title: In vivo EPR oximetry using an isotopically-substituted nitroxide: Potential for quantitative measurement of tissue oxygen.
abstract: Variations in brain oxygen (O2) concentration can have profound effects on brain physiology. Thus, the ability to quantitate local O2 concentrations noninvasively in vivo could significantly enhance understanding of several brain pathologies. However, quantitative O2 mapping in the brain has proven difficult. The electron paramagnetic resonance (EPR) spectra of nitroxides are sensitive to molecular O2 and can be used to estimate O2 concentrations in aqueous media. We recently synthesized labile-ester-containing nitroxides, such as 3-acetoxymethoxycarbonyl-2,2,5,5-tetramethyl-1-pyrrolidinyloxyl (nitroxide 4), which accumulate in cerebral tissue after in situ hydrolysis, and thus enable spatial mapping of O2 concentrations in the mouse brain by EPR imaging. In an effort to improve O2 quantitation, we prepared 3-acetoxymethoxycarbonyl-2,2,5,5-tetra((2)H3)methyl-1-(3,4,4-(2)H3,1-(15)N)pyrrolidinyloxyl (nitroxide 2), which proved to be a more sensitive probe than its normo-isotopic version for quantifying O2 in aqueous solutions of various O2 concentrations. We now demonstrate that this isotopically substituted nitroxide is ∼2-fold more sensitive in vivo than the normo-isotopic nitroxide 4. Moreover, in vitro and in vivo EPR spectral-spatial imaging results with nitroxide 2 demonstrate significant improvement in resolution, reconstruction and spectral response to local O2 concentrations in cerebral tissue. Thus, isotopic-substituted nitroxides, such as 2, are excellent sensors for in vivo O2 quantitation in tissues, such as the brain.
authors: Department of Pharmaceutical Sciences, College of Pharmacy, University of New Mexico Health Sciences Center, Albuquerque, NM 87131, United States; Center of Biomedical Research Excellence, College of Pharmacy, University of New Mexico, Albuquerque, NM 87131, United States. Electronic address: jmweaver@salud.unm.edu.
authors: John
authors: J
authors: Weaver
authors: Center for Biomedical Engineering and Technology, University of Maryland School of Medicine, Baltimore, MD 21201, United States; Department of Physiology, University of Maryland School of Medicine, Baltimore, MD 21201, United States; Center for EPR Imaging In Vivo Physiology, University of Maryland, Baltimore, MD 21201, United States.
authors: Scott R
authors: SR
authors: Burks
authors: Department of Pharmaceutical Sciences, College of Pharmacy, University of New Mexico Health Sciences Center, Albuquerque, NM 87131, United States; Center of Biomedical Research Excellence, College of Pharmacy, University of New Mexico, Albuquerque, NM 87131, United States.
authors: Ke Jian
authors: KJ
authors: Liu
authors: Center for Biomedical Engineering and Technology, University of Maryland School of Medicine, Baltimore, MD 21201, United States; Department of Physiology, University of Maryland School of Medicine, Baltimore, MD 21201, United States; Center for EPR Imaging In Vivo Physiology, University of Maryland, Baltimore, MD 21201, United States.
authors: Joseph P Y
authors: JP
authors: Kao
authors: Center for Biomedical Engineering and Technology, University of Maryland School of Medicine, Baltimore, MD 21201, United States; Center for EPR Imaging In Vivo Physiology, University of Maryland, Baltimore, MD 21201, United States; Department of Pharmaceutical Sciences, University of Maryland School of Pharmacy, Baltimore, MD 21201, United States.
authors: Gerald M
authors: GM
authors: Rosen
mesh_terms: D000818:Animals; D001921:Brain / Q000502:physiology*; D004578:Electron Spin Resonance Spectroscopy; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D010092:Oximetry / Q000379:methods*; D010100:Oxygen / Q000032:analysis*
chemical_list: D010100:Oxygen
keywords: (15)N-perdeuterionitroxide; Blood brain barrier; Brain oxygen; Electron paramagnetic resonance; In vivo oxygen probes; Labile-ester-containing nitroxides