Hyperpolarized ¹³ C dehydroascorbate as an endogenous redox sensor for in vivo metabolic imaging

Abstract

Reduction and oxidation (redox) chemistry is involved in both normal and abnormal cellular function, in processes as diverse as circadian rhythms and neurotransmission. Intracellular redox is maintained by coupled reactions involving NADPH, glutathione (GSH), and vitamin C, as well as their corresponding oxidized counterparts. In addition to functioning as enzyme cofactors, these reducing agents have a critical role in dealing with reactive oxygen species (ROS), the toxic products of oxidative metabolism seen as culprits in aging, neurodegenerative disease, and ischemia/ reperfusion injury. Despite this strong relationship between redox and human disease, methods to interrogate a redox pair in vivo are limited. Here we report the development of [1-13 C] dehydroascorbate [DHA], the oxidized form of Vitamin C, as an endogenous redox sensor for in vivo imaging using hyperpolarized 13 C spectroscopy. In murine models, hyperpolarized [1-13 C] DHA was rapidly converted to [1-13 C] vitamin C within the liver, kidneys, and brain, as well as within tumor in a transgenic prostate cancer mouse. This result is consistent with what has been previously described for the DHA/Vitamin C redox pair, and points to a role for hyperpolarized [1-13 C] DHA in characterizing the concentrations of key intracellular reducing agents, including GSH. More broadly, these findings suggest a prognostic role for this new redox sensor in determining vulnerability of both normal and abnormal tissues to ROS.MRI | molecular imaging | probe | kinetics

Noninvasive Interrogation of Cancer Metabolism with Hyperpolarized 13C MRI

“…Increased reduction of 1-13 C-dehydroscorbate to 1-13 C-vitamin C is an indicator of high glutathione concentrations, which can be associated with malignancy. 13 C MRSI with hyperpolarized 1-13 C-dehydroscorbate in a transgenic adenocarcinoma of the mouse prostate model revealed high 1-13 C-vitamin C in the liver, kidney, and prostate tumor (31). Moreover, the rodent brain demonstrated high rates of dehydroscorbate reduction to vitamin C, highlighting the reductive capacity of the brain.…”

Recent Developments in Combined PET/MRI

“…Hyperpolarized (HP) 13 C magnetic resonance spectroscopy (HP-MR) is an emerging technique which has found application to the study of a variety of physiologic properties, including metabolism [89,90], tissue pH [91,92], redox state [93], necrosis [94], and blood flow [95]. This method has recently been applied to patients with prostate cancer.…”

Design of a 13C Magnetic Resonance Probe Using a Deuterated Methoxy Group as a Long‐Lived Hyperpolarization Unit

“…[2] Recently, it was demonstrated that the concept of hyperpolarization can be extended to MR probes for surveying the chemical status of living systems. [4][5][6][7][8][9][10][11][12] Because carbon atoms are present in almost all chemical probes, and sophisticated 13 C-isotope labeling procedures are available, 13 C-labeled probes could be a choice for designing a hyperpolarized MR probe. In practice, 13 C-carbon dioxide, [10] 13 C-benzoylformic acid, [11] and 13 C-ascorbic acid [12] have been successfully designed as hyperpolarized MR probes to sense pH, H 2 O 2 , and redox status, respectively.…”