Real-time monitoring of drug-induced changes in the stomach acidity of living rats using improved pH-sensitive nitroxides and low-field EPR techniques

• Published in: Journal of magnetic resonance (1997) Vol. 182; no. 1; pp. 1 - 11
• Main Authors: Potapenko, Dmitrii I., Foster, Margaret A., Lurie, David J., Kirilyuk, Igor A., Hutchison, James M.S., Grigor’ev, Igor A., Bagryanskaya, Elena G., Khramtsov, Valery V.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01-09-2006
• Subjects: Animals; Cyclic N-Oxides - chemistry; Cyclic N-Oxides - metabolism; Electron Spin Resonance Spectroscopy - methods; Gastric Acid - metabolism; Hydrogen-Ion Concentration; Imidazolidines - metabolism; In vivo EPR techniques; In vivo pH measurement; Male; Molecular Structure; Nitroxide; Rats; Rats, Sprague-Dawley; Spin Labels; Stomach - metabolism; Stomach acidity; Stomach acidity; In vivo pH measurement; Nitroxide; In vivo EPR techniques
• ISSN: 1090-7807; 1096-0856
• DOI: 10.1016/j.jmr.2006.06.002

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 p
K
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-1
H-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 1
h or longer period of time. The results show the applicability of the techniques for monitoring drug pharmacology and disease in the living animals.