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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 | Yi-Jing Wang | en |
dc.contributor.author | 王怡菁 | zh_TW |
dc.date.accessioned | 2021-06-08T00:06:55Z | - |
dc.date.copyright | 2013-09-24 | |
dc.date.issued | 2013 | |
dc.date.submitted | 2013-08-12 | |
dc.identifier.citation | 1. Kang, K.; Park, S.; Kim, Y. S.; Lee, S.; Back, K. Biosynthesis and biotechnological production of serotonin derivatives. Appl. Microbiol. Biotechnol. 2009, 83, 27-34.
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Role of 5-HT7 receptors in the modulation of learning and memory. Neurobiologia. 2009, 72, 125-135. 8. Krobert, K. A.; Levy, F. O. The human 5-HT7 serotonin receptor splice variants: constitutive activity and inverse agonist effects. Br. J. Pharmacol. 2002, 135, 1563-1571. 9. Links, J. M.; Becker, L. C.; Rigo, P. Combined corrections for attenuation, depth-dependent blur and motion in cardiac SPECT: a multicancer trial. J. Nucl, Cardiol. 2000, 7, 414-425. 10. Ametamey, S. M.; Honer, M.; Schubiger, P. A. Molecular imaging with PET. Chem. Rev. 2008, 108, 1501-1516. 11. Pimlott, S. L.; Sutherland, A. Molecular tracers for the PET and SPECT imaging of disease. Chem. Soc. Rev. 2011, 40, 149-162. 12. Miller, P. W.; Long, N. J.; Vilar, R.; Gee, A. D. Synthesis of 11C, 18F, 15O, and 13N radiolabels for positron emission tomography. Angew. Chem. 2008, 47, 8998-9033. 13. Lisheng, C.; Shuiyu, L.; Pike, V. W. Chemistry with [18F] fluoride ion. Eur. J. Org. Chem. 2008, 2853–2873. 14. Adam, M. J.; Wilbur, D. S. Radiohalogens for imaging and therapy. Chem. Soc. Rev. 2005, 34, 153-163. 15. Chi, M. L.; Farde, L.; Using positron emission tomography to facilitate CNS drug development. Phar. Sci. 2006, 27, 310-316. 16. Lemoine, L.; Julien, A.; Bars, D. L.; Billard, T.; Zimmer, L. Comparison of 4 radiolabeled antagonists for serotonin 5-HT7 receptor neuroimaging: toward the first PET radiotracer. J. Nucl. Med. 2011, 52, 1811-1818. 17. Lasne, M.C.; Perrio, C.; Rouden, J.; Barre, L.; Roeda, D.; Dolle, F.; Crouzel, C. -emitting compounds based on fluorine-18. Top. Curr. Chem.2002,222,201-258. 18. Saari, W. S.; King, S. W. Synthesis and biological activity of some aporphine derivatives related to apomorphine. J. Med. Chem. 1974, 17, 1086-1090. 19. Henry, T. A. The plant alkaloids, 4thed., 1949. 20. Vermeulen, E. S.; Smeden, M. V.; Schmidt, A. W.; Sprouse, J. S.; Grol, C. J. Novel 5-HT7 receptor inverse agonists. Synthesis and molecular modeling of arylpiperazine- and 1,2,3,4-tetrahydroisoquinoline-based arylsulfonamides. J. Med. Chem. 2004, 47, 5451-5466 21. Hsin, L.W.; Wang, S. C.; Yang, C.Y. Design and synthesis of 8-phenyl-1,2,3,4-tetrahydroisoquinolines as 5-HT7 receptor ligands. ACS 2012 Spring Metting. 22. Kikuchi, C.; Nagaso, H.; Hiranuma, T.; Koyama, M. Tetrahydrobenzindoles: selective antagonists of the 5-HT7 receptor. J. Med. Chem. 1999, 42, 533-535. 