2H,15N–Substituted Nitroxides as Sensitive Probes for Electron Paramagnetic Resonance Imaging

Electron paramagnetic resonance imaging (EPRI) using nitroxides is an emergent imaging method for studying in vivo physiology, including O2 distribution in various tissues. Such imaging capabilities would allow O2 mapping in tumors and in different brain regions following hypoxia or drug abuse. We have recently demonstrated that the anion of 3-carboxy-2,2,5,5-tetramethyl-1-pyrrolidinyloxyl (2) can be entrapped in brain tissue to quantitate O2 concentration in vivo. To increase the sensitivity of O2 measurement by EPR imaging, we synthesized 3-carboxy-2,2,5,5-tetra(2H3)methyl-1-(3,4,4-2H3,1-15N)pyrrolidinyloxyl (7). EPR spectroscopic measurements demonstrate that this fully isotopically substituted nitroxide markedly improves signal-to-noise ratio and, therefore, the sensitivity of EPR imaging. The new isotopically substituted nitroxide shows increased sensitivity to changes in O2 concentration, which will enable more accurate O2 measurement in tissues using EPRI.