Redox Imaging using Nitroxides and MRI

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Summary Nitroxides are efficient antioxidants and radiation protectors and recent studies have shown that they can be used as functional MRI contrast probes. Because nitroxides are paramagnetic their presence in tissue can be monitored non-invasively by MRI. Further the disappearance of nitroxide induced MR intensity enhancement in tissue is a result of intracellular reduction of the nitroxides to the hydroxylamine. By following the rate of reduction of the nitroxide in tissue the redox rate can be determined. This property distinguishes nitroxides as functional MR contrast agents revealing information about the intracellular redox capacity of cells/tissues. An extensive study of nitroxide reduction rates in different normal tissues in mice and various types of tumors using a 5-membered ring nitroxide (3CP) and a 6-membered ring nitroxide, Tempol has been completed. Reduction rates were found to vary greatly among normal tissues and selected tumor types. In general, reduction rates were slower for the five membered nitroxide than the six membered nitroxide. It was found that 3CP was reduced 3 to 11 times slower (depending on the tissue) than Tempol in vivo and that maximum tissue concentration varies substantially between tissues (0.6 to 7.2 mM). For a given tissue, the maximum concentration usually did not vary between the two nitroxides. Furthermore, using electron paramagnetic resonance spectroscopy, we showed that the nitroxide reduction rate depends only weakly on cellular oxygen concentration in the oxygen range expected in vivo. These observations, taken with the marked variation in nitroxide reduction rates observed between tissues, suggest that tissue oxygen concentration is not a major determinant of the nitroxide reduction rate in vivo. For the purpose of redox imaging, 3CP was shown to be an optimal choice based on the achievable concentrations and bioreduction observed in vivo. Another five membered ring nitroxide (designated 23c) was found to provide T1 contrast in the brain, suggesting that nitroxides penetrate the blood brain barrier. Pharmacokinetic studies revealed that 23c is an effective redox imaging agent in the mouse brain, and that 23c may allow functional imaging of the myocardium as well. 23c may be useful in studies assessing radiation-induced neurocognitive damage and other damage to the brain including ischemia reperfusion injury. This nitroxide was also found to be a very potent protector against radiation damage in normal tissues (mouse). Since nitroxides readily penetrate cell membranes and are potent antioxidants, they may be of use in other areas of medical research such as ischemia reperfusion injury studies, stroke, prevention of cataracts, inflammatory processes, and aging. Nitroxide based MRI evaluation may have clinical utility in defining the above-mentioned conditions.