Use of 3-acetoxymethoxycarbonyl-2,2,5,5-tetramethyl-1-pyrrolidinyloxyl as an EPR oximetry probe: Potential for in vivo measurement of tissue oxygenation in mouse brain
✍ Scribed by Jiangang Shen; Shimin Liu; Minoru Miyake; Wenlan Liu; Aaron Pritchard; Joseph P.Y. Kao; Gerald M. Rosen; Yao Tong; Ke Jian Liu
- Publisher
- John Wiley and Sons
- Year
- 2006
- Tongue
- English
- Weight
- 286 KB
- Volume
- 55
- Category
- Article
- ISSN
- 0740-3194
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✦ Synopsis
Abstract
Measurement of oxygen concentration and distribution in the brain is essential for understanding the pathophysiology of stroke. Low‐frequency electron paramagnetic resonance (EPR) spectroscopy with a paramagnetic probe is an attractive imaging modality that potentially can be used to map O~2~ concentration in the brain. We examined two nitroxides, 3‐methoxycarbonyl‐2,2,5,5‐tetramethyl‐1‐pyrrolidinyloxyl [2] and 3‐acetoxymethoxycarbonyl‐2,2,5,5‐tetramethyl‐1‐pyrrolidinyloxyl [3], as pro‐imaging agents to deliver 3‐carboxy‐2,2,5,5‐tetramethyl‐1‐pyrrolidinyloxyl [1] across the blood–brain barrier (BBB). In primary cultured neurons, nitroxide [3] but not [2] was hydrolyzed by intracellular esterases to [1], which, being anionic at physiologic pH, was well retained intracellularly. In contrast, [2] was not well retained by neurons. In vivo pharmacokinetic and pharmacodynamic studies in mice suggested that esterase‐labile nitroxide [3] crossed the BBB, and was converted to [1] and retained. Retention occurred in brain tissue and not in the extensive vasculature, as evidenced by the fact that removal of blood by whole‐body saline perfusion did not eliminate the nitroxide EPR signal from the brain. The EPR linewidths of [1] and [3] were more O~2~‐sensitive than that of the commonly‐used oximetry probe 4‐oxo‐2,2,6,6‐tetramethylpiperidine‐d~16~‐1‐^15^N‐oxyl [4]. Moreover, we used [3] in vivo to estimate O~2~ concentration in mouse brains. These results indicate that nitroxide [3] could be useful for mapping O~2~ distribution in the brain following stroke. Magn Reson Med, 2006. © 2006 Wiley‐Liss, Inc.