Enhanced Solubility and Polarization of ¹³C-Fumarate with Meglumine Allows for In Vivo Detection of Gluconeogenic Metabolism in Kidneys

Abstract

Hyperpolarized 13 C-labeled fumarate probes tissue necrosis via the production of 13 C-malate. Despite its promises in detecting tumor necrosis and kidney injuries, its clinical translation has been limited, primarily due to the low solubility in conventional glassing solvents. In this study, we introduce a new formulation of fumarate for dissolution dynamic nuclear polarization (DNP) by using meglumine as a counterion, a nonmetabolizable derivative of sorbitol. We have found that meglumine fumarate vitrifies by itself with enhanced water solubility (4.8 M), which is expected to overcome the solubilityrestricted maximum concentration of hyperpolarized fumarate after dissolution. The achievable liquid-state polarization level of meglumine-fumarate is more than doubled (29.4 ± 1.3%) as compared to conventional dimethyl sulfoxide (DMSO)-mixed fumarate (13.5 ± 2.4%). In vivo comparison of DMSO-and meglumine-prepared 50-mM hyperpolarized [1,4-13 C 2 ]fumarate shows that the signal sensitivity in rat kidneys increases by 10-fold. As a result, [1,4-13 C 2 ]aspartate and [ 13 C]bicarbonate in addition to [1,[4][5][6][7][8][9][10][11][12][13] C 2 ]malate can be detected in healthy rat kidneys in vivo using hyperpolarized meglumine [1,4-13 C 2 ]fumarate. In particular, the appearance of [ 13 C]bicarbonate indicates that hyperpolarized meglumine [1,4-13 C 2 ]fumarate can be used to investigate phosphoenolpyruvate carboxykinase, a key regulatory enzyme in gluconeogenesis.