Redox‐ and Hypoxia‐Responsive MRI Contrast Agents

Abstract

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.

Modifying LnHPDO3A Chelates for Improved T1 and CEST MRI Applications

“…Among these, CEST agents affect the intensity of the bulk water signal by transferring saturated magnetization from an exchangeable pool of protons, which are properly irradiated by a radiofrequency field centered at their absorption frequency. They have the great advantage to be frequency‐encoding systems, thus 1) there is no need to acquire a pre‐contrast image, 2) it is possible to detect more agents in the same image by selecting the proper saturation field, and 3) it is possible to assess parameters of pathological interest (pH, temperature, enzyme activity) by applying a ratiometric approach …”

MR imaging probes: design and applications

“…19,22,133-135 Alterations in extracellular pH, pO 2 , redox potential, labile metal concentrations, expression of specific enzymes, etc. accompany cancers, ischemia, infection, vascular injury, inflammation and numerous other disease states.…”

Non‐Macrocyclic Schiff Base Complexes of Iron(II) as ParaCEST Agents for MRI

“…Transition metal paraCEST agents are primarily sought to eliminate the use of Ln III based contrast agents. A second motivation is the anticipation that transition metal paraCEST agents will provide an increased Fermi contact contribution to the hyperfine shifts (Δ ω ) of protons in the ligand backbone . Proton hyperfine shifts arise through contact and pseudo‐contact interactions between the proton spin and the unpaired electrons of the metal ion , .…”