請用此 Handle URI 來引用此文件：
http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/77392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 | Ka-Pou Hao | en |
| dc.contributor.author | 侯嘉寶 | zh_TW |
| dc.date.accessioned | 2021-07-10T21:59:37Z | - |
| dc.date.available | 2021-07-10T21:59:37Z | - |
| dc.date.copyright | 2019-08-28 | |
| dc.date.issued | 2019 | |
| dc.date.submitted | 2019-05-16 | |
| dc.identifier.citation | 1. McHugh, P. C.; Buckley, D. A., The structure and function of the dopamine transporter and its role in CNS diseases. In Vitamins & Hormones, Elsevier: 2015; Vol. 98, pp 339-369.
2. Chinta, S. J.; Andersen, J. K., Dopaminergic neurons. The international journal of biochemistry & cell biology 2005, 37 (5), 942-946. 3. Chen, N.; Reith, M. E., Structure and function of the dopamine transporter. European journal of pharmacology 2000, 405 (1-3), 329-339. 4. Torres, G. E.; Gainetdinov, R. R.; Caron, M. G., Plasma membrane monoamine transporters: structure, regulation and function. Nature Reviews Neuroscience 2003, 4 (1), 13. 5. Pimlott, S. L.; Sutherland, A., Molecular tracers for the PET and SPECT imaging of disease. Chemical Society Reviews 2011, 40 (1), 149-162. 6. Ametamey, S. M.; Honer, M.; Schubiger, P. A., Molecular imaging with PET. Chemical reviews 2008, 108 (5), 1501-1516. 7. Cai, L.; Lu, S.; Pike, V. W., Chemistry with [18F] fluoride ion. European Journal of Organic Chemistry 2008, 2008 (17), 2853-2873. 8. Fletcher, J. W.; Djulbegovic, B.; Soares, H. P.; Siegel, B. A.; Lowe, V. J.; Lyman, G. H.; Coleman, R. E.; Wahl, R.; Paschold, J. C.; Avril, N., Recommendations on the use of 18F-FDG PET in oncology. Journal of Nuclear Medicine 2008, 49 (3), 480-508. 9. Brooks, D. J., Molecular imaging of dopamine transporters. Ageing research reviews 2016, 30, 114-121. 10. Chalon, S.; Hall, H.; Saba, W.; Garreau, L.; Dollé, F.; Halldin, C.; Emond, P.; Bottlaender, M.; Deloye, J.-B.; Helfenbein, J., Pharmacological Characterization of (E)-N-(4-Fluorobut-2-enyl)-2β-carbomethoxy-3β-(4′-tolyl) nortropane (LBT-999) as a Highly Promising Fluorinated Ligand for the Dopamine Transporter. Journal of Pharmacology and Experimental Therapeutics 2006, 317 (1), 147-152. 11. Varrone, A.; Stepanov, V.; Nakao, R.; Tóth, M.; Gulyás, B.; Emond, P.; Deloye, J. B.; Vercouillie, J.; Stabin, M. G.; Jonsson, C., Imaging of the striatal and extrastriatal dopamine transporter with 18F-LBT-999: quantification, biodistribution, and radiation dosimetry in nonhuman primates. Journal of Nuclear Medicine 2011, 52 (8), 1313-1321. 12. Gorelick, D. A.; Gardner, E. L.; Xi, Z.-X., Agents in development for the management of cocaine abuse. Drugs 2004, 64 (14), 1547-1573. 13. Herman, B. H.; Elkashef, A.; Vocci, F., Medications for the treatment of cocaine addiction: Emerging candidates. Drug Discovery Today: Therapeutic Strategies 2005, 2 (1), 87-92. 14. Benedetti, P.; Mannhold, R.; Cruciani, G.; Pastor, M., GBR compounds and mepyramines as cocaine abuse therapeutics: chemometric studies on selectivity using grid independent descriptors (GRIND). Journal of medicinal chemistry 2002, 45 (8), 1577-1584. 15. Hsin, L.-W.; Chang, L.-T.; Rothman, R. B.; Dersch, C. M.; Jacobson, A. E.; Rice, K. C., Design and Synthesis of 2-and 3-Substituted-3-phenylpropyl Analogs of 1-[2-[Bis (4-fluorophenyl) methoxy] ethyl]-4-(3-phenylpropyl) piperazine and 1-[2-(Diphenylmethoxy) ethyl]-4-(3-phenylpropyl) piperazine: Role of Amino, Fluoro, Hydroxyl, Methoxyl, Methyl, Methylene, and Oxo Substituents on Affinity for the Dopamine and Serotonin Transporters. Journal of medicinal chemistry 2008, 51 (9), 2795-2806. 