23. Orekhov, A. P. The chemistry of the alkaloids, 1955. 24. Xing, F.; Ping, Z. T.; Kula, N. S.; Baldessarini, R.; Tamagnan, G. Synthesis, receptor potency, and selectivity of halogenated diphenylpiperidines as serotonin 5-HT2A ligands for PET or SPECT brain imaging. J. Med. Chem. 2002, 45, 2319-2324. 25. Andries, J.; Lemoine, L.; Blaisot, A. M.; Tang, S.; Bars, D. L.; Zimmer, L.; Billard, T. Looking for a 5-HT7 radiotracer for positron emission tomography. Bioorg. Med. Chem. Lett. 2010, 20, 3730–3733. 26. Forbes, I. T.; Dabbs, S.; Duckworth, D. M.; Jennings, A. J.; King, F. D.; Lovell, P. J.; Brown, A. M.; Collin, L.; Hagan, J. J.; Middlemiss, D. N.; Riley, G. J.; Thomas, D. R.; Upton, N. (R)-3, N-dimethyl-N-[1-methyl-3-(4-methylpiperidin-1-yl)propyl] bezenesulfonamide: the first selective 5-HT7 receptor antagonist. J. Med. Chem. 1998, 41, 655-657. 27. Lovell, P. J.; Bromidge, S. M.; Dabbs, S.; Duckworth, D. M.; Forbes, I. T.; Jennings, A. J.; King, F. D.; Middlemiss, D. N.; Rahman, S. K.; Saunders, D. V.; Collin, L. L.; Hagan, J. J.; Riley, G. J.; Thomas, D. R. A novel, potent, and selective 5-HT7 antagonist:(R)-3-(2-(2-(4-Methylpiperidin-1-yl)-ethyl)pyrrolidine-1-sulfonyl) phenol (SB-269970). J. Med. Chem. 2000, 43, 342-345. 28. Hsin, L. W.; Dersch, C. M.; Baumann, M. H.; Stafford, D.; Glowa, J. R.; Rothman, R. B.; Jacobson, A. E.; Rice K.C.Development of long-acting dopamine transporter ligands as potential cocaine-abuse therapeutic agents: chiral hydroxyl-containing derivatives of1-[2-[bis(4-fluorophenyl)methoxy]ethyl] -4-(3-phenylpropyl)piperazine and1-[2-(diphenylmethoxy)ethyl]-4- (3-phenylpropyl)piperazine. J. Med. Chem. 2002, 45, 1321-1329. 29. Naturale, G.; Lamblin, M.; Commandeur, C.; Felpin, F.X.; Dessloin, J. Direct C–H akylation of naphthoquinones with amino acids through a revisited Kochi–Anderson radical decarboxylation: trends in reactivity and applications. Eur. J. Org. Chem. 2012, 5774–5788. 30. Huang, W. J.; Chen, C. H.; Singh, O. V.; Lee, S. L.; Lee, S. S. A facile method for the synthesis of glaucine and norglaucine from boldine. Syn. Communications. 2002, 32, 3681-3686. 31. Bobbitt,J. M.; Judith M. K.; Khanna, K. L.; Ebermann, R. Synthesis of isoquinolines.III. A new synthesis of 1,2,3,4-tetrahydroisoquinolines. J. Org. Chem.1965,30,2247–2250. 32. Buchini, S.; Buschiazzo, A.; Withers, S. G. A new generation of specificTrypanosomacruzitrans-sialidase inhibitors.Angew. Chem.2008,47,2700-2703. | |
dc.identifier.uri | http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/17325 | - |
dc.description.abstract | 5-HT7受體在人體中扮演著重要角色,認為與多種CNS的功能息息相關,例如:體溫調節、晝夜節律、學習、記憶、睡眠及憂鬱等,若是能了解5-HT7受體與各種相關疾病之間的關係,那麼將能進一步探討疾病成因及病理機轉。正子斷層掃描(Possitron Emission Tomography, PET)有較佳的靈敏度及空間解析度已被廣泛應用於診斷癌症、心臟病、神經退化及精神疾病。其中5-HT1A及5HT2A兩種亞型之正子造影劑已經發展出來,本研究為發展具高親和力與選擇性之5-HT7受體配體做為有潛力之正子掃描造影劑,以6-methoxy-8-(2-methoxyphenyl)-1,2,3,4-
