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      Synthesis and evaluation of 13C-labeled 5-5-dimethyl-1-pyrroline-N-oxide aimed at in vivo detection of reactive oxygen species using hyperpolarized 13C-MRI

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          Abstract

          Effective means to identify the role of reactive oxygen species (ROS) mediating several diseases including cancer, ischemic heart disease, stroke, Alzheimer’s and other inflammatory conditions in in vivo models would be useful. The cyclic nitrone 5,5-Dimethyl-1-pyrroline-N-oxide (DMPO) is a spin trap frequently used to detect free radicals in vitro using Electron Paramagnetic Resonance (EPR) spectroscopy. In this study, we synthesized 13 C-labeled DMPO for hyperpolarization by dynamic nuclear polarization, in which 13 C NMR signal increases more than 10000-fold. This allows in vivo 13 C MRI to investigate the feasibility of in vivo ROS detection by the 13 C-MRI. DMPO was 13 C-labeled at C5 position, and deuterated to prolong the T 1 relaxation time. The overall yield achieved for 5- 13 C-DMPO-d 9 was 15%. Hyperpolarized 5- 13 C-DMPO-d provided a single peak at 76 ppm in the 13 C-spectrum, and the T 1 was 60 s in phosphate buffer making it optimal for in vivo 13 C MRI. The buffered solution of hyperpolarized 5- 13 C-DMPO-d 9 was injected into a mouse placed in a 3 T scanner, and 13 C-spectra were acquired every 1 s. In vivo studies showed the signal of 5- 13 C-DMPO-d 9 was detected in the mouse, and the T 1 decay of 13 C signal of hyperpolarized 5- 13 C-DMPO-d 9 was 29 s. 13 C-chemical shift imaging revealed that 5- 13 C-DMPO-d 9 was distributed throughout the body in a minute after the intravenous injection. A strong signal of 5- 13 C-DMPO-d 9 was detected in heart/lung and kidney, whereas the signal in liver was small compared to other organs. The results indicate hyperpolarized 5- 13 C-DMPO-d 9 provided sufficient 13 C signal to be detected in the mouse in several organs, and can be used to detect ROS in vivo.

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          Author and article information

          Journal
          Free Radical Biology and Medicine
          Free Radical Biology and Medicine
          Elsevier BV
          08915849
          February 2019
          February 2019
          : 131
          : 18-26
          Article
          10.1016/j.freeradbiomed.2018.11.013
          6983923
          30471347
          © 2019

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