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標題: | 設計與合成具潛力用於正子斷層掃描的腫瘤造影劑 Design and Synthesis of Potential Tumor Imaging Agents for Positron Emission Tomography |
作者: | Pi-Hung Kao 高碧鴻 |
指導教授: | 忻凌偉 |
關鍵字: | 正子斷層掃描,氟化胺基蒽,醌,類抗腫瘤化合物, Positron emission tomography,Fluoroaminoanthraquinone, |
出版年 : | 2007 |
學位: | 碩士 |
摘要: | 正子斷層掃描是近年來在醫藥研究領域,發展出來的新興非侵入性造影技術,目前已被應用於癌症的診斷、基因治療情形的監控、心肌功能的評估以及生物體內酵素、接受器和轉運體的定位及造影等;而且正子斷層掃描在藥物的開發及研究方面,也扮演相當重要的角色。由於先前一系列比mitoxantrone(MX)和ametantrone(AT)有更高抗癌活性的蒽醌類抗癌藥物已被製備出來,因此,本研究的目的為結合製備這些蒽醌類抗癌藥物的觀念,以及正子斷層掃描的技術,設計與合成一系列新穎的氟化胺基蒽醌類抗腫瘤化合物,做為正子斷層掃描測量腫瘤細胞增生的腫瘤造影劑。
放射氟十八標記的去氧葡萄糖目前已被廣泛使用於正子斷層掃描的腫瘤造影,但因為正常細胞也會攝取利用葡萄糖,造成氟十八去氧葡萄糖的專一性不佳。因此,設計與合成放射性標記胸腺嘧啶類的衍生物,就能克服這個問題;且因為氟十八胸腺嘧啶在生物體內不會被分解,但會代謝滯留在增生的細胞內,所以此為目前最有潛力的放射造影試劑。並且,可供放射標記成氟十八胸腺嘧啶的前導物1也成功地被合成出來,且經過一次再結晶後,其純度和市面販售但價格昂貴的前趨產品不相上下。而藉由和台大醫院核醫部技術合作,氟十八胸腺嘧啶已成功地被製備,並且在狗及人的正子斷層掃描實驗中,都獲得相當良好的造影效果。 接著,將氟基接上MX和AT骨架而合成的無放射活性氟化胺基蒽醌類’’冷化合物’’被合成出來後(化合物2-1 ~ 5-3),再從中挑選出較具藥理活性者,將來改以放射標記製備成’’熱化合物’’ ,即可做為正子斷層掃描的腫瘤造影試劑。一邊保留MX和AT的-[(2-胺乙基)胺基]或-[(2-羥乙基)乙二胺基]支鏈、另一邊則為氟基接合不同碳數支鏈的氟化胺基蒽醌類化合物已被合成出來,並可藉此來評估氟基和胺基不同的位置和距離,對生物活性可能會造成的影響。最後,參考文獻利用測定DNA的熔化溫度,來探討這些合成的蒽醌類抗癌化合物之抗癌機轉,及其和DNA雙股螺旋間的作用關係,即可以此做為後續藥理活性篩選的初步評估。 Positron emission tomography (PET) is a newly developed noninvasive imaging technique and is now regularly used in the diagnosis and staging of cancer, monitoring gene therapy, assessment of myocardium function and mapping for enzyme, receptor and transporter. Additionally, PET also plays an important role in the drug discovery and development. In our laboratory, previously, many anthraquinones that have better anti-tumor activity than mitoxantrone (MX) and ametantrone (AT) have been synthesized. The aim of this study is to combine the concept of anthraquinone synthesis and the PET technique to design and synthesize novel antitumor imaging agents that can be employed to measure tissue and tumor proliferation with PET. [18F]Fluorodeoxyglucose ([18F]FDG) is widely used for tumor imaging with PET, but it is not specific because other normal cells can also utilize glucose. Thus, radiolabeled thymidine derivatives have been developed to overcome the limitations of [18F]FDG. One of their analogs, [18F]fluorine-labeled thymidine (3’-deoxy-3’- fluorothymidine, [18F]FLT) appears to be the most promising radiopharmaceutical because of the lack of in vivo degradation and metabolic trapping in proliferating cells. Precursor 1 for synthesizing [18F]FLT had been synthesied in our lab. After purified by recrystallization, the purity of the precursor 1 was comparable with that of the commercial product. Through the cooperation with the department of Nuclear Medicine of National Taiwan University Hospital, we have prepared [18F]FLT successfully with our precursor 1 and the image quality for PET in humans and dogs was good. Fluoroaminoanthraquinones with fluorine attached to MX and AT backbones have been synthesized as “cold compounds” (compounds 2-1 ~ 5-3). Among them, more potent compounds will be choosed for radiolabeling as “hot compounds” for PET tumor imaging. First, the compounds with one -[(aminoethyl)amino] or -[(2-hydroxyethyl)ethylenediamino] side chain of MX and AT and the other one side chain of fluorine-substituted alkyl groups with different carbon numbers have been synthesized. Then the different positions and chain lengths between fluorine and the amine group may influence the pharmacological activities of these fluoroaminoanthraquinones. And these can be used as the authentic samples for identifying the 18F-labeled compounds in the future. Finally, we utilized the DNA melting temperature (△Tm) measurement technique to provide information about the interaction of the synthetic anthraquinones with the DNA double helix; these can be the initial pharmacological evaluation for our synthetic compounds in the future. |
URI: | http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/28934 |
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