Acetoxymethoxycarbonyl Nitroxides as Electron Paramagnetic Resonance Proimaging Agents to Measure O2 Levels in Mouse Brain: A Pharmacokinetic and Pharmacodynamic Study

  1. Minoru Miyake,
  2. Jiangang Shen,
  3. Shimin Liu,
  4. Honglian Shi,
  5. Wenlan Liu,
  6. Zhongrui Yuan,
  7. Aaron Pritchard,
  8. Joseph P. Y. Kao,
  9. Ke Jian Liu and
  10. Gerald M. Rosen
  1. Center of Biomedical Research Excellence, College of Pharmacy, University of New Mexico, Albuquerque, New Mexico (M.M., J.S., S.L., H.S., W.L., Z.Y., A.P., K.J.L.); School of Chinese Medicine, University of Hong Kong, Hong Kong (J.S.); Medical Biotechnology Center, University of Maryland Biotechnology Institute and Department of Physiology, University of Maryland School of Medicine, Baltimore, Maryland (J.P.Y.K.); and Department of Pharmaceutical Sciences, University of Maryland School of Pharmacy and Center for Electron Paramagnetic Resonance Imaging for In Vivo Physiology and Medical Biotechnology Center, University of Maryland Biotechnology Institute, Baltimore, Maryland (G.M.R.)
  1. Address correspondence to:
    Dr. Gerald M. Rosen, Department of Pharmaceutical Sciences, University of Maryland School of Pharmacy, 725 West Lombard St., Baltimore, MD 21201. E-mail: grosen{at}umaryland.edu

Abstract

Measurement of O2 concentration and distribution in brain is essential to understanding the pathophysiology of stroke. Low-frequency electron paramagnetic resonance (EPR) spectroscopy with a paramagnetic probe is an attractive imaging modality that can potentially map O2 concentration in the brain. In a previous study, we demonstrated that, after intraperitoneal administration of 3-acetoxymethoxycarbonyl-2,2,5,5-tetramethyl-1-pyrrolidinyloxyl (1) to mice, this nitroxide crossed the blood-brain barrier into brain tissue where, after hydrolysis, 3-carboxy-2,2,5,5-tetramethyl-1-pyrrolidinyloxyl (2) was liberated and entrapped. This pilot study suggested that nitroxide 1 is a proimaging agent that can deliver nitroxide 2 to brain tissue, where O2 levels can be estimated. In the present study, we conducted a series of pharmacokinetic and pharmacodynamic experiments designed to assess the uptake of structurally disparate nitroxides into brain tissue and retention, after hydrolysis, of the anions of the corresponding nitroxide acids. From these findings, nitroxide 1 and trans-3,4-di(acetoxymethoxycarbonyl)-2,2,5,5-tetramethyl-1-pyrrolidinyloxyl (5) meet the requirement as EPR proimaging agents for mapping O2 distribution in the brain following stroke.

Footnotes

  • This research was supported in part National Institutes of Health Grants P20 RR15636 (to K.J.L.), P41-EB-2034 (to G.M.R.), and GM56481 (to J.P.Y.K.); the American Heart Association Grant 0040041N (to K.J.L.); and the Hong Kong Research Grants Council CERG 7495/04M (to J.S.).

  • doi:10.1124/jpet.106.106245.

  • ABBREVIATIONS: EPR, electron paramagnetic resonance; PBS, phosphate-buffered saline; mp, melting point; HBSS, Hanks' balanced salt solution; i.v., intravenous; i.a., intra-arterial; i.p., intraperitoneal.

    • Received April 17, 2006.
    • Accepted June 2, 2006.
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  1. Published online before print June 6, 2006, doi: 10.1124/jpet.106.106245 JPET September 2006 vol. 318 no. 3 1187-1193
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