New bifunctional contrast agents:: Bis-amide derivatives of C-substituted Gd-DTPA

In order to expand upon and confirm previous observations on the positive and adverse roles played by the functionalization and substitution of the parent MRI contrast agent Gd-DTPA, two new bi-functionalized contrast agents namely Gd-(S)-EOB-DTPA-BMA and Gd-(S)-C(4)Bz-DTPA-BMA have been synthesized, purified, and characterized by multinuclear NMR studies. Water H-1 nuclear magnetic relaxation dispersion profiles were recorded at several temperatures. tau(R) was determined by 2 H NMR on the diamagnetic lanthanum complex. tau(M), the water residence time, was obtained by O-17 NMR measurements and the stability versus transmetallation by zinc was evaluated by proton relaxometry. The residence time of water molecules in the first coordination sphere of the Gd complexes has confirmed the antagonistic effects of amide functions and C-4 substitution on the reduction of the water residence time, a critical parameter of relaxivity. This C-4 position is thus particularly appropriate for the substitution required by the design of new contrast agents covalently bound to macromolecules or carrying specific vectors. (C) Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2004.