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完整後設資料紀錄
DC 欄位 | 值 | 語言 |
---|---|---|
dc.contributor.advisor | 忻凌偉(Ling-Wei Hsin) | |
dc.contributor.author | Hsin-Yi Shen | en |
dc.contributor.author | 沈欣毅 | zh_TW |
dc.date.accessioned | 2021-06-16T08:36:14Z | - |
dc.date.available | 2019-02-25 | |
dc.date.copyright | 2014-02-25 | |
dc.date.issued | 2013 | |
dc.date.submitted | 2013-11-11 | |
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dc.identifier.uri | http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/58877 | - |
dc.description.abstract | N,N-Dimethyl-2-(arylthio)benzylamines被報導對血清素轉運體具有高度的結合力與選擇性,其中較具潛力的有[11C]MADAM和[18F]5-FADAM,並利用它們作為先導化合物,以氟18聚乙二醇側鏈在B環4’位置做修飾,合成MADAM衍生物7、14與18與其氟-18標定前驅物26-28,5-FADAM衍生物45與46。另外也合成已知化合物43與44當作比較。
使用2-amino-5-methoxybenzoic acid為起始物,經過diazotization轉換成thiol group並個別與1-bromo-4-methyl-2-nitrobenzene、1-bromo-2-nitrobenzene與1-bromo-4-fluoro-2-nitrobenzene進行SNAr反應,並經過二甲胺置換羧酸與去甲基得到關鍵中間體3、33與34。關鍵中間體經過氧-烷化、醇-氟基置換及還原反應得到標準品7、14、18與43-46。氟-18標定前驅物26-28由關鍵中間體3經氧-烷化、還原反應與甲磺醯化反應而得。另外利用SnCl2還原硝基而意外得到的化合物8與18,藥理實驗還在進行中。 化合物7、14和18在分布係數評估中,隨著聚乙二醇長度增加,其Log D減少,水溶性增加。藥理實驗中,7、14和18隨著聚乙二醇長度增加,其結合力並無顯著下降,Ki分別為0.25、0.5和1.32 nM。而氟18標定化合物18F-7、18F-14和18F-18中,只有18F-7和18F-14在大鼠腦內有高度吸收,但此兩個化合物清除率慢,且SERT特異性結合尚需進一步確認。 已知化合物43與44與[18F]5-FADAM衍生物45與46,其Log D值為3.37、3.30、3.70、3.63。綜合比較Log D值,A環五位置取代其脂溶性由大到小分別是氟取代、甲基取代和無取代,而當聚乙二醇越長時其Log D越小,極性越大。已知化合物43和44與具潛力化合物45與46之藥理評估還在進行中。 | zh_TW |
dc.description.abstract | N, N-Dimethyl-2-(arylthio)benzylamines were reported to have high affinity and selectivity toward SERT. Choosing the promising [11C]MADAM and [18F]5-FADAM as lead compound, we designed and synthesis of the B ring on 4’ position by adding several PEG unit to afford [11C]MADAM derivatives 7, 14, 18 and their F-18 labeled precursor 26-28, and [18F]5-FADAM derivatives 45, 46. In addition, we also prepared known compound 43 and 44 for comparison.
Using 2-amino-5-methoxybenzoic acid as the starting material and then go through diazotization into thiol group. The thiol group individually reacts with 1-bromo-4-methyl-2-nitrobenzene, 1-bromo-2-nitrobenzene and 1-bromo-4-fluoro -2-nitrobenzene for SNAr reaction and then through displacement of carboxylic acid and demethylation to afford key intermediate 3, 33 and 34. The key intermediate undergo SN2, conversion from alcohols to the alkyl fluorides, and reduction to afford 7、14、18 and 43-46 and also using key intermediate to prepare F-18 labeled precursor 26-28 by SN2 reaction, reduction and mesylation. The in vitro binding assay are in progress. As 7, 14, 18 PEG substitution chain length increase, Log D value were reduced and accompanied by increased water solubility. In vitro binding assay of compound 7, 14, 18, the longer the PEG, the decreasing affinity toward SERT will happen. The Ki value are 0.25、0.5 and 1.32 nM, respectively. From the the rat biodistribution evaluation of 18F-7, 18F-14 and 18F-18, only 18F-7 and 18F-14 showed high brain uptake but showed slow washed out rate. Furthermore, it is necessary to confirm that 18F-7, 18F-14 and 18F-18 are specific binding toward SERT in vivo. The Log D of known compound 43, 44 and the [18F]5-FADAM derivatives 45, 46 are 3.37、3.30、3.70、3.63 respectively. Comprehensive comparison of the Log D value can conclude: (1) the increasing hydrophilicity on 5 position substitution is fluorine-substituted, methyl substituted, unsubstituted and (2) the longer the PEG side chain substitution on 4’ position, the more the hydrophilicity will be. The known compound 43, 44 and our potential SERT ligand 45, 46 in vitro assay are in progress. | en |
