Effect of Magnetic Coupling on Water Proton Relaxivity in a Series of Transition Metal Gd^III Complexes

A fundamental challenge in the design of bioresponsive (or bioactivated) Gd^III-based magnetic resonance (MR) imaging probes is the considerable background signal present in the "preactivated" state that arises from outer-sphere relaxation processes. When sufficient concentrations of a bioresponsive agent are present (i.e., a detectable signal in the image), the inner- and outer-sphere contributions to r₁ may be misinterpreted to conclude that the agent has been activated, when it has not. Of the several parameters that determine the observed MR signal of an agent, only the electron relaxation time (T_1e) impacts both the inner- and outer-sphere relaxation. Therefore, strategies to minimize this background signal must be developed to create a near zero-background (or truly "off" state) of the agent. Here, we demonstrate that intramolecular magnetic exchange coupling when Gd^III is coupled to a paramagnetic transition metal provides a means to overcome the contribution of second- and outer-sphere contributions to the observed relaxivity. We have prepared a series of complexes with the general formula LMLn(μ-O₂CCH₃)(O₂CCH₃)₂ (M = Co, Cu, Zn). Solid-state magnetic susceptibility measurements reveal significant magnetic coupling between Gd^III and the transition metal ion. Nuclear magnetic relaxation dispersion (NMRD) analysis confirms that the observed differences in relaxivity are associated with the modulation of T_1e at Gd^III. These results clearly demonstrate that magnetic exchange coupling between Gd^III and a transition metal ion can provide a significant decrease in T_1e (and therefore the relaxivity of Gd^III). This design strategy is being exploited to prepare new generations of preclinical bioresponsive MR imaging probes with near zero-background.