Abstract:
Hyperpolarized 13C-labeled fumarate probes tissue necrosis via the production of 13C-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 solubility-restricted 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 [1,4-13C2]fumarate shows that the signal sensitivity in rat kidneys increases by 10-fold. As a result, [1,4-13C2]aspartate and [13C]bicarbonate in addition to [1,4-13C2]malate can be detected in healthy rat kidneys in vivo using hyperpolarized meglumine [1,4-13C2]fumarate. In particular, the appearance of [13C]bicarbonate indicates that hyperpolarized meglumine [1,4-13C2]fumarate can be used to investigate phosphoenolpyruvate carboxykinase, a key regulatory enzyme in gluconeogenesis.
摘要:
超极化的13C标记的富马酸盐通过产生13C-苹果酸来探测组织坏死。尽管它承诺检测肿瘤坏死和肾损伤,它的临床翻译是有限的,主要是由于在常规玻璃化溶剂中的低溶解度。在这项研究中,通过使用葡甲胺作为抗衡离子,我们介绍了一种用于溶解动态核极化(DNP)的富马酸盐的新配方,一种不可代谢的山梨醇衍生物。我们已经发现富马酸葡甲胺本身具有增强的水溶性(4.8M),这有望克服溶解后超极化富马酸盐的溶解度限制的最大浓度。与常规二甲基亚砜(DMSO)混合富马酸盐(13.5±2.4%)相比,富马酸葡甲胺可实现的液态极化水平增加了一倍以上(29.4±1.3%)。DMSO-和葡甲胺制备的50-mM超极化[1,4-13C2]富马酸盐的体内比较表明,大鼠肾脏的信号敏感性增加了10倍。因此,使用超极化葡甲胺[1,4-13C2]富马酸酯可以在体内健康大鼠肾脏中检测到除[1,4-13C2]苹果酸之外的[1,4-13C2]天冬氨酸和[13C]碳酸氢盐。特别是,[13C]碳酸氢盐的出现表明超极化葡甲胺[1,4-13C2]富马酸酯可用于研究磷酸烯醇丙酮酸羧激酶,糖异生的关键调节酶。