Multinuclear and multifrequency NMR study of gadolinium(III) complexes with bis-amide derivatives of ethylenedioxydiethylenedinitrilotetraacetic acid

Abstract

New cationic gadolinium complexes have been synthesized and their ¹H and ¹⁷O relaxometric properties investigated in view of their possible use as MRI contrast agents. The reaction of the bicyclic anhydride of ethylenedioxydiethylenedinitrilotetraacetic acid (H₄egta) with NH₃, isobutylamine and phenylpropylamine gave the octadentate bis-amide ligands 1–3 in high yields. The gadolinium(III) complexes were prepared from GdCl₃ and the acid form of the ligands. The stability constants of the complexes were obtained from potentiometric data and are about five orders of magnitude lower than for the parent [Gd(egta)]⁻ complex. The magnetic field dependence of the proton relaxivity at 6, 25 and 39 °C was quantitatively analysed in order to obtain the relaxation parameters and indicated that one water molecule occupies a site of the co-ordination sphere of the complexes. The temperature dependence of the relaxivity, measured at 20 MHz, suggested that the water exchange rate, k_ex = 1/τ_M, is sensibly reduced compared to that of the parent compound. ¹⁷O NMR data were acquired at 2.1 T and allowed an accurate estimation of τ_M which, at 298 K, resulted to be 230, 133 and 211 ns for Gd·1, Gd·2 and Gd·3 respectively. The two complexes bearing hydrophobic residues on the amide nitrogens form non-covalent adducts with serum albumin whose relaxivity is limited by the water exchange rate.