F-18标记的酪氨酸类化合物的合成、动物实验及临床实验研究
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摘要
正电子发射断层显像(positron emission tomography，PET)作为临床诊断肿瘤的一种有力手段已在全世界广泛应用。PET显像剂有多种，目前最常应用的是糖代谢显像剂~(18)F-FDG，它已成功地应用于鉴别肿瘤的良恶性、评价肿瘤的恶性程度以及指示肿瘤的预后情况等。但它存在着特异性差，某些肿瘤细胞对它不摄取，炎性细胞也有摄取等问题；尤其是不易显示脑肿瘤，因为正常脑组织摄取较高。因此，研制开发特异性强、灵敏度高的肿瘤显像剂已成为一项十分迫切的任务。
在癌细胞中，蛋白质的代谢也会增加，因此标记氨基酸就成为另一类重要的代谢显像剂。与~(18)F-FDG相比，标记氨基酸具有更好的肿瘤特异性；在正常脑组织摄取少，肿瘤显像时病灶部位更清晰，更便于区分炎性组织，尤其对脑肿瘤显像很有发展前景。O-(2-[~(18)F]氟代乙基)-L-酪氨酸(~(18)F-FET)是一种人工合成的酪氨酸类似物，不会被进一步代谢和参入蛋白质，但恶性细胞中增加的氨基酸转运同样可以体现组织中增加的氨基酸需求。~(18)F-FET具有标记简单、收率较高、~(18)F的半衰期长等优点，近年来国外已开始试用于临床，但国内还未见临床报道。为了弥补这方面的空白，在原有工作的基础上，经过多次实验，找到适合本实验室的最佳反应条件，合成出~(18)F-FET，其放化纯度大于95％，室温下放置6小时稳定；其临床前研究(包括异常毒性实验、细菌及细菌内毒素的检查)各项指标均符合中国药典标准。对脑瘤患者进行的与~(18)F-FDG-PET的显像结果显示，正常脑组织中~(18)F-FET的摄取明显低于肿瘤组织，肿瘤组织摄取高于~(18)F-FDG，显像清晰，进一步证实了它的临床诊断价值。
另一个L-酪氨酸的类似物6-[~(18)F]氟代-L-多巴(6-FDOPA)在诊断帕金森病(Parkinson's disease，PD)中起着重要的作用。PD是中、老年人较为常见的进行性神经系统退变性疾病，严重危害着患者的健康和生活质量。用6-FDOPA可以无创地诊断及鉴别PD。我们首先合成了芳烃的三甲基铵盐作为不对称合成6-FDOPA的反应前体，经亲核取代法引入氟，通过手性烷基化试剂实现立体定向合成，整个反应过程需
Positron emission tomography (PET) , which is an important tool for the clinical detection of tumors, has been widely employed all over the world. There are many kinds of PET imaging agents. The most commonly used one is ~(18)F-FDG, which has been used in oncology for the differentiation of benign from malignant lesions, the detection and staging of malignancy, and the follow-up of therapeutic responses. However, several recent studies have demonstrated diagnostic limitations of ~(18)F-FDG-PET such as its low specificity, no uptake in some tumor cells and appreciable uptake in inflammatory lesion. Furthermore, for brain tumor imaging, contrast between tumor tissue and normal brain is often low owing to the high glucose utilization of normal grey matter. Therefore designing and synthesizing specific and sensitive tumor imaging agents would be an important research field.
The metabolism of protein will increase in cancer cells, so radiolabelled amino acids constitute another class of metabolic imaging agents which have higher specificity for differentiating inflammatory lesions from tumors, lower uptake in normal tissues, clearer images of brain tumors than those of ~(18)F-FDG. ~(18)F-FET is a synthetic analogue of L-tyrosine that is not metabolized in cells and does not incorporate into proteins. The increased amino acid transport into malignant cells reflects the increasing amino acid requirement in tissues. ~(18)F-FET can be synthesized easily with relatively high radiochemical yield and has been put into clinical trial in several isolated cases, but so far there has been no such clinical report in China. We have synthesized ~(18)F-FET with radiochemical purity of 95% which remained stable for 6 hours. A series of experiments have been carried out to seek for the optimal reaction conditions. Preclinical studies including sterility, endotoxin and toxicity tests were performed and the results accorded with the standards of Chinese Pharmacopoeia. Several brain tumor cases were studied using F-FET-PET and compared with ~(18)F-FDG-PET. The results demonstrated that the uptake of ~(18)F-FET in the normal brain tissues was significantly lower than that of the tumor, and the images of the brain tumor were clearer than those of ~(18)F-FDG. So, it appears to be a very promising agent for the diagnosis of tumors.
