Importance of outer-sphere and aggregation phenomena in the relaxation properties of phosphonated gadolinium complexes with potential applications as MRI contrast agents

A series composed of a tetra-, a tris- and a bisphosphonated ligand based on a pyridine scaffold (L⁴, L³ and L², respectively) was studied within the frame of lanthanide (Ln) coordination. The stability constants of the complexes formed with lanthanide cations (Ln=La, Nd, Eu, Gd, Tb, Er and Lu) were determined by potentiometry in aqueous solutions (25.0 °C, 0.1 M NaClO₄), showing that the tetraphosphonated complexes are among the most stable Ln^III complexes reported in the literature. The complexation of L⁴ was further studied by different titration experiments using mass spectrometry and various spectroscopic techniques including UV/Vis absorption, and steady state and time-resolved luminescence (Ln=Eu and Tb). Titration experiments confirmed the formation of highly stable [LnL⁴] complexes. ³¹P NMR experiments of the LuL⁴ complex revealed an intramolecular interconversion process which was studied at different temperatures and was rationalized by DFT modelling. The relaxivity properties of the Gd^III complexes were studied by recording their ¹H NMRD profiles at various temperatures, by temperature dependent ¹⁷O NMR experiments (GdL⁴) and by pH dependent relaxivity measurements at 0.47 T (GdL³ and GdL²). In addition to the high relaxivity values observed for all complexes, the results showed an important second-sphere contribution to relaxivity and pH dependent variations associated with the formation of aggregates for GdL² and GdL³. Finally, intravenous injection of GdL⁴ to a mouse was followed by dynamic MRI imaging at 1.5 T, which showed that the complex can be immediately found in the blood stream and rapidly eliminated through the liver and in large part through the kidneys.