Second-Sphere and Outer-Sphere Proton Relaxation of Paramagnetic Complexes: From EPR to NMRD

Magnetic resonance imaging often utilizes paramagnetic contrast agents (PCAs) to increase contrast between adjacent tissues. PCAs enhance the contrast by increasing the spin−lattice proton relaxation rate through processes known as inner-sphere, second-sphere, and outer-sphere mechanisms. Past studies on PCAs often described relaxation rates that are not caused by inner-sphere processes as outer-sphere, since comparatively little is known about second-sphere water. Utilizing vanadyl complexes (ethylenediaminetetraacetate (EDTA) and diethylenetriaminepentaacetate (DTPA)) that do not have an inner-sphere proton relaxation contribution and those with similar functional groups of different sizes, we find that the outer-sphere model does not adequately describe the relaxivity profiles. The observed relaxivity profiles are, however, consistent with a model that includes both second-sphere and outer-sphere contributions. Vanadyl ethoxybenzyl-diethylenetriaminepentaacetate (VOEOB-DTPA) exhibited relaxivity similar to that of DTPA, even though it is larger. This is attributed to a hydrophobic moiety on EOB-DTPA that prevents protons from binding to the second coordination sphere. The combined model developed for the vanadyl complexes is used to simulate the gadolinium triethylenetetraaminehexaacetate (GdTTHA) proton NMRD profile, and the results are extrapolated to deconvolute GdDTPA and GdEOB-DTPA proton NMRD profiles into inner-sphere, second-sphere, and outer-sphere contributions. We find that the second-sphere mechanism is significant and may contribute about 30% of the relaxivity in GdDTPA and about 10% in GdEOB-DTPA.