多种细胞死亡和肿瘤显像剂的PET显像研究

发布时间：2018-06-10 16:34

本文选题：细胞凋亡 + 细胞死亡　；参考：《天津大学》2014年博士论文

【摘要】：位于动物细胞内膜的磷脂酰乙醇胺（phosphatidylethanolamine, PE）是一个新的细胞死亡显像剂分子结合位点，耐久霉素(duramycin)可以选择性与磷脂酰乙醇胺结合。本实验通过制备中间体4-nitrophenyl2-[18F]fluoropropionate ([18F]NFP)，并将其与耐久霉素反应得到N-(2-18F-Fluoropropionyl)duramycin([18F]FPDuramycin)，[18F]FPDuramycin的放化标记过程需120分钟，放化收率为10±5.0%(n=10,衰减矫正)，相对比活度为23.7±13.7GBq/μmol (n=8)。体外细胞结合实验研究表明，相较于肿瘤活细胞，[18F]FPDuramycin与由anti-Fas抗体诱发的凋亡肿瘤细胞的结合力明显增加了；与由反复冻融诱发的坏死肿瘤细胞的结合实验中，[18F]FPDuramycin表现出较肿瘤活细胞三倍的结合力。生物分布的实验中，[18F]FPDuramycin表现出了高血浆和肾脏清除率，经尾静脉注射后120分钟测定，其主要蓄积在肝脏和脾脏中。小动物PET显像实验表明，[18F]FPDuramycin可成功检测到动物体内肿瘤治疗引起的细胞凋亡过程。总之，[18F]FPDuramycin是一种潜在的PET显像剂，可用于活体检测化疗引起的肿瘤细胞死亡。此外，实验还设计合成了已报道的小分子细胞凋亡显像剂ML-10的类似物[18F]ML-8，和双靶向分子[18F]-DFESB，目前已完成这两种小分子PET显像剂的放化标记和生物评估实验。本实验组早前报道肿瘤显像剂N-(2-[18F]fluoropropionyl)-L-methionine([18F]FPMET)可选择性地蓄积在肿瘤组织中，然而，由于[18F]FPMET的药代动力学不甚理想，将其转化为临床示踪剂的实验较难进行。因此本实验又设计出更加合理的肿瘤显像剂—N-端用[18F]和[11C]标记的谷氨酸类似物显像剂[18F]FPGLU，[18F]FPGLU放化标记过程需130分钟，放化收率为30±10%(n=10,衰减矫正)，相对比活度为40±25GBq/μmol (n=10)。体外细胞实验结果表明，[18F]FPGLU主要通过XAG 系统转运，并且未参与蛋白质合成过程，稳定性试验表明，[18F]FPGLU在尿液、肿瘤组织和血浆中均稳定，并且在将[18F]FPGLU用于动物模型PET显像研究中，，可获得较高的肿瘤肌肉比值。此外，还完成了肿瘤显像剂[18F]FPWAVGHLM和[18F]FPArg的初步生物学评价研究。此外，本论文还介绍了可用于体外无创检测乳腺癌的PET显像剂[18F]FES前体—表雌三醇的合成研究。
[Abstract]:Phosphatidylethanolamine (PE), a novel molecular binding site of phosphatidylethanolamine, is located in the endomembrane of animal cells, and duramycin can selectively bind to phosphatidylethanolamine. In this experiment, the intermediate 4-nitrophenyl2- [18F] fluoropropionate ([18F] NFPU) was prepared and reacted with duramycin ([18F] FPDuramycinin ([18F] FPDuramycin, [18F] FPDuramycin). The radiochemical labeling process took 120 minutes. The radiochemical yield of 4-nitrophenyl2- [18F] fluoropropionate ([18F] NFPX) was 10 卤5.0%. The decay correction was achieved. The relative specific activity was 23.7 卤13.7q/ 渭 mol. In vitro cell binding assay showed that [18F] FPDuramycin significantly increased the binding power of [18F] FPDuramycin to apoptotic tumor cells induced by anti-FAS antibody. The binding ability of [18F] FPDuramycin to necrotic tumor cells induced by repeated freezing and thawing was three times as high as that of living tumor cells. In biodistribution experiments, [18F] FPDuramycin showed high plasma and renal clearance rates, which were measured 120 minutes after caudal vein injection and were mainly accumulated in liver and spleen. Small animal PET imaging showed that [18 F] FPDuramycin could successfully detect apoptosis induced by tumor therapy in vivo. In conclusion, [18 F] FPDuramycin is a potential PET imaging agent for in vivo detection of chemotherapy-induced tumor cell death. In addition, We also designed and synthesized the reported [18F] ML-8, a small molecular apoptosis imaging agent ML-10, and a double target molecule [18F] -DFESB.At present, we have completed the radiochemical labeling and bioevaluation experiments of these two small molecular PET imaging agents. N-F- [18F] fluoropropionyl-L-methionine ([18F] FPMET) can selectively accumulate in tumor tissue, However, because the pharmacokinetics of [18F] FPMET is not ideal, it is difficult to transform it into a clinical tracer. Therefore, a more reasonable tumor imaging agent-N- terminal [18F] and [11C] labeled FPGLU [18F] FPGLU was designed. The radiochemical labeling process of [18F] FPGLU took 130min, the radiochemical yield was 30 卤10GBq / 10, attenuation correction was achieved, and the relative specific activity was 40 卤25GBq / 渭 mol. The results of cell experiments in vitro showed that [18F] FPGLU was mainly transported through XAG system and was not involved in protein synthesis. The stability test showed that [18F] FPGLU was stable in urine, tumor tissue and plasma, and [18F] FPGLU was used in PET imaging of animal model. A higher ratio of tumor muscle can be obtained. In addition, the preliminary biological evaluation studies of tumor imaging agents [18F] FPWAVGHLM and [18F] FPArg were completed. In addition, the synthesis of [18F] FES precursor, a precursor of [18F] FES, and [18F] FPArg, which could be used for noninvasive detection of breast cancer in vitro, was also introduced.
【学位授予单位】：天津大学
【学位级别】：博士
【学位授予年份】：2014
【分类号】：R817;R730.44

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