A Hydrogen Peroxide-Responsive Hyperpolarized ¹³C MRI Contrast Agent

Abstract

We report a new reaction-based approach for the detection of hydrogen peroxide (H2O2) using hyperpolarized 13C magnetic resonance imaging (13C MRI) and the H2O2-mediated oxidation of α-ketoacids to carboxylic acids. 13C-benzoylformic acid (13C-BFA) reacts selectively with H2O2 over other reactive oxygen species (ROS) to generate 13C-benzoic acid (BA) and can be hyperpolarized using dynamic nuclear polarization (DNP), providing a method for dual-frequency detection of H2O2. Phantom images collected using frequency-specific imaging sequences demonstrate the efficacy of this responsive contrast agent to monitor H2O2 at pre-clinical field strengths. The combination of reaction-based detection chemistry and hyperpolarized 13C magnetic resonance imaging (13C MRI) provides a potentially powerful new methodology for non-invasive multianalyte imaging in living systems.

Reaction-based small-molecule fluorescent probes for chemoselective bioimaging

“…Moreover, NBzF can be used to visualize endogenous H 2 O 2 bursts generated by macrophages and cancer cells. In parallel efforts to this work, our laboratory exploited the H 2 O 2 -mediated oxidation of ketoacids to carboxylic acids to develop a H 2 O 2 -responsive hyperpolarized 13 C MRI contrast agent 37 . Specifically, 13 C-labelled benzoylformic acid ( 13 C-BFA) reacts selectively with H 2 O 2 over other ROS to generate the corresponding 13 C-benzoic acid.…”

Chemistry and biochemistry of13C hyperpolarized magnetic resonance using dynamic nuclear polarization

“…Recent studies have also suggested a positive role for ROS in normal cell-signaling, mediated by the NADPH oxidase (NOX) enzymes. 130 A reaction-based approach was developed to detect H 2 O 2 based on its oxidation of an α-ketoacid ( 13 C-benzoyl-formic acid or BFA) to a carboxylic acid ( 13 C-benzoic acid), readily observable by chemical shift 35 (Fig. 10).…”

“…HP Images were acquired after ~37 s of reaction with H 2 O 2 with a TR = 150 ms, FOV 40 × 40 × 40 mm, 16 × 12 × 12 matrix, and zero-filled to a final resolution of 1.25 mm isotropic, at 14 T. Adapted from ref. 35.…”

Redox‐ and Hypoxia‐Responsive MRI Contrast Agents

“…[92, 93] Hyperpolarized [2- 13 C]benzoylformic acid has also been used for the 13 C MR imaging of H 2 O 2 . [94] Several methods including polarography, immunohistochemical staining, ESR oximetry, optical imaging, PET and SPECT imaging, as well as MR techniques (BOLD MRI, 19 F MRS) are available for the assessment of hypoxia, each having its own advantages and disadvantages. These have been reviewed elsewhere.…”