Real-time monitoring of drug-induced changes in the stomach acidity of living rats using improved pH-sensitive nitroxides and low-field EPR techniques
Real-time monitoring of drug-induced changes in the stomach acidity of living rats using improved pH-sensitive nitroxides and low-field EPR techniques
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DOI：
10.1016/j.jmr.2006.06.002
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发表时间：
2006-09-01
影响因子：
2.2
通讯作者：
Khramtsov, Valery V.
中科院分区：
文献类型：
--
作者：
Potapenko, Dmitrii I.;Foster, Margaret A.;Khramtsov, Valery V.
新的改进的pH敏感的氮氧自由基应用于体内研究。通过在顺磁性N-O片段附近引入庞大的乙基，实现了探针对还原的稳定性增加。此外，该方法的pH敏感性范围通过合成具有两个可电离基团的探针来扩展，因此具有两个pK（a）值。使用290 MHz射频（RF）和X-波段电子顺磁共振（EPR），纵向检测EPR（LODEPR）和场循环动态核极化（FC-DNP）技术在体外测定了三种新探针的还原稳定性和光谱特性。新合成的探针4-[双（2-羟乙基）氨基]-2-吡啶-4-基-2，5，5-三乙基-2，5-二氢-1H-咪唑氧基被认为是最适合应用于胃中的探针，因为其具有较高的稳定性和方便的pH敏感性（pH 1.8至6）。用LODEPR、FC-DNP和质子电子双共振成像（PEDRI）技术检测大鼠胃内氮氧自由基的定位和酸度。改进的探针特性使我们能够在体内跟踪药物诱导的胃酸扰动及其在I小时或更长时间内的正常化。结果表明，监测药物药理学和疾病的技术在活体动物的适用性。(c)2006年爱思唯尔公司All rights reserved.
New improved pH-sensitive nitroxides were applied for in vivo studies. An increased stability of the probes towards reduction was achieved by the introduction of the bulky ethyl groups in the vicinity of the paramagnetic N-O fragment. In addition, the range of pH sensitivity of the approach was extended by the synthesis of probes with two ionizable groups, and, therefore, with two pK(a) values. Stability towards reduction and spectral characteristics of the three new probes were determined in vitro using 290 MHz radiofrequency (RF)- and X-band electron paramagnetic resonance (EPR), longitudinally detected EPR (LODEPR), and field-cycled dynamic nuclear polarization (FC-DNP) techniques. The newly synthesized probe, 4-[bis(2-hydroxyethyl)amino]-2-pyridine-4-yl-2,5,5-triethyl-2,5-,dihydro-1H-imidazol-oxyl, was found to be the most appropriate for the application in the stomach due to both higher stability and convenient pH sensitivity range from pH 1.8 to 6. LODEPR, FC-DNP and proton-electron double resonance imaging (PEDRI) techniques were used to detect the nitroxide localization and acidity in the rat stomach. Improved probe characteristics allowed us to follow in vivo the drug-induced perturbation in the stomach acidity and its normalization afterwards during I h or longer period of time. The results show the applicability of the techniques for monitoring drug pharmacology and disease in the living animals. (c) 2006 Elsevier Inc. All rights reserved.