1H and 17O-NMR Relaxometric Investigations of Paramagnetic Contrast Agents for MRI. Clues for Higher Relaxivities

The analysis of ¹H- and ¹⁷O-NMR relaxometric data allows us to get a better insight into the understanding of the structural and dynamic factors responsible for the relaxivity of a given paramagnetic system. High relaxivities are obtained in the presence of a long molecular reorientational time and fast exchange of the water molecule(s) coordinated to the paramagnetic metal ion. Long molecular reorientational times are pursued either through the formation of covalent conjugates between a paramagnetic complex and a macromolecular substrate or through the formation of non-covalent adducts between suitably functionalized complexes and endogenous (e.g. serum albumin) or exogenous (e.g. poly-β-cyclodextrin) substrates. Within the class of covalent conjugates, it has been shown that the use of a DOTA-like chelate bearing the squaric acid as linking moiety leads to an improved relaxivity with respect to analogous systems obtained through reactions involving the bifunctional DTPA bisanhydride. As far as the exchange of the coordinated water in Gd(III) chelates is concerned, it depends on the energy difference between the ground ennea-coordinated state and the activated octa-coordinated state. In the presence of bulky substituents, the ground state is destabilized with a consequent increase of the exchange rate. An elongation of the exchange lifetime can occur upon the interaction with serum albumin. This behaviour may result in a decrease of the attainable relaxivity. Finally, it has been shown that Mn(II) chelates may represent a viable alternative to Gd(III) complexes. In fact, in spite of the lower effective magnetic moment, the non-covalent adducts between Mn(II) chelates and albumin display very high relaxivities. This result has been accounted for in terms of the very short exchange lifetime of the Mn(II) coordinated water molecule.