Surprising Impact of Donor Charge on the Water Exchange Rates of Gd(III) AAZTA Derivatives

We report the synthesis of three new heptadentate ligands derived from H4AAZTA (6-amino-6-methylperhydro-1,4-diazepinetetraacetic acid) that contain a dimethyl-amide group (AAZTA-MA)3-, two dimethyl-amide groups (AAZTA-BMA)2- or two acetylglycine groups (AAZTA(Gly)2)4-. The corresponding Gd(III) complexes were investigated using 1H NMR relaxometry and 17O NMR chemical shifts and transverse relaxation rates. A computational DFT study was also performed to aid the analysis of the NMR data. The Gd(III) complexes contain two water molecules coordinated to the metal ion. In contrast to the prevailing trend, the amide derivatives discussed in this context exhibit comparatively rapid water exchange rates that do not align with the changes in the overall electric charge of the complexes: kex298=14.4x106 s-1, 14.5x106 s-1 and 9.56x106 s-1 for [Gd(AAZTA-MA)(H2O)2], [Gd(AAZTA-BMA)(H2O)2]+ and [Gd(AAZTA(Gly)2(H2O)2]-, respectively. The analysis of the data and the computational work suggest that the relatively fast water exchange rates could be linked to the occurrence of associatively activated mechanisms, which is somewhat unexpected for nine-coordinated complexes. Coordinated water molecules in Bis-hydrated Gd(III)-AAZTA derivatives have unexpectedly fast exchange rates, which do not follow the trend with complex charge observed previously for contrast agents used in magnetic resonance imaging (MRI). image