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標題: | 開發新穎腦部正子斷層掃描造影組蛋白去乙醯化酶放射性追蹤劑 Novel Histone Deacetylase Radiotracers for Brain PET Imaging |
作者: | Yen-Ting Chi 吉彥婷 |
指導教授: | 忻凌偉(Ling-Wei Hsin) |
關鍵字: | 正子斷層掃描造影,組蛋白去乙醯化?,放射性追蹤劑,腦部, Histone Deacetylase,Radiotracer,Brain PET Imaging, |
出版年 : | 2017 |
學位: | 碩士 |
摘要: | 生物體內的酵素共同調節染色質組蛋白的乙醯化程度,在細胞增生與分化的表觀遺傳調控上扮演了重要的角色。現今,許多科學家專注於研究組織蛋白去乙醯化酶(HDACs),因其影響許多重要細胞的功能,導致如癌症、神經系統退化、記憶認知障礙、藥物成癮、憂鬱症等疾病。然而,對於這些人類疾病中正常組織蛋白去乙醯化酶的密度及活性的轉變過程卻仍不完全明確,且缺乏非侵入性的方式用以追蹤生物活體投以藥物後的組織蛋白去乙醯酶作用的分布情形。因此,使用正子斷層掃描造影技術,不僅是一種非侵入性的醫學影像檢查,更能成為一套有用的工具,用以即時監測染色質調控酵素在動物或人體內的作用情形。
我們的目標為合成出多種苯甲醯胺結構之衍生物,發展組織蛋白去乙醯化酶抑制劑之前驅物合成標幟方法,從中篩選出最佳候選診斷藥物並開發成能進入腦部的正子斷層掃描造影組織蛋白去乙醯化酶放射性追蹤劑,藉由其放射性同位素特性標幟作用,從影像資訊中進一步探究其參與表觀遺傳調控及致病的機制,以及了解藥物治療效果,成為協助治療疾病的利器。 根據許多先進們在醫藥化學上的貢獻,我們參考已報導使用在能進入神經系統引起藥效的組織蛋白去乙醯化酶抑制劑藥物的化學結構,作其化學結構上的修飾,合成出具有類似的藥理活性結構,進而設計化合物10, 12系列衍生物含有多碳鏈氟的基團、化合物7系列衍生物含有金剛烷胺基團,提高化學分子能進入血腦障壁的機會。在候選的藥物設計、結構修飾的過程中,我們希望能先經由體外的化合物對組織蛋白去乙醯化酶藥理活性測試試驗以及其達抑制酵素50%活性的濃度試驗中選擇先導化合物,未來的其他目標亦會著重於為進行化合物的放射性同位素標幟作用,如:碳-11及氟-18。 Regulating histone acetylation in vivo is an integral aspect of chromatin modulation which plays a critical role in cell proliferation and differentiation. To date, much attention to this regard has been paid to the histone deacetylase (HDAC) family of enzymes correlated with several forms of cancer and impact on CNS functions such as neuronal differentiation, memory formation, drug addiction and depression. However, our knowledge of normal HDACs density and alterations in HDACs with human disease remains limited and invasive methodologies used to investigate HDACs distribution are not compatible with translational medicine. Therefore, the non-invasive imaging technique, positron emission tomography (PET), is a valuable tool to visualize chromatin-modifying enzymes in animals and human. Our goal is to develop a PET imaging probe of novel HDAC inhibitors from the benzoylamide and ortho-aminoanilide chemical classes which can evaluate the expression and distribution of these epigenetic enzymes will improve our understanding of their relationship with disease and would provide an opportunity to intervene with treatment. In medicinal chemistry efforts by others, mimicking the structures have been reported as the potent HDAC inhibitors or a chemical moiety frequently used developing in CNS-penetrant compounds, we designed compound 10, 12 series containing a fluoroalkyl group and compound 7 series containing an adamantyl group as a ‘blood brain barrier (BBB) carrier’. Ex vivo prioritization of compounds should be achieved using a validated functional recombinant HDAC assay and IC50 values for candidate molecules to elucidate how structural modifications impact target HDAC subtypes engagement. Furthermore, another object of the invention is to label lead compounds with radionuclides, such as Carbon-11 and Fluorine-18. |
URI: | http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/20978 |
DOI: | 10.6342/NTU201700505 |
全文授權: | 未授權 |
顯示於系所單位: | 藥學系 |
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