Redox- and Hypoxia-Responsive MRI Contrast Agents

The development of responsive or “smart” magnetic resonance imaging (MRI) contrast agents that can report specific biomarker or biological events has been the focus of MRI contrast agent research over the past 20 years. Among various biological hallmarks of interest, tissue redox and hypoxia are particularly important owing to their roles in disease states and metabolic consequences. Herein we review the development of redox‐/hypoxia‐sensitive T1 shortening and paramagnetic chemical exchange saturation transfer (PARACEST) MRI contrast agents. Traditionally, the relaxivity of redox‐sensitive Gd3+‐based complexes is modulated through changes in the ligand structure or molecular rotation, while PARACEST sensors exploit the sensitivity of the metal‐bound water exchange rate to electronic effects of the ligand‐pendant arms and alterations in the coordination geometry. Newer designs involve complexes of redox‐active metal ions in which the oxidation states have different magnetic properties. The challenges of translating redox‐ and hypoxia‐sensitive agents in vivo are also addressed. The big picture: This review focuses on redox‐/hypoxia‐sensitive T1 shortening and paramagnetic chemical exchange saturation transfer (PARACEST) magnetic resonance imaging (MRI) contrast agents. These agents show redox‐dependent contrast enhancement due to a change in the redox state of either the ligand or the metal ion. Progress in the in vitro and in vivo MR imaging applications of these agents is discussed.