Nitronyl Nitroxides as a Spin Probe in EPR Tomography In Vivo

• Published in: Applied magnetic resonance Vol. 45; no. 8; pp. 743 - 758
• Main Authors: Strizhakov, R. K., Shundrin, L. A., Kolosova, N. G., Stefanova, N. A., Fursova, E. U., Ovcharenko, V. I., Bagryanskaya, E. G.
• Format: Journal Article
• Language: English
• Published: Vienna Springer Vienna 01-08-2014; Springer Nature B.V
• Subjects: Acids; Aqueous solutions; Ascorbic acid; Atoms and Molecules in Strong Fields; Biocompatibility; Blood; Cellular biology; Contrast agents; Diamagnetism; Genetics; Imidazole; In vivo methods and tests; Laser Matter Interaction; Magnetic resonance imaging; Nitric oxide; Organic Chemistry; Physical Chemistry; Physics; Physics and Astronomy; Rate constants; Reaction products; Reagents; Reducing agents; Sodium; Solid State Physics; Spectroscopy/Spectrometry; Spectrum analysis; Tomography; Nitric Oxide; Nitroxides; Electron Paramagnetic Resonance; Electron Paramagnetic Resonance Signal; Electron Paramagnetic Resonance Spectrum
• ISSN: 0937-9347; 1613-7507
• DOI: 10.1007/s00723-014-0555-1

Recently, new water- and blood-soluble nitronyl nitroxides, 2-(5-methyl-1H-imidazole-4-yl)-4,4,5,5-tetramethyl-4,5-dihydroimidazole-3-oxide-1-oxyl (NN1) and 2-(1H-imidazole-4-yl)-4,4,5,5-tetramethyl-4,5-dihydroimidazole-3-oxide-1-oxyl (NN2), (Fig. 
1
), were synthesized and used as contrast agents for MRI (Savelov et al. Dokl Academ Nauk 416(4): 493–495, 2007). Taking into account the high rate constants of NN’s reduction by ascorbic acid and other biologically relevant reductants, it is not clear which factors helped with the use of these nitroxides in vivo as a contrast reagent. Moreover, due to high solubility in an aqueous solution and low toxicity (Ovcharenko et al. in Dokl Academ Nauk 404(2):198–200, 2005, Eriksson et al. in Drug Metab Dispos 15(2):155–160, 1987, Afzal et al. in Polyhedron 22(14):1957–1964, 2003) of NNs, it seems possible to use them as a spin probe for NO in vivo with EPR tomography. In this paper, we studied reduction of NN1 and NN2 in model conditions (by ascorbic acid) and in vitro. In addition, the possibility of NN1 and NN2 to be used as paramagnetic probes for L-band EPR imaging in vivo was investigated. Nitric oxide (NO) expression in vivo leads to the decrease in concentrations of NN1, 2 upon the injection in a mouse body, that can be explained by the reaction of studied radicals with NO and fast transformation of the reaction products to diamagnetic species. Pharmacokinetics of NN1, 2 and limitations of their application as contrast agents in MRI are discussed also. Finally, the results of EPR tomography were compared with MRI data. It is shown that the fast reduction of the reaction product of NN with NO—imino nitroxides—is the main obstacle to use NN as a spin probe in vivo.
Fig. 1
The chemical structures of the nitronyl nitroxides NN1 and NN2 and corresponding imino nitroxides IN1 and IN2. X = CH
3
for NN1 and IN1; X = H for NN2 and IN2