Mechanisms of Zn^II-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. ¹³C 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.