) and K₆[La₂(DTPA)₂(HPO₄)]·10H₂O (6) are used for comparison. The phosphate and phosphite groups are able to substitute the coordinated water molecules in 1 and 4 in a close physiological aqueous solution, and act as bridging ligands to link adjacent Ln(DTPA)²⁻ (Ln = Gd and La) into dimeric structures. Solid state and solution ¹³C NMR spectra of dimer 4 show complete dissociation into its monomeric species in solution, while no dissociation is observed for lanthanum phosphite 5 and phosphate 6 in solution, which show only one set of ¹³C spectra with the largest downfield shifts at 182.0 and 182.3 ppm respectively. Comparisons of the bond distances and spectral data indicate that the interaction between DTPA and central Ln³⁺ cations are weakened after the substitutions, which support phosphate substituted Gd-DTPA as an initial intermediate in nephrogenic systemic fibrosis.