Lanthanide(III) Complexes of Phosphorus Acid Analogues of H₄DOTA as Model Compounds for the Evaluation of the Second-Sphere Hydration

Graphical Abstract

The set of DOTA-like complexes lacking a directly coordinated water molecule is studied to explore the relationship between the second hydration sphere and MRI-relevant parameters, and the influence of the ligand pendant arms (size, hydrophilicity) on the complex properties is discussed.

Abstract

Five DOTA-like ligands lacking a water molecule in the first coordination sphere of their Gd^III complexes, namely the phosphinates H₄DOTP^H, H₄DOTP^hm and H₄DOTP^Et, and the phosphonate monoesters H₄DOTP^OEt and H₄DOTP^OBu, were synthesized with the aim of exploring the influence of the second hydration sphere on the relaxivity of Gd^III complexes. The H₄DOTP^H, H₄DOTP^hm and H₄DOTP^OEt ligands and their Ln^III complexes were characterized by potentiometry and time-resolved luminescence; the Gd^III complexes are thermodynamically much less stable than that of H₄DOTA, and no water is coordinated in the inner sphere. The crystal structures of the free ligand H₄DOTP^OEt and of the Gd^III complexes of H₄DOTP^H and H₄DOTP^OEt were determined by X-ray diffraction. The complexes have the expected octadentate coordination mode with an N₄O₄ arrangement; no water molecule is bound to the Gd^III ion. Information on the structures of the Ln^III complexes of all five ligands in aqueous solution were obtained from ¹H and ³¹P NMR spectra. The NMR spectra of the [Ln(DOTP^hm)]^– and [Ln(DOTP^Et)]^– complexes show that these compounds have a clear preference for a specific arrangement of phosphorus atoms which gives rise to the symmetrical RRRR (or SSSS) isomer. However, many diastereoisomers were observed for all other complexes. Ln^III-induced ¹⁷O NMR shift data reveal that the spatial location of the second-sphere water molecules for the two groups of complexes differs. The parameters governing the effect of the second hydration sphere on the relaxivity of the Gd^III complexes of all ligands were evaluated by EPR, variable-temperature ¹⁷O NMR spectroscopy and ¹H NMRD relaxometry. The presence of second-sphere water molecules is clearly confirmed, depending on the character of the pendant arms. As the relaxivity does not depend significantly on the nature of the phosphorus substituents and/or on the isomerism present in solution, the second-sphere water molecules should be located close to the phosphorus–oxygen atoms.(© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2009)