16. 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 of 1-[2-[bis (4-fluorophenyl) methoxy] ethyl]-4-(3-phenylpropyl) piperazine and 1-[2-(diphenylmethoxy) ethyl]-4-(3-phenylpropyl) piperazine. Journal of medicinal chemistry 2002, 45 (6), 1321-1329. 17. Hsin, L.-W.; Prisinzano, T.; Wilkerson, C. R.; Dersch, C. M.; Horel, R.; Jacobson, A. E.; Rothman, R. B.; Rice, K. C., Synthesis and dopamine transporter affinity of chiral 1-[2-[bis (4-fluorophenyl) methoxy] ethyl]-4-(2-hydroxypropyl) piperazines as potential cocaine abuse therapeutic agents. Bioorganic & medicinal chemistry letters 2003, 13 (3), 553-556. 18. Lewis, D. B.; Matecka, D.; Zhang, Y.; Hsin, L.-W.; Dersch, C. M.; Stafford, D.; Glowa, J. R.; Rothman, R. B.; Rice, K. C., Oxygenated analogues of 1-[2-(diphenylmethoxy) ethyl]-and 1-[2-[bis (4-fluorophenyl) methoxy] ethyl]-4-(3-phenylpropyl) piperazines (GBR 12935 and GBR 12909) as potential extended-action cocaine-abuse therapeutic agents. Journal of medicinal chemistry 1999, 42 (24), 5029-5042. 19. Yusubov, M. S.; Svitich, D. Y.; Larkina, M. S.; Zhdankin, V. V., Applications of iodonium salts and iodonium ylides as precursors for nucleophilic fluorination in Positron Emission Tomography. ARKIVOC: Online Journal of Organic Chemistry 2013. 20. Merritt, E. A.; Olofsson, B., Diaryliodonium salts: a journey from obscurity to fame. Angewandte Chemie International Edition 2009, 48 (48), 9052-9070. 21. 曹楚善，國立台灣大學醫學院藥學研究所碩士論文，105年7月，Synthesis and biological activity of pyridyl-substituted 1-[2-(diphenylmethoxy)ethyl-4-(3-phenylpropyl)piperazine derivatives. 22. 張莉德，國立台灣大學醫學院藥學研究所博士論文，101年3月，Part 1:Synthesis and Monoamine Transporter Activity of Fluoro-Substituted GBR12909 and GBR12935 Derivatives. 23. Subramanian, P. K.; Woodard, R. W., Synthesis of (R)-and (S)-1-amino [2, 2-2H2] cyclopropane-1-carboxylic acids. The Journal of Organic Chemistry 1987, 52 (1), 15-18. 24. Waterhouse, R. N., Determination of lipophilicity and its use as a predictor of blood–brain barrier penetration of molecular imaging agents. Molecular Imaging & Biology 2003, 5 (6), 376-389. 25. van de Waterbeemd, H.; Smith, D. A.; Jones, B. C., Lipophilicity in PK design: methyl, ethyl, futile. Journal of computer-aided molecular design 2001, 15 (3), 273-286. 26. Waring, M. J.; Johnstone, C., A quantitative assessment of hERG liability as a function of lipophilicity. Bioorganic & medicinal chemistry letters 2007, 17 (6), 1759-1764. 27. Organization for Economic Cooperation and Development (OECD) (2004) Guideline for testing of chemicals 117, partition coefficient (n-octanol/water)-high performance liquid chromatography (HPLC) method. 28. Organization for Economic Cooperation and Development (OECD) (2004) Guideline for testing of chemicals 107, shake flask method. 29. Baron, O.; Knochel, P., Preparation and selective reactions of mixed bimetallic aromatic and heteroaromatic boron–magnesium reagents. Angewandte Chemie International Edition 2005, 44 (20), 3133-3135. 30. Núnez, A.; Cuadro, A. M.; Alvarez-Builla, J.; Vaquero, J. J., A new approach to polycyclic azonia cations by ring-closing metathesis. Organic letters 2007, 9 (16), 2977-2980. 31. Sanmartín, C.; Echeverría, M.; Mendívil, B.; Cordeu, L.; Cubedo, E.; García-Foncillas, J.; Font, M.; Palop, J. A., Synthesis and biological evaluation of new symmetrical derivatives as cytotoxic agents and apoptosis inducers. Bioorganic & medicinal chemistry 2005, 13 (6), 2031-2044. | |
| dc.identifier.uri | http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/77392 | - |
