Real-time molecular imaging of tricarboxylic acid cycle metabolism in vivo by hyperpolarized 1-(13)C diethyl succinate.
Real-time molecular imaging of tricarboxylic acid cycle metabolism in vivo by hyperpolarized 1-(13)C diethyl succinate.
复制标题
超极化 1-(13)C 琥珀酸二乙酯对体内三羧酸循环代谢的实时分子成像。
DOI：
10.1021/ja2040865
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发表时间：
2012
影响因子：
15
通讯作者：
Bhattacharya,Pratip
中科院分区：
文献类型：
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作者：
Zacharias,NikiM;Chan,HenryR;Sailasuta,Napapon;Ross,BrianD;Bhattacharya,Pratip
克雷布斯三羧酸循环（TCA）是代谢能量产生的核心，并且已知在许多疾病状态下会发生改变。体内TCA循环的实时分子成像对于理解几种疾病的代谢基础将是重要的。正电子发射断层扫描（PET）与FDG-葡萄糖（2-[18 F]氟-2-脱氧-d-葡萄糖）已被用作临床代谢显像剂。然而，FDG-葡萄糖没有揭示任何过去的葡萄糖摄取和磷酸化。我们已经开发了一种新的代谢成像剂，超极化丁二酸二乙酯-1-13 C-2，3-d2，允许TCA循环的实时体内成像和光谱学。丁二酸二乙酯在水溶液中可通过仲氢诱导极化（PHIP）超极化，与玻尔兹曼极化相比信号增强5000倍。正常小鼠注射10-20 μmol超极化丁二酸二乙酯后，在体内获得13 C磁共振波谱（MRS）和磁共振成像（MRI）。超极化琥珀酸二乙酯的下游代谢产物在体内被鉴定为苹果酸盐、琥珀酸盐、富马酸盐和天冬氨酸盐。在将动物暴露于3-硝基丙酸酯（一种已知的琥珀酸脱氢酶不可逆抑制剂）后，琥珀酸二乙酯的代谢发生改变。根据我们的研究结果，超极化的琥珀酸二乙酯可以进行实时体内MRI和MRS，具有高信噪比，并且可以可视化三羟乙酸循环的多个步骤。琥珀酸二乙酯的超极化及其在体内的应用可能揭示了一个全新的制度，其中TCA循环代谢的局部状态在秒至分钟的时间尺度上以前所未有的化学特异性和MR灵敏度进行询问。
The Krebs tricarboxylic acid cycle (TCA) is central to metabolic energy production and is known to be altered in many disease states. Real-time molecular imaging of the TCA cycle in vivo will be important in understanding the metabolic basis of several diseases. Positron emission tomography (PET) with FDG-glucose (2-[18F]fluoro-2-deoxy-d-glucose) is already being used as a metabolic imaging agent in clinics. However, FDG-glucose does not reveal anything past glucose uptake and phosphorylation. We have developed a new metabolic imaging agent, hyperpolarized diethyl succinate-1-13C-2,3-d2, that allows for real-time in vivo imaging and spectroscopy of the TCA cycle. Diethyl succinate can be hyperpolarized via parahydrogen-induced polarization (PHIP) in an aqueous solution with signal enhancement of 5000 compared to Boltzmann polarization.13C magnetic resonance spectroscopy (MRS) and magnetic resonance imaging (MRI) were achieved in vivo seconds after injection of 10–20 μmol of hyperpolarized diethyl succinate into normal mice. The downstream metabolites of hyperpolarized diethyl succinate were identified in vivo as malate, succinate, fumarate, and aspartate. The metabolism of diethyl succinate was altered after exposing the animal to 3-nitropropionate, a known irreversible inhibitor of succinate dehydrogenase. On the basis of our results, hyperpolarized diethyl succinate allows for real-time in vivo MRI and MRS with a high signal-to-noise ratio and with visualization of multiple steps of the TCA cycle. Hyperpolarization of diethyl succinate and its in vivo applications may reveal an entirely new regime wherein the local status of TCA cycle metabolism is interrogated on the time scale of seconds to minutes with unprecedented chemical specificity and MR sensitivity.