本文選題：細(xì)胞凋亡 + 細(xì)胞死亡　； 參考：《天津大學(xué)》2014年博士論文

【摘要】：位于動(dòng)物細(xì)胞內(nèi)膜的磷脂酰乙醇胺（phosphatidylethanolamine, PE）是一個(gè)新的細(xì)胞死亡顯像劑分子結(jié)合位點(diǎn)，耐久霉素(duramycin)可以選擇性與磷脂酰乙醇胺結(jié)合。本實(shí)驗(yàn)通過(guò)制備中間體4-nitrophenyl2-[18F]fluoropropionate ([18F]NFP)，并將其與耐久霉素反應(yīng)得到N-(2-18F-Fluoropropionyl)duramycin([18F]FPDuramycin)，[18F]FPDuramycin的放化標(biāo)記過(guò)程需120分鐘，放化收率為10±5.0%(n=10,衰減矯正)，相對(duì)比活度為23.7±13.7GBq/μmol (n=8)。體外細(xì)胞結(jié)合實(shí)驗(yàn)研究表明，相較于腫瘤活細(xì)胞，[18F]FPDuramycin與由anti-Fas抗體誘發(fā)的凋亡腫瘤細(xì)胞的結(jié)合力明顯增加了；與由反復(fù)凍融誘發(fā)的壞死腫瘤細(xì)胞的結(jié)合實(shí)驗(yàn)中，[18F]FPDuramycin表現(xiàn)出較腫瘤活細(xì)胞三倍的結(jié)合力。生物分布的實(shí)驗(yàn)中，[18F]FPDuramycin表現(xiàn)出了高血漿和腎臟清除率，經(jīng)尾靜脈注射后120分鐘測(cè)定，其主要蓄積在肝臟和脾臟中。小動(dòng)物PET顯像實(shí)驗(yàn)表明，[18F]FPDuramycin可成功檢測(cè)到動(dòng)物體內(nèi)腫瘤治療引起的細(xì)胞凋亡過(guò)程。總之，[18F]FPDuramycin是一種潛在的PET顯像劑，可用于活體檢測(cè)化療引起的腫瘤細(xì)胞死亡。此外，實(shí)驗(yàn)還設(shè)計(jì)合成了已報(bào)道的小分子細(xì)胞凋亡顯像劑ML-10的類似物[18F]ML-8，和雙靶向分子[18F]-DFESB，目前已完成這兩種小分子PET顯像劑的放化標(biāo)記和生物評(píng)估實(shí)驗(yàn)。 本實(shí)驗(yàn)組早前報(bào)道腫瘤顯像劑N-(2-[18F]fluoropropionyl)-L-methionine([18F]FPMET)可選擇性地蓄積在腫瘤組織中，然而，由于[18F]FPMET的藥代動(dòng)力學(xué)不甚理想，將其轉(zhuǎn)化為臨床示蹤劑的實(shí)驗(yàn)較難進(jìn)行。因此本實(shí)驗(yàn)又設(shè)計(jì)出更加合理的腫瘤顯像劑—N-端用[18F]和[11C]標(biāo)記的谷氨酸類似物顯像劑[18F]FPGLU，[18F]FPGLU放化標(biāo)記過(guò)程需130分鐘，放化收率為30±10%(n=10,衰減矯正)，相對(duì)比活度為40±25GBq/μmol (n=10)。體外細(xì)胞實(shí)驗(yàn)結(jié)果表明，[18F]FPGLU主要通過(guò)XAG 系統(tǒng)轉(zhuǎn)運(yùn)，并且未參與蛋白質(zhì)合成過(guò)程，穩(wěn)定性試驗(yàn)表明，[18F]FPGLU在尿液、腫瘤組織和血漿中均穩(wěn)定，并且在將[18F]FPGLU用于動(dòng)物模型PET顯像研究中，，可獲得較高的腫瘤肌肉比值。此外，還完成了腫瘤顯像劑[18F]FPWAVGHLM和[18F]FPArg的初步生物學(xué)評(píng)價(jià)研究。 此外，本論文還介紹了可用于體外無(wú)創(chuàng)檢測(cè)乳腺癌的PET顯像劑[18F]FES前體—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 鹵5.0%. The decay correction was achieved. The relative specific activity was 23.7 鹵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 鹵10GBq / 10, attenuation correction was achieved, and the relative specific activity was 40 鹵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.
【學(xué)位授予單位】：天津大學(xué)
【學(xué)位級(jí)別】：博士
【學(xué)位授予年份】：2014
【分類號(hào)】：R817;R730.44

【參考文獻(xiàn)】

相關(guān)期刊論文 前1條

1 胡孔珍;王紅亮;唐剛?cè)A;;~(18)F標(biāo)記多肽方法研究進(jìn)展[J];同位素;2012年04期

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