Optimizing Water Exchange Rates and Rotational Mobility for High-Relaxivity of a Novel Gd-DO3A Derivative Complex Conjugated to Inulin as Macromolecular Contrast Agents for MRI.

Thanks to the understanding of the relationships between the residence lifetime τM of the coordinated water molecules to macrocyclic Gd-complexes and the rotational mobility τR of these structures, and according to the theory for paramagnetic relaxation, it is now possible to design macromolecular contrast agents with enhanced relaxivities by optimizing these two parameters through ligand structural modification. We succeeded in accelerating the water exchange rate by inducing steric compression around the water binding site, and by removing the amide function from the DOTA-AA ligand [1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid mono(p-aminoanilide)] (L) previously designed. This new ligand 10[2(1-oxo-1-p-propylthioureidophenylpropyl]-1,4,7,10-tetraazacyclodecane-1,4,7-tetraacetic acid (L1 ) was then covalently conjugated to API [O-(aminopropyl)inulin] to get the complex API-(GdL1 )x with intent to slow down the rotational correlation time (τR ) of the macromolecular complex. The evaluation of the longitudinal relaxivity at different magnetic fields and the study of the 17 O-NMR at variable temperature of the low-molecular-weight compound (GdL1 ) showed a slight decrease of the τM value (τM310 = 331 ns vs. τM310 = 450 ns for the GdL complex). Consequently to the increase of the size of the API-(GdL1 )x complex, the rotational correlation time becomes about 360 times longer compared to the monomeric GdL1 complex (τR  = 33,700 ps), which results in an enhanced proton relaxivity.