Nitroxides have been shown to be efficient antioxidants and radiation protectors. Nitroxides are paramagnetic and their presence in tissue can be monitored non-invasively by MRI. The disappearance of nitroxide induced MR intensity enhancement (nitroxide metabolism) in tissue is a result of intracellular reduction of the nitroxides to the hydroxylamine (not paramagnetic). The rate of nitroxide reduction can increase or decrease due to oxidative stress, suggesting that nitroxides can provide an imaging-based assay of tissue redox status. In addition, the concentration of the nitroxide in tissue can be determined using MR technology.A study of nitroxide reduction rates in different normal tissues in mice and various types of tumors using a 5-membered ring nitroxide (3-CP) and a 6-membered ring nitroxide, Tempol has revealed that reduction rates can vary substantially among normal tissues and selected tumor types and that in general 6-membered nitroxide are reduced faster than 5-membered nitroxides. Maximum nitroxide tissue levels achievable in mouse approach 8 mM, while in selected rodent tumors the values were much less (0.6-0.8 mM). This differential in concentration may explain the differential radioprotection of Tempol in normal tissues and not tumor. For a given tissue, the maximum nitroxide concentration usually did not vary between the two nitroxides. While it has long been thought that nitroxide reduction would be faster in hypoxic tumor tissue, several normal tissues were found to have comparable reduction rates to hypoxic tumors, suggesting that tissue pO2 is not a major determinant of the nitroxide reduction rate in vivo. In addition to tumor hypoxia, redox-recycling systems such as NADP/NADPH may contribute to nitroxide reduction. For the purpose of redox imaging, 3-CP was shown to be an optimal choice based on the achievable concentrations and bioreduction observed in vivo.Another 5-membered ring nitroxide (designated 23c) was found to provide T1 contrast in the brain and myocardium of mice. We have identified a number of nitroxides that cross the blood brain barrier, but 23c to date is the most efficient. Not only did 23c cross the blood brain barrier, but also the maximal concentration obtained was approximately 3.6 mM. Further, it was found that the rate of 23c reduction was greater in the ventral as opposed to the dorsal brain region, suggesting that 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-induced lethality by total body radiation. 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.

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Matsumoto, Atsuko; Matsumoto, Ken-ichiro; Matsumoto, Shingo et al. (2011) Intracellular hypoxia of tumor tissue estimated by noninvasive electron paramagnetic resonance oximetry technique using paramagnetic probes. Biol Pharm Bull 34:142-5
Matsumoto, Ken-ichiro; Hyodo, Fuminori; Anzai, Kazunori et al. (2011) Brain redox imaging. Methods Mol Biol 711:397-419
Davis, Ryan M; Mitchell, James B; Krishna, Murali C (2011) Nitroxides as cancer imaging agents. Anticancer Agents Med Chem 11:347-58
Day, Sam E; Kettunen, Mikko I; Cherukuri, Murali Krishna et al. (2011) Detecting response of rat C6 glioma tumors to radiotherapy using hyperpolarized [1- 13C]pyruvate and 13C magnetic resonance spectroscopic imaging. Magn Reson Med 65:557-63
Davis, Ryan M; Matsumoto, Shingo; Bernardo, Marcelino et al. (2011) Magnetic resonance imaging of organic contrast agents in mice: capturing the whole-body redox landscape. Free Radic Biol Med 50:459-68
Davis, Ryan M; Sowers, Anastasia L; DeGraff, William et al. (2011) A novel nitroxide is an effective brain redox imaging contrast agent and in vivo radioprotector. Free Radic Biol Med 51:780-90
Citrin, Deborah; Cotrim, Ana P; Hyodo, Fuminori et al. (2010) Radioprotectors and mitigators of radiation-induced normal tissue injury. Oncologist 15:360-71
Hyodo, Fuminori; Matsumoto, Shingo; Devasahayam, Nallathamby et al. (2009) Pulsed EPR imaging of nitroxides in mice. J Magn Reson 197:181-5
Hyodo, Fuminori; Chuang, Kai-Hsiang; Goloshevsky, Artem G et al. (2008) Brain redox imaging using blood-brain barrier-permeable nitroxide MRI contrast agent. J Cereb Blood Flow Metab 28:1165-74
Hyodo, Fuminori; Murugesan, Ramachandran; Matsumoto, Ken-ichiro et al. (2008) Monitoring redox-sensitive paramagnetic contrast agent by EPRI, OMRI and MRI. J Magn Reson 190:105-12

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