PET Imaging of 18F-(2S,4R)4-Fluoroglutamine Accumulation in Breast Cancer: From Xenografts to Patients
PET Imaging of 18F-(2S,4R)4-Fluoroglutamine Accumulation in Breast Cancer: From Xenografts to Patients
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DOI：
10.1021/acs.molpharmaceut.8b00430
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发表时间：
2018-08-01
影响因子：
4.9
通讯作者：
Yang, Zhi
中科院分区：
文献类型：
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作者：
Liu, Fei;Xu, Xiaoxia;Yang, Zhi
维持肿瘤细胞的生长需要额外的能量和代谢构件。除了消耗葡萄糖外，谷氨酰胺还可以作为生长和生存的替代营养来源。我们的目标是表征谷氨酰胺类似物 F-18-(2S,4R)4-氟谷氨酰胺 (F-18-(2S,4R)4-FGln)，作为显像剂，用于探究谷氨酰胺在肿瘤细胞体外研究和乳腺癌患者临床表现中的作用。通过放射高效液相色谱 (radio-HPLC) 测量纯度，并在磷酸盐缓冲盐水 (PBS)、盐水以及小鼠和人血清缓冲液中评估生产后的稳定性。使用 qPCR 进行 MCF-7 和 U87 细胞中 Myc 表达的存在。将 MCF-7 和 U87 细胞中 F-18-(2S,4R)4-FGln 的体外细胞摄取直接与 F-18-氟脱氧葡萄糖 (F-18-FDG) 进行比较。对携带 MCF-7 的 BALB/c 裸鼠中的 F-18-(2S,4R)4-FGln 进行体内生物分布和微型 PET 成像。将 F-18-(2S,4R)4-FGln 的 PET/CT 成像与同组乳腺癌患者 (n = 10) 中的 F-18-FDG 进行比较。我们成功合成了具有高放射化学纯度（>98%）的F-18-(25,4R)4-FGln，并且在PBS和盐水缓冲液中孵育2小时期间放射化学纯度没有变化。 18F(25,4R)4-FGln 的体外细胞摄取研究显示，与 F-18-FDG 相比，MCF-7 和 U87 细胞的摄取快速且更高。生物分布和微型 PET 图像显示 F-18-(2S,4R)4-FGln 在 MCF-7 植入的小鼠肿瘤模型中具有良好的肿瘤积累。在一项初步临床研究中，F-18-(2S,4R)4-FGln/PET 比 F-18-FDG/PET 在乳腺癌患者中检测到更多病灶（90% vs 80%）。此外，在一名乳腺小叶癌患者中，经 PET 成像测定，F-18-(2S,4R)4-FGIn 的病灶平均标准化摄取值 (SUI/mean) 和最大标准化摄取值 (SUVmax) 高于 F-18-FDG 获得的值。 (25,4R)4-FGln 可能是一种有用的谷氨酰胺靶向代谢探针，用于乳腺癌无创成像。
Sustaining the growth of tumor cells requires extra energy and metabolic building blocks. In addition to consuming glucose, glutamine may play the role as an alternative source of nutrient for growth and survival. We aim to characterize a glutamine analog, F-18-(2S,4R)4-fluoroglutamine (F-18-(2S,4R)4-FGln), as an imaging agent for interrogating the role of glutamine from the in vitro study of tumor cells to clinical manifestation in breast cancer patients. Purity was measured by radio-high-performance liquid chromatography (radio-HPLC), and the stability after production was evaluated in phosphate buffer saline (PBS), saline, and mouse and human serum buffers. The presence of Myc expression in MCF-7 and U87 cells was conducted using qPCR In vitro cell uptake of F-18-(2S,4R)4-FGln in MCF-7 and U87 cells was directly compared with F-18-fluorodeoxyglucose (F-18-FDG). In vivo biodistribution and micro-PET imaging of F-18-(2S,4R)4-FGln in MCF-7 bearing BALB/c nude mice were performed. PET/CT imaging of F-18-(2S,4R)4-FGln was compared with F-18-FDG in the same group of breast cancer patients (n = 10). We successfully synthesized F-18-(25,4R)4-FGln with a high radiochemical purity (>98%), and the radiochemical purity was unchanged in PBS and saline buffers during a 2 h incubation. In vitro cell uptake studies of 18F(25,4R)4-FGln displayed a rapid and higher uptake in MCF-7 and U87 cells as compared with F-18-FDG. Biodistribution and micro-PET images showed excellent tumor accumulation of F-18-(2S,4R)4-FGln in the MCF-7-implanted mice tumor model. In a preliminary clinical study, F-18-(2S,4R)4-FGln/PET detected more lesions in breast cancer patients than F-18-FDG/PET (90% vs 80%). Additionally, in one patient with breast lobular carcinoma, there was a lesion mean standardized uptake value (SUI/mean) and maximum standardized uptake value (SUVmax) for F-18-(2S,4R)4-FGIn higher than those obtained by F-18-FDG, as determined by PET imaging. (25,4R)4-FGln may be a useful glutamine-targeting metabolic probe for noninvasive imaging of breast cancer.