| dc.description.abstract | 多巴胺轉運體與注意力不足過動症、帕金森氏症等中樞神經疾病息息相關，正子造影示蹤劑可幫助這些疾病的早期診斷及追蹤，也可協助新藥開發。為發展具潛力的多巴胺轉運體正子造影示蹤劑，一系列2-吡啶基取代之GBR12935衍生物被設計及合成，並評估這些衍生物對血腦屏障的穿透力及脂溶性。在此系列衍生物中，所有的衍生物皆顯示適當的脂溶性 (Log P從4.09降至2.55) 及血腦屏障穿透能力 (Pe% = 57%-66%)，未來可望用於發展多巴胺轉運體正子造影示蹤劑。
為合成出易於進行放射標記氟化反應的前驅物，必須解決在電子密度大的芳香環上不易進行放射標記氟化反應的問題。具有缺電子及易作離去基等特點的不對稱雙芳香環碘鹽是利於氟原子進行親核性取代反應的前驅物，而硼酸化合物則常被設計為合成不對稱雙芳香環碘鹽前驅物的中間體。本研究以2-吡啶基取代之GBR12935衍生物22作為氟化反應的目標產物，探討關鍵中間體硼酸化合物21的合成。先以turbo Grignard reagent 合成具硼酸酯取代的雙芳香環醇15，經偶合反應及水解反應後成功製備關鍵中間體硼酸化合物21，未來可用於合成放射標記氟化反應的前驅物。 | zh_TW |
| dc.description.abstract | 英文摘要
Dopamine transporters are related to central nervous system diseases such as attention deficit hyperactivity disorder and Parkinson's disease. Positron emission tomography (PET) tracers help early diagnosis and monitoring of these diseases, and also assist new drug discovery and development. To develop potential PET radiotracer for dopamine transporter (DAT), a series of 2-pyridyl-substituted 1- (2- (diphenyl-methoxy) ethyl) -4- (3-phenylpropyl) piperazine (GBR12935) derivatives was designed and synthesized. In this series, all the compounds show desirable lipophilicity (from LogPof 4.09 to 2.55) and blood-brain barrier (BBB) penetration ability, and maybe used to develop DAT PET radiotracers. To synthesis a precursor that can be easy to label 18F, the problem of 18F labeling on electron-rich aromatic ring need to be solved. Diaryliodonium salts possess electron-deficient and good leaving group properties, in favor of nucleophilic substitution with fluoride proceeding, and boronic acid compounds are used as intermediate for preparation of diaryliodonium salts. In this study, the 2-pyridyl substituted GBR12935 derivative 22 was designed as target product and the synthesis of the key intermediate boronic acid compound 21 was explored. By using turbo Grignard reagent to synthesis pinacol substituted diaryl alcohol 15, through coupling reaction and hydrolysis reaction to produce key intermediate boronic acid compound 21, which may use for the preparation of diaryliodonium salt precursor in future. | en |
| dc.description.provenance | Made available in DSpace on 2021-07-10T21:59:37Z (GMT). No. of bitstreams: 1 ntu-108-R05423025-1.pdf: 6782588 bytes, checksum: 43d398264b4ec1aae1521e5bbb49b9a7 (MD5) Previous issue date: 2019 | en |
| dc.description.tableofcontents | 目錄
誌謝 I 中文摘要 II 英文摘要 III 縮寫表 V 目錄 VII 圖目錄 IX 表目錄 X 路徑目錄 XI 第一章 緒論 1 1.1多巴胺及多巴胺轉運體在人體內的角色 1 1.2多巴胺轉運體與正子斷層掃描 2 1.3 GBR12935及GBR12909 4 1.4在芳香環上作放射合成氟十八標記之正子斷層掃描造影劑前驅物的合成研究 6 1.5 研究動機與目的 8 第二章 結果與討論 9 2.1 吡啶基取代的GBR12935衍生物合成研究 9 2.1.1 逆合成分析 9 2.1.2 核心結構中間體之合成 11 2.1.3 合成目標化合物(S)-11、(R)-11、(S)-12、(R)-12 13 2.2化合物的物化性質研究 16 2.3合成正子斷層掃描造影劑前驅物的關鍵中間體 19 2.3.1 逆合成分析 19 2.3.2核心結構中間體之合成 20 2.3.3關鍵中間體化合物21之合成 22 第三章 結論 24 第四章 實驗 25 4.1 試劑及溶劑來源 25 4.2 一般儀器及方法 27 4.2.1 化合物的血腦屏障及胃腸道穿透能力測定 28 4.3 合成步驟及數據分析 30 參考文獻 69 附表目錄 74 附圖目錄 75 | |
| dc.language.iso | zh-TW | |
| dc.title | 新穎多巴胺轉運體探針之合成與評估 | zh_TW |
| dc.title | Synthesis and Evaluation of Novel Dopamine Transporter Probes | en |
| dc.type | Thesis | |
| dc.date.schoolyear | 107-2 | |
| dc.description.degree | 碩士 | |
| dc.contributor.oralexamcommittee | 陳基旺(Ji-Wang Chern),胡明寬(Ming-Kuan Hu),林美香(Mei-Hsiang Lin),高佳麟(Chai-Lin Kao) | |
| dc.subject.keyword | 多巴胺轉運體,正子造影, | zh_TW |
| dc.subject.keyword | Dopamine transporter,PET, | en |
| dc.relation.page | 124 | |
| dc.identifier.doi | 10.6342/NTU201900756 | |
| dc.rights.note | 未授權 | |
| dc.date.accepted | 2019-05-16 | |
| 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 | |
文件中的檔案：
| 檔案 | 大小 | 格式 | |
|---|---|---|---|
| ntu-108-R05423025-1.pdf 目前未授權公開取用 | 6.62 MB | Adobe PDF |
系統中的文件，除了特別指名其著作權條款之外，均受到著作權保護，並且保留所有的權利。