Mechanisms of ZnII-Activated Magnetic Resonance Imaging Agents

We report on the mechanism of a series of Zn-II-activated magnetic resonance contrast agents that modulate the access of water to a paramagnetic Gd-III ion to create an increase in relaxivity upon binding of Zn-II, In the absence and presence of Zn-II, the coordination at the Gd-III center is modulated by appended Zn-II binding groups. These groups were systematically varied to optimize the change in coordination upon Zn-II binding. We observe that at least one appended aminoacetate must be present as a coordinating group to bind Gd-III and effectively inhibit access of water. At least two binding groups are required to efficiently bind Zn-II, creating an unsaturated complex and allowing access of water. C-13 isotopic labeling of the acetate binding groups for NMR spectroscopy provides evidence of a change in the metal coordination of these groups upon the addition of Zn-II supporting our proposed mechanism of activation as presented.