Facile Synthesis [5-13C-4-2H2]-L-Glutamine for Hyperpolarized MRS Imaging of Cancer Cell Metabolism
Facile Synthesis [5-13C-4-2H2]-L-Glutamine for Hyperpolarized MRS Imaging of Cancer Cell Metabolism
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DOI：
10.1016/j.acra.2011.05.002
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发表时间：
2011-08-01
影响因子：
4.8
通讯作者：
Kung, Hank F.
中科院分区：
文献类型：
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作者：
Qu, Wenchao;Zha, Zhihao;Kung, Hank F.
理由和目的：最近的报道表明，癌细胞可能使用谷氨酰胺而不是葡萄糖作为代谢能量的替代来源。这表明超极化C-13谷氨酰胺可能是一种有用的磁共振成像剂，用于检测癌细胞或组织中谷氨酰胺代谢的变化。材料与方法：通过7步合成[5-C-13-4-H-2(2)]- l -谷氨酰胺，总收率为44%。两种稳定同位素分别通过(NaBH4)- h -2混合酸酐还原和(KCN)- c -13亲核取代引入。通过脱保护和控制氰化物水解的一锅反应，成功地得到了所需的[5-C-13-4-H-2(2)]- l -谷氨酰胺。超极化[5-C-13-4-H-2(2)]-L-谷氨酰胺样品在人胶质瘤细胞（myc上调的胶质瘤细胞，SF188-Bcl-x(L)）中进行了检测。采用9.4特斯拉89-mm孔径核磁共振波谱仪和直接探测多核探针获取MRS信号。结果：[5-C-13-4-H-2(2)]- l -谷氨酰胺的初始极化度近似于5%，初始C-13信噪比近似于100:1。将超极化谷氨酰胺注入细胞后，在数秒内检测到谷氨酸。谷氨酸与谷氨酰胺的比例非常高，表明谷氨酸的转化速度很快。使用[H-3]- l -谷氨酰胺的类似细胞摄取研究也表明，细胞摄取高于[F-18]氟脱氧葡萄糖。结论：我们报道了第一个使用特殊氘化[5-C-13-4-H-2(2)]- l -谷氨酰胺结合超极化MRS研究增殖肿瘤细胞“谷氨酰胺溶解”的例子。
Rationale and Objectives: Recent reports suggest that cancer cells may use glutamine, instead of glucose, as an alternative source of metabolic energy. This suggests that hyperpolarized C-13 glutamine may be useful as a magnetic resonance spectroscopy (MRS) imaging agent for detecting changes in glutamine metabolism in cancerous cells or tissues.Materials and Methods: Synthesis of [5-C-13-4-H-2(2)]-L-glutamine was accomplished through a seven-step synthetic pathway with a 44% overall yield. The introduction of two stable isotopes was performed by a (NaBH4)-H-2-mixed anhydride reduction and (KCN)-C-13-nuclophilic substitution, respectively. The desired [5-C-13-4-H-2(2)]-L-glutamine was successfully obtained by a one-pot reaction of deprotection and controlled cyanide hydrolysis. Hyperpolarized [5-C-13-4-H-2(2)]-L-glutamine samples were tested in human glioma cells (myc upregulated glia cells, SF188-Bcl-x(L)). MRS signals were obtained with a 9.4 Tesla 89-mm bore nuclear magnetic resonance spectrometer and a direct-detection multi-nuclear probe.Results: The initial degree of polarization for [5-C-13-4-H-2(2)]-L-glutamine was similar to 5% and the initial C-13 signal to noise ratio was similar to 100:1. Glutamate was detected within seconds after the injection of hyperpolarized glutamine into the cells. The ratio of glutamate to glutamine was very high, indicating rapid conversion to glutamate. Similar cell uptake studies using [H-3]-L-glutamine also demonstrated cell uptakes higher than that of [F-18]fluorodeoxyglucose.Conclusion: We are reporting the first example of using specifically deuterated [5-C-13-4-H-2(2)]-L-glutamine in conjunction with hyperpolarized MRS for studying "glutaminolysis" in proliferating tumor cells.