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完整後設資料紀錄
DC 欄位 | 值 | 語言 |
---|---|---|
dc.contributor.advisor | 忻凌偉 | |
dc.contributor.author | Pin-Sen Lien | en |
dc.contributor.author | 連品森 | zh_TW |
dc.date.accessioned | 2021-06-16T17:29:15Z | - |
dc.date.available | 2022-12-31 | |
dc.date.copyright | 2012-09-19 | |
dc.date.issued | 2012 | |
dc.date.submitted | 2012-08-16 | |
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dc.identifier.uri | http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/64082 | - |
dc.description.abstract | 第一部分:
為了開發用於多巴胺轉運體 (dopamine transporter) 正子斷層造影 (positron emission tomography, PET) 之影像劑 (imaging agent),LTC1000被設計且合成,在經過生物活性的測試,發現LTC1000具有高度選擇性 (SERT/DAT = 311) 及適當的脂溶性 (logP = 3.41),LTC1000被認為是具有潛力能開發為多巴胺轉運體正子斷層造影的影像劑,目前大部分正子藥物的應用皆受限於放射性同位素的半衰期過短影響而造成合成及分析上的困難。在本研究中以微波輔助加熱的方式進行Mannich反應快速製備化合物3-{4-[2-(benzhydryloxy)ethyl]piperazin-1-yl}-1- phenylpropan- 1-one (2),並利用高效能液相層析儀 (high performance liquid chromatography, HPLC) 和液相層析質譜儀 (liquid chromatography-mass spectrometry, LC-MS) 監測反應。相較原文獻合成方法,此方法的建立大幅提高了合成的效率,最佳化後的反應條件是具有潛力應用於開發正子斷層造影影像劑的方法。 第二部份: 一系列氮取代以8-phenyl-1,2,3,4-tetrahydroisoquinoline為架構的衍生物已經被設計與合成;經過5-HT2A與5-HT7受體親合力的評估,此類化合物對於5-HT2A受體不具顯著的親和力 (no significant response),但對5-HT7受體顯示了高度的選擇性 (selectivity)。消旋化合物20對於5-HT7受體顯示高度的親和力 (Ki = 7.41 nM),為了探討化合物20與5-HT7受體的結合模式,單一鏡像異構物已經被合成且生物活性已在評估中。在側鏈具有羰基修飾的衍生物中,側鏈2號碳上的酯類官能基若為極性較小的甲基酯和乙基酯取代衍生物23與27則具有較佳的5-HT7受體親和力 (23, Ki = 6.53 nM; 27, Ki = 8.64 nM)。一系列具有氟取代長碳鏈的衍生物32-34以及胺基取代衍生物24-25已經被合成,且生物活性已在評估中。 | zh_TW |
dc.description.abstract | Part 1:
To develop novel positron emission tomography (PET) imaging agents for dopamine transporter (DAT). LTC1000 was designed and synthesized with high selectivity (SERT/DAT = 192) and suitable lipophilicity (logP = 3.41). The utilities of most traditional organic synthetic method for the preparation of 18F-labeled PET imaging agents are limited due to the very short half-life of 18F. In this study, 3-{4-[2-(benzhydryloxy)ethyl]piperazin-1-yl}-1-phenylpropan-1-one (2) was rapidly prepared by microwave-assisted Mannich reaction. The progress of reaction was monitored by HPLC and LC-MS and this method is more efficient than previous methods. The optimized reaction condition has potential to be used for the preparation of 18F-labeled PET imaging agents. Part 2: A series of N-substituted 8-phenyl-1,2,3,4-tetrahydroisoquinoline derivatives was synthesized and evaluated for their 5-HT2A and 5-HT7 receptor binding affinity. All of these compounds had no significant binding to 5-HT2A receptor