dc.description.provenance | Made available in DSpace on 2021-06-16T08:36:14Z (GMT). No. of bitstreams: 1 ntu-102-R00423022-1.pdf: 6442123 bytes, checksum: 0c3776f5ef936f3edf6a264e71a9dc02 (MD5) Previous issue date: 2013 | en |
dc.description.tableofcontents | 致謝 I
摘要 II Abstract III 英文縮寫表 V 圖目錄 IX 表目錄 X 路徑目錄 XI 1. 緒論 1 1.1 血清素轉運體之正子斷層掃描示蹤劑 1 1.2 正子斷層掃描 2 1.3 血清素轉運體造影劑之發展 4 1.4 氟化聚乙二醇 (fluorinated polyethylene glycol, FPEG) 特性與AV-45藥物開發 6 1.5 研究動機與目的 7 2. 結果與討論 9 2.1 逆合成分析 9 2.2 第一階段關鍵中間體3的合成 10 2.3 目標化合物7之合成 12 2.4 目標化合物14之合成 14 2.5 目標化合物18之合成 16 2.6 意外分離之化合物8與19之合成分析與SAR探討 18 2.7 製備氟-18標定之前驅物26-28 19 2.8 第二階段目標化合物設計與合成 21 3. 分佈係數探討與生物活性評估 24 3.1 分佈係數 (log D) 探討 24 3.2 Binding affinity 26 3.3 In vivo biodistribution 27 4. 結論 29 5. 實驗 30 5.1 實驗藥品及溶劑來源 30 5.2 自製無水溶劑 33 5.3 一般儀器與方法 33 5.4 藉由HPLC確認化合物純度測定 34 5.5 Log D determination method 35 5.6 合成步驟與數據分析 38 參考文獻 85 附圖目錄 93 附表目錄 93 圖譜目錄 93 圖目錄 圖 一、血清素轉運體於神經細胞突觸上回收血清素之情形3 1 圖 二、正子斷層掃描原理10 2 圖 三、Isoquinoline、Tropane、Quipazines 類血清素轉運體代表化合物 5 圖 四、[11C]MADAM結構與編碼和5-FADAM結構 5 圖 五、AV-45之發展 6 圖 六、本研究設計之標準品血清素轉運體示蹤劑與其18F-標定前驅物 7 圖 七、已發表之血清素轉運體示蹤劑標準品43與44與5-FADAM衍生物45與46 8 圖 八、Nitroindazole為起始物還原得到aminoindazole與意外得到之氯化產物aminoindazole 18 圖 九、Aminoindazole為起始物無法得到氯化產物 19 圖 十、親電子氯化反應之可能機制 19 圖 十一、MADAM與其相關衍生物之SAR比較 19 圖 十二、第二階段目標化合物合成 21 圖 十三、第一階段與第二階段目標化合物 24 圖 十四、氟-18標定化合物18F-7、18F-14和18F-18 27 圖 十五、18F-7在腦部之SUV和SUR (左圖為18F-7在腦部之SUV、右圖為18F-7在腦部之SUR) 28 圖 十六、18F-14在腦部之SUV和SUR (左圖為18F-14在腦部之SUV、右圖為18F-14在腦部之SUR) 28 圖 十七、18F-18在腦部之SUV和SUR (左圖為18F-18在腦部之SUV、右圖為18F-18在腦部之SUR) 28 表目錄 表 一、常見用於正子斷層掃描的核種 3 表 二、ChemDrawR Ultra 10.0之Log P計算值與實驗之Log D值 25 表 三、第一階段目標化合物與已知化合物Ki value 26 表 四、Conditions of RP HPLC 35 路徑目錄 路徑 一、第一階段目標化合物之逆合成分析 10 路徑 二、合成diphenyl sulfides骨架1 11 路徑 三、轉換羧酸得到醯胺中間體 11 路徑 四、去甲基得到第一階段關鍵中間體3 12 路徑 五、利用關鍵中間體與側鏈進行氧-烷化反應得到中間體4 12 路徑 六、還原醯胺得到中間體6 12 路徑 七、目標化合物7之合成與意外得到之化合物8 13 路徑 八、利用BH3-THF分別以一鍋化或分批還原得到化合物7 14 路徑 九、氟取代之二聚乙二醇合成 14 路徑 十、利用關鍵中間體與側鏈進行氧-烷化反應得到中間體11 15 路徑 十一、側鏈之醇基團轉換成氟取代的方法得到化合物12 15 路徑 十二、利用化合物12經BH3-THF還原得到目標化合物14 16 路徑 十三、利用DAST轉換醇基團至氟取代側鏈9 16 路徑 十四、利用關鍵中間體與氟化側鏈進行氧-烷化反應得到中間體16 17 路徑 十五、利用BH3-THF還原醯胺得到化合物17 17 路徑 十六、目標化合物18之合成與意外得到之產物19 17 路徑 十七、試圖溴化目標化合物7 18 路徑 十八、氟-18標定之逆合成分析 20 路徑 十九、利用關鍵中間體與三種側鏈進行烷-氧反應得到21、11和22 20 路徑 二十、利用BH3-THF還原醯胺得到中間體23-25 20 路徑 二十一、甲磺醯化反應得到氟-18標定之前驅物26-28 21 路徑 二十二、第二部分之關鍵中間體合成33、34 22 路徑 二十三、目標化合物合成43-46 23 | |
dc.language.iso | zh-TW | |
dc.title | 合成並評估新穎血清素轉運體配體做為正子斷層掃描示蹤劑 | zh_TW |
dc.title | Synthesis and evaluation of novel serotonin transporter ligands as potential positron emission tomography imaging agents | en |
dc.type | Thesis | |
dc.date.schoolyear | 102-1 | |
dc.description.degree | 碩士 | |
dc.contributor.oralexamcommittee | 陳基旺(Ji-Wang Chern),孔繁璐(Fan-Lu Kung),王光昭(Kuang-Chao Wang) | |
dc.subject.keyword | 血清素轉運體配體, | zh_TW |
dc.subject.keyword | serotonin transporter ligands, | en |
dc.relation.page | 148 | |
dc.rights.note | 有償授權 | |
dc.date.accepted | 2013-11-11 | |
dc.contributor.author-college | 醫學院 | zh_TW |
dc.contributor.author-dept | 藥學研究所 | zh_TW |
顯示於系所單位: | 藥學系 |
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