tetrahydroisoquinolin-7-ol為核心結構,在氮的位置上以雙鹵素取代之苯乙基側鏈與苯磺醯胺官能基及不同長度之碳鏈(n = 3-5)修飾取代以形成一系列衍生物。經過生物活性及脂溶性評估,發現化合物27 (Ki = 1.62 nM) 展現了高度的5-HT7受體之親和力及脂溶性,極有潛力作為5-HT7受體之18F標定正子斷層造影劑。硝基衍生物32與38也被合成作為日後18F放射標定所需之前驅物。 | zh_TW |
dc.description.abstract | The 5-HT7 is considered to be closely related to various functions of CNS such as thermoregulation, circadian rhythm, learning, memory, sleep and depression. Exploring the important role of 5-HT7 receptor in human body will give us in sight of the etiology and pathophysiology of related diseases. Positron emission tomography (PET) has high sensitivity and spatial resolution in the molecular imaging and it is used in the diagnosis of cancer, heart disease, neurological and neurodegenerative disease. The PET imaging agents of the 5-HT1A and 5HT2A have been developed. Therefore, for the development of high affinity and selective 5-HT7 receptor ligands as potential positron emission tomography imaging agents for 5-HT7 receptor, we chose 6-methoxy-8-(2-methoxyphenyl)-1,2,3,4-tetrahydroisoquinolin-7-ol as the core structure, and modified the amino group of the core structure with dihalide substituted phenyl group and phenylsulfonamide alkyl side chains. According to the binding affinity data and distribution coefficient data, the compound 27 shows high 5-HT7 receptor affinity (Ki = 1.62 nM) and ideal log D to be a potential 18F-labeled PET imaging agent for 5-HT7 receptor. The nitro-substituted precursor 32 and 38 were also synthesized as precursor of 18F-labeled PET imaging agent. | en |
dc.description.provenance | Made available in DSpace on 2021-06-08T00:06:55Z (GMT). No. of bitstreams: 1 ntu-102-R00423021-1.pdf: 7104176 bytes, checksum: 691ae599475be3305389015ea01c6ed9 (MD5) Previous issue date: 2013 | en |
dc.description.tableofcontents | 口試委員會審定書……………………………………………………I
致謝………………………………………………………………………II 摘要……………………………………………………………………III Abstract……………………………………………………………… IV 英文縮寫表……………………………………………………………V 總目錄……………………………………………………………………VI 圖目錄…………………………………………………………………VIII 表目錄………………………………………………………………VIII 路徑目錄………………………………………………………………IX 緒論………………………………………………………………………1 1.1 血清素之研究………………………………………………………1 1.2 正子斷層掃描原理及其應用………………………………………3 1.3 化合物結構設計的理論根據………………………………………………..6 1.4 研究動機與目的……………………………………………………………..7 結果與討論……………………………………………………………………….......9 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……….……..9 2. 2 合成關鍵中間體4以快速製備目標化合物……………………………….9 2.3 第一階段目標化合物選定………………………………………………....11 2.3.1 苯環上雙鹵素取代基側鏈製備………………………………………….11 2.3.2 目標化合物6, 8, 10之合成研究………………………………………...11 2.4 第二階段目標化合物選定…………………………………………………12 2.4.1 苯磺醯胺官能基側鏈製備……………………………………………….13 2.4.2 目標化合物12, 20之合成研究……………………………………….…13 2.4.3 目標化合物18之合成研究……………………………………………...14 2.4.4 氟取代苯磺醯胺官能基側鏈製備……………………………………….16 2.4.5 目標化合物22, 25, 27, 30之合成研究………………………………….17 2.4.6 目標化合物23, 28之合成研究………………………………………….17 2.5 第三階段目標化合物選定……………………………………………....