and moderate to high binding affinity for 5-HT7 receptor. In the series, the racemic 2-(3-hydroxy-3- phenylpropyl)-6-methoxy-8-(2-methoxyphenyl)-1,2,3,4-tetrahydroisoquinolin-7-ol (20), displayed the highest binding affinity (Ki = 7.41 nM) for 5-HT7 receptor. To investigate the enantioselectivity of 5-HT7 receptor binding, R and S enantiomers of 20 were synthesized and their binding affinity is currently under evaluation. Hydrophobic group-substituted esters 23 and 27 showed high affinity (23, Ki = 6.53 nM, 27, Ki = 8.64 nM) for 5-HT7 receptor than corresponding hydrophilic group-substituted ester. The fluoro-substituted derivatives 32-34 and enantiomeric amino-substituted derivatives 24-25 were synthesized and their binding affinity is currently under evaluation. | en |
dc.description.provenance | Made available in DSpace on 2021-06-16T17:29:15Z (GMT). No. of bitstreams: 1 ntu-101-R99423019-1.pdf: 5280640 bytes, checksum: 18080990c1819e96d1cf1de596e6520a (MD5) Previous issue date: 2012 | en |
dc.description.tableofcontents | 口試委員會審定書 I
致謝 II 中文摘要 III Abstract V 總目錄 VII 圖目錄 IX 表目錄 X 路徑目錄 XI 英文縮寫表 XII 第一部分 1 第一章、緒論 2 1.1 多巴胺轉運體 2 1.2 正子斷層造影 3 1.3 先前GBR12935系列化合物作為多巴胺轉運體抑制劑之研究 4 1.4 研究動機與目的 5 第二章、結果與討論 6 2.1 化合物2的合成方法比較 6 2.2 微波反應條件之最佳化 7 2.3 化合物2的還原反應之研究 11 2.4 HPLC與LC-MS分析方法的建立 12 第三章、結論 16 第二部分 17 第一章、緒論 18 1.1 血清素之研究 18 1.2 血清素受體 20 1.3 本實驗室對於8-phenyl-1,2,3,4-tetrahydroisoquinoline之研究 22 1.4 研究動機與目的 25 第二章、結果與討論 27 2.1 2, 8號位上具有取代基修飾異喹啉類化合物之逆合成分析 27 2.2 化合物A的合成之研究 28 2.3 異喹啉類化合物烷基化合成之研究 29 2.4 溴化異喹啉類化合物合成之研究 35 2.5 Suzuki偶合異喹啉類化合物合成之研究 36 2.6 利用關鍵中間體快速製備目標化合物 37 2.7 酸基取代側鏈異喹啉類化合物合成之研究 38 2.8 化合物 (R)-20與 (S)-20合成與分析之研究 39 2.9 具長碳鏈修飾的異喹啉類化合物合成之研究 50 2.10 生物活性 53 第三章、結論 55 實驗部分 56 一、實驗藥品及溶劑來源 56 二、一般儀器與方法 59 三、合成步驟與數據分析 61 參考文獻 97 附圖目錄 104 附圖 106 | |
dc.language.iso | zh-TW | |
dc.title | "第一部分:微波輔助Mannich反應之研究
第二部分:氮取代8-苯基-1,2,3,4-四氫異喹啉衍生物之合成及生物活性評估" | zh_TW |
dc.title | Part I:Study of Microwave-assisted Mannich Reaction
Part II:Synthesis and Biological Activity of N-Substituted 8-Phenyl-1,2,3,4-tetrahydroisoquinolines | en |
dc.type | Thesis | |
dc.date.schoolyear | 100-2 | |
dc.description.degree | 碩士 | |
dc.contributor.oralexamcommittee | 王光昭,顧記華,梁碧惠 | |
dc.subject.keyword | 微波,Mannich反應,8-苯基-1,2,3,4-四氫異喹,啉,衍生物, | zh_TW |
dc.subject.keyword | Microwave,Mannich Reaction,8-Phenyl-1,2,3,4-tetrahydroisoquinolines, | en |
dc.relation.page | 131 | |
dc.rights.note | 有償授權 | |
dc.date.accepted | 2012-08-16 | |
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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