Use of 3-acetoxymethoxycarhonyl-2,2,5,5-tetramethyl-1-pyrrolidinyloxyl as an EPR oximetry probe: Potential for in vivo measurement of tissue oxygenation in mouse brain
Use of 3-acetoxymethoxycarhonyl-2,2,5,5-tetramethyl-1-pyrrolidinyloxyl as an EPR oximetry probe: Potential for in vivo measurement of tissue oxygenation in mouse brain
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DOI：
10.1002/mrm.20894
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发表时间：
2006-06-01
影响因子：
3.3
通讯作者：
Liu, Ke Jian
中科院分区：
文献类型：
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作者：
Shen, Jiangang;Liu, Shimin;Liu, Ke Jian
脑内氧浓度和分布的测量对于理解脑卒中的病理生理学是必不可少的。低频电子顺磁共振（EPR）光谱与顺磁探针是一个有吸引力的成像模式，有可能被用来映射在大脑中的O-2浓度。我们研究了两种氮氧自由基，3-甲氧羰基-2，2，5，5-四甲基-1-吡咯烷氧基[2]和3-乙酰氧基-甲氧羰基-2，2，5，5-四甲基-1-吡咯烷氧基[3]，一种前成像剂，用于递送3-羧基-2，2，5，5-四甲基-吡咯烷氧基[1]穿过血脑屏障（BBB）。在原代培养的神经元中，氮氧化物[3]而不是[2]被细胞内酯酶水解为[1]，[1]在生理pH下为阴离子，在细胞内保留良好。相反，[2]不能很好地被神经元保留。小鼠体内药代动力学和药效学研究表明，酯酶不稳定的氮氧化物[3]穿过血脑屏障，并转化为[1]和保留。滞留发生在脑组织中，而不是在广泛的血管系统中，这一事实证明，通过全身盐水灌注去除血液并没有消除来自大脑的氮氧化物EPR信号。[1]和[3]的EPR线宽比常用的血氧探针4-oxo-2，2，6，6-tetramethylpiperidine-d-（16）-1-N-15- oxyl [4]更敏感。此外，我们使用[3]在体内估计小鼠大脑中的O-2浓度。这些结果表明，氮氧自由基[3]可用于绘制中风后脑中的O-2分布。
Measurement of oxygen concentration and distribution in the brain is essential for understanding the pathophysiology 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-acetoxy-methoxycarbonyl-2,2,5,5-tetramethyl-l-pyrrolidinyloxyl [3], a pro-imaging agents to deliver 3-carboxy-2,2,5,5-tetramethyl-pyrrolidinyloxyl [1] across the blood-brain barrier (BBB). In primary cultured neurons, nitroxide [3] but not [2] was hydrolyze by intracellular esterases to [1], which, being anionic at physologic 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] an retained. Retention occurred in brain tissue and not in the extensive vasculature, as evidenced by the fact that removal 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-use oximetry probe 4-oxo-2,2,6,6-tetramethylpiperidine-d-(16)-1-N-15- 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.