…18 2.5.1 合成關鍵中間體35以快速製備目標化合物…………………………...19 2.5.2 硝基取代苯磺醯胺官能基側鏈製備…………………………………….19 2.5.3 目標化合物32之合成研究……………………………………………...20 2.5.4 目標化合物36, 37, 38之合成研究……………………………………...20 2.6 分佈係數(log D)探討……….………………………………………………21 2.6.1 碳鏈長度 VS. log D……………………………………………………...22 2.6.2 氟取代位置 VS. log D…………………………………………………...22 2.6.3 對位不同取代基 VS. log D……………………………………………...23 2.6.4 七號碳之取代基 VS. log D……………………………………………...24 2.7 Binding affinity...……………………………………………………………27 結論……………………………………………………………………………………29 實驗部分……………………………………………………………………………...30 一、實驗藥品及溶劑來源...……………………………………………….....…..30 二、一般儀器與方法……………………………………………………………..32 三、合成步驟與數據分析………………………………………………………..33 參考文獻……………………………………………………………………………...71 附表目錄………………………………………………………………………….76 附圖目錄………………………………………………………………………….76 附表……………………………………………………………………………….78 附圖……………………………………………………………………………….80 圖目錄 圖一、5-HT與LSD之結構……………………………………………………………....1 圖二、SB269970與SB656104之結構………………………………………………....2 圖三、正子斷層掃描原理………………………………………………………………………………....3 圖四、aporphine alkaloids之基本骨架……………………………………………….....6 圖五、thaliporphine化學結構式…………………………………..………………….....6 圖六、8-phenyl-1,2,3,4-tetrahydroisoquinolne之基本架構.…...6 圖七、CYY-217..…………………..........8 圖八、CYY082-d.…………………................8 圖九、側鏈為苯環上以雙鹵素取代基碳鏈與苯磺醯胺官能基碳鏈的異喹啉衍生….8 圖十、第一階段之目標化合物. ....................11 圖十一、第二階段之目標化合物............12 圖十二、第三階段之目標化合物................18 圖十三、碳鏈長度與log D比較圖............22 圖十四、氟取代位置與log D比較圖.........23 圖十五、對位不同取代基與log D比較圖...23 圖十六、七號碳之取代基與log D比較圖.....24 表目錄 表一、常用於正子斷層掃描之核種.................4 表二、新化合物之分佈係數數據...................21 表三、目標化合物之5-HT7受體親合力.......28 路徑目錄 路徑一、異喹啉類目標化合物之逆合成分析...9 路徑二、關鍵中間體4之合成.......................10 路徑三、以化合物4做為中間體以製備目標化合物...................10 路徑四、苯環上雙鹵素取代基側鏈5, 7, 9製備..........11 路徑五、目標化合物6, 8, 10之合成......................12 路徑六、苯磺醯胺官能基側鏈11,19的製備....13 路徑七、目標化合物12, 20之合成..................14 路徑八、目標化合物18之逆合成分析.............14 路徑九、目標化合物18之合成................15 路徑十、氟取代苯磺醯胺官能基側鏈21, 24的製備...................16 路徑十一、氟取代苯磺醯胺官能基側鏈26, 29的製備..................16 路徑十二、目標化合物22, 25, 27, 30之合成....................17 路徑十三、目標化合物23, 28之合成..........18 路徑十四、關鍵中間體35之合成...........19 路徑十五、硝基取代苯磺醯胺官能基側鏈31的製備..................19 路徑十六、目標化合物32之合成.................20 路徑十七、目標化合物36, 37, 38之合成.........20 | |
dc.language.iso | zh-TW | |
dc.title | 合成8-苯基異喹啉衍生物作為有潛力之5-HT7受體正子斷層掃描追蹤劑 | zh_TW |
dc.title | Synthesis of 8-Phenylisoquinolines as Potential Positron Emission Tomography Imaging Agents for 5-HT7 Receptor | en |
dc.type | Thesis | |
dc.date.schoolyear | 101-2 | |
dc.description.degree | 碩士 | |
dc.contributor.oralexamcommittee | 王光昭(Kuang-Chao Wang),陳基旺(Ji-Wang Chern),孔繁璐(Fan-Lu Kung) | |
dc.subject.keyword | 8-苯基異??,5-HT7受體,正子斷層掃描, | zh_TW |
dc.subject.keyword | 8-Phenylisoquinolines,Positron Emission Tomography,5-HT7 Receptor, | en |
dc.relation.page | 114 | |
dc.rights.note | 未授權 | |
dc.date.accepted | 2013-08-13 | |
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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