A pathway toward clinical translation of hyperpolarized [1,4-C,2,3-d]fumarate as an imaging biomarker for early cellular necrosis in vivo.

Purpose: The detection of hyperpolarized carbon-13 (HP C)-fumarate conversion to C-malate using C-MRSI is a biomarker for early detection of cellular necrosis. Here, we describe the translation of HP C-fumarate as a novel human imaging agent, including the evaluation of biocompatibility and scaling up of the hyperpolarization methods for clinical use.

Methods: Preclinical biological validation was undertaken in fumarate hydratase-deficient murine tumor models and controls. Safety and biocompatibility of C-fumarate was assessed in healthy rats (N = 18) and in healthy human volunteers (N = 9). The dissolution dynamic nuclear polarization process for human doses of HP C-fumarate was optimized in phantoms. Finally, 2D C-MRSI following injection of HP C-fumarate was performed in an ischemia-reperfusion porcine kidney model (N = 6).

Results: Fumarate-to-malate conversion was reduced by 42%-71% in the knockdown murine tumor model compared to wildtype tumors. Twice-daily injection of C-fumarate in healthy rats at the maximum evaluated dose (120 mg/kg/day) showed no significant persistent blood or tissue effects. Healthy human volunteers injected at the maximum dose (3.84 mg/kg) and injection rate (5 mL/s) showed no statistically significant changes in vital signs or blood measurements 1 h post-injection. Spectroscopic evidence of fumarate-to-malate conversion was observed in the ischemic porcine kidney (0.96 mg/kg).

Conclusion: HP C-fumarate has shown promise as a novel and safe hyperpolarized agent for monitoring cellular necrosis. This work provides the basis for future imaging of HP C-fumarate metabolism in humans.