Another analogue of L-tyrosine is 6-[~(18)F]fluoro-L-dopa which plays an important role in diagnosing Pakinson's disease. It is well known that Pakinson's disease is a progressive degenerative disease of nervous system which usually affects middle-aged and elderly
在癌细胞中，蛋白质的代谢也会增加，因此标记氨基酸就成为另一类重要的代谢显像剂。与~(18)F-FDG相比，标记氨基酸具有更好的肿瘤特异性；在正常脑组织摄取少，肿瘤显像时病灶部位更清晰，更便于区分炎性组织，尤其对脑肿瘤显像很有发展前景。O-(2-[~(18)F]氟代乙基)-L-酪氨酸(~(18)F-FET)是一种人工合成的酪氨酸类似物，不会被进一步代谢和参入蛋白质，但恶性细胞中增加的氨基酸转运同样可以体现组织中增加的氨基酸需求。~(18)F-FET具有标记简单、收率较高、~(18)F的半衰期长等优点，近年来国外已开始试用于临床，但国内还未见临床报道。为了弥补这方面的空白，在原有工作的基础上，经过多次实验，找到适合本实验室的最佳反应条件，合成出~(18)F-FET，其放化纯度大于95％，室温下放置6小时稳定；其临床前研究(包括异常毒性实验、细菌及细菌内毒素的检查)各项指标均符合中国药典标准。对脑瘤患者进行的与~(18)F-FDG-PET的显像结果显示，正常脑组织中~(18)F-FET的摄取明显低于肿瘤组织，肿瘤组织摄取高于~(18)F-FDG，显像清晰，进一步证实了它的临床诊断价值。
另一个L-酪氨酸的类似物6-[~(18)F]氟代-L-多巴(6-FDOPA)在诊断帕金森病(Parkinson's disease，PD)中起着重要的作用。PD是中、老年人较为常见的进行性神经系统退变性疾病，严重危害着患者的健康和生活质量。用6-FDOPA可以无创地诊断及鉴别PD。我们首先合成了芳烃的三甲基铵盐作为不对称合成6-FDOPA的反应前体，经亲核取代法引入氟，通过手性烷基化试剂实现立体定向合成，整个反应过程需
Positron emission tomography (PET) , which is an important tool for the clinical detection of tumors, has been widely employed all over the world. There are many kinds of PET imaging agents. The most commonly used one is ~(18)F-FDG, which has been used in oncology for the differentiation of benign from malignant lesions, the detection and staging of malignancy, and the follow-up of therapeutic responses. However, several recent studies have demonstrated diagnostic limitations of ~(18)F-FDG-PET such as its low specificity, no uptake in some tumor cells and appreciable uptake in inflammatory lesion. Furthermore, for brain tumor imaging, contrast between tumor tissue and normal brain is often low owing to the high glucose utilization of normal grey matter. Therefore designing and synthesizing specific and sensitive tumor imaging agents would be an important research field.
The metabolism of protein will increase in cancer cells, so radiolabelled amino acids constitute another class of metabolic imaging agents which have higher specificity for differentiating inflammatory lesions from tumors, lower uptake in normal tissues, clearer images of brain tumors than those of ~(18)F-FDG. ~(18)F-FET is a synthetic analogue of L-tyrosine that is not metabolized in cells and does not incorporate into proteins. The increased amino acid transport into malignant cells reflects the increasing amino acid requirement in tissues. ~(18)F-FET can be synthesized easily with relatively high radiochemical yield and has been put into clinical trial in several isolated cases, but so far there has been no such clinical report in China. We have synthesized ~(18)F-FET with radiochemical purity of 95% which remained stable for 6 hours. A series of experiments have been carried out to seek for the optimal reaction conditions. Preclinical studies including sterility, endotoxin and toxicity tests were performed and the results accorded with the standards of Chinese Pharmacopoeia. Several brain tumor cases were studied using F-FET-PET and compared with ~(18)F-FDG-PET. The results demonstrated that the uptake of ~(18)F-FET in the normal brain tissues was significantly lower than that of the tumor, and the images of the brain tumor were clearer than those of ~(18)F-FDG. So, it appears to be a very promising agent for the diagnosis of tumors.
Another analogue of L-tyrosine is 6-[~(18)F]fluoro-L-dopa which plays an important role in diagnosing Pakinson's disease. It is well known that Pakinson's disease is a progressive degenerative disease of nervous system which usually affects middle-aged and elderly
引文
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