Second Coordination Sphere Water Molecules and Relaxivity of Gadolinium(III) Complexes: Implications for MRI Contrast Agents

Abstract

Dipolar interaction between the metal ion and proximate water molecules represents an efficient mechanism for solvent relaxation in Gd3+ complexes currently employed as MRI contrast agents. Besides inner sphere (metal bound) and outer sphere hydration molecules, a well-defined second coordination shell may provide an additional mechanism for paramagnetic relaxation leading to a strong enhancement of the relaxivity of the complexes. Through a careful choice of hydrogen-bond-acceptor groups on the ligand we may: (1) promote the formation of a strong interaction; (2) increase the number of water molecules in the second hydration shell; (3) decrease their average distance from the paramagnetic metal center. These possibilities have been explored by considering complexes bearing phosphinate, phosphonate and carboxoamide pendant arms, by exploiting the formation of ion-pairs with cationic substrates and inclusion compounds of these adducts with -cyclodextrin. Finally, the contribution of this relaxation mechanism to the relaxivity of the commercially available MRI contrast agents is discussed and the NMRD data reevaluated and compared with crystallographic data.β