Probing Lactate Dehydrogenase Activity in Tumors by Measuring Hydrogen/Deuterium Exchange in Hyperpolarized L-[1-13C,U-2H]Lactate
Probing Lactate Dehydrogenase Activity in Tumors by Measuring Hydrogen/Deuterium Exchange in Hyperpolarized L-[1-13C,U-2H]Lactate
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DOI：
10.1021/ja300222e
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发表时间：
2012-03-14
影响因子：
15
通讯作者：
Brindle, Kevin M.
中科院分区：
文献类型：
--
作者：
Kennedy, Brett W. C.;Kettunen, Mikko I.;Brindle, Kevin M.
C-13磁共振光谱和光谱成像测量外源性给药的[1-C-13]丙酮酸和内源性乳酸之间的超极化C-13标记交换，由乳酸脱氢酶（LDH）催化，已被证明是一个强大的方法探测体内组织代谢。该实验具有临床潜力，特别是在肿瘤学中，它可用于评估肿瘤分级和对治疗的反应。该方法的局限性在于丙酮酸盐必须以超生理浓度在体内施用。通过使用超极化[1-C-13]乳酸盐可以避免这个问题，该乳酸盐可以在生理浓度下使用。然而，在这种情况下，灵敏度受到丙酮酸合并液大小相对较小的限制，这将导致即使乳酸和丙酮酸合并液之间存在完全的标记平衡，也仅观察到低水平的标记丙酮酸。我们在这里展示了一种更灵敏的方法，其中双标记的乳酸物种可用于测量LDH催化的交换在体内。在该实验中，通过在异源H-1/C-I3自旋回波实验中监测自旋耦合超极化C-13信号的相位调制，间接观察到注射的超极化L-[1-C-13，U-H-2]乳酸盐和内源性未标记乳酸盐之间的C2氘标记交换。
C-13 magnetic resonance spectroscopy and spectroscopic imaging measurements of hyperpolarized C-13 label exchange between exogenously administered [1-C-13]pyruvate and endogenous lactate, catalyzed by lactate dehydrogenase (LDH), has proved to be a powerful approach for probing tissue metabolism in vivo. This experiment has clinical potential, particularly in oncology, where it could be used to assess tumor grade and response to treatment. A limitation of the method is that pyruvate must be administered in vivo at supra-physiological concentrations. This problem can be avoided by using hyperpolarized [1-C-13]lactate, which can be used at physiological concentrations. However, sensitivity is limited in this case by the relatively small pyruvate pool size, which would result in only low levels of labeled pyruvate being observed even if there was complete label equilibration between the lactate and pyruvate pools. We demonstrate here a more sensitive method in which a doubly labeled lactate species can be used to measure LDH-catalyzed exchange in vivo. In this experiment exchange of the C2 deuterium label between injected hyperpolarized L-[1-C-13,U-H-2]lactate and endogenous unlabeled lactate is observed indirectly by monitoring phase modulation of the spin-coupled hyperpolarized C-13 signal in a heteronuclear H-1/C-I3 spin echo experiment.