(3.236.122.9) 您好!臺灣時間:2021/05/09 07:25
字體大小: 字級放大   字級縮小   預設字形  
回查詢結果

詳目顯示:::

: 
twitterline
研究生:曹馨心
研究生(外文):Tsao Hsin Hsin
論文名稱:9-Fluoropropyl-(+)-dihydrotetrabenazine[FP-(+)-DTBZ]與大鼠第二型囊泡單胺轉運體之結合研究
論文名稱(外文):Binding of 9-fluoropropyl-(+)-dihydrotetrabenazine [FP-(+)-DTBZ] to the vesicular monoamine transporter type 2 (VMAT2) in rats
指導教授:魏孝萍
指導教授(外文):S. P. Wey
學位類別:碩士
校院名稱:長庚大學
系所名稱:醫學物理暨影像科學研究所
學門:醫藥衛生學門
學類:醫學技術及檢驗學類
論文種類:學術論文
論文出版年:2009
畢業學年度:97
論文頁數:125
中文關鍵詞:囊泡單胺轉運體正子造影劑氟18結合實驗
外文關鍵詞:VMATPET tracerF-18binding assay
相關次數:
  • 被引用被引用:0
  • 點閱點閱:361
  • 評分評分:系統版面圖檔系統版面圖檔系統版面圖檔系統版面圖檔系統版面圖檔
  • 下載下載:22
  • 收藏至我的研究室書目清單書目收藏:0
文獻證實放射性同位素 (如碳-11或氟-18) 標誌Tetrabenazine (TBZ)類化合物可有效偵測第二型囊泡單胺轉運體 (vesicular monoamine transporter subtype 2; VMAT2),運用於臨床PET影像探討腦神經退化性疾病及與糖尿病有關的胰臟細胞 (beta-cell mass) 評估。
氟-18-FP-(+)-DTBZ是最新發展用於VMAT2 PET造影的放射藥物,本研究將各別試驗氟-18-FP-(+)-DTBZ對於Sprague-Dawley大鼠腦部與胰臟組織的結合能力。試驗組織包括大腦的紋狀體與下視丘,胰臟的胰島細胞與外分泌細胞,將組織均質後進行體外的結合實驗 (binding assay)。腦組織與胰臟切片之氟-18-FP-(+)-DTBZ ex-vivo及in-vitro自動輻射曝光顯影(autoradiography)影像分別以anti-VMAT2及anti-insulin之免疫組織化學染色(immonohistochemistry)加以驗證。
結果發現氟-18-FP-(+)-DTBZ對於大鼠腦紋狀體及下視丘的VMAT2具有極佳結合能力 (Kd分別為0.19及0.25 nM);自動輻射曝光顯影也證實氟-18-FP-(+)-DTBZ可作為偵測腦部VMAT2分布的理想造影劑。氟-18-FP-(+)-DTBZ在大鼠的胰島細胞有兩種結合位置 (Kd分別為6.76及241 nM; Bmax分別為60及1500 fmol/mg protein);外分泌細胞具有較弱的結合能力及更多的結合位置 (Kd及Bmax分別為209 nM與74400 fmol/mg protein);in-vitro自動輻射顯影結果發現氟-18-FP-(+)-DTBZ活度聚集與胰島素抗體標示的胰島細胞位置互相吻合,而ex-vivo顯影結果由於背景強烈導致無法有效辨別出胰島細胞與VMAT2分布。
結論:氟-18-FP-(+)-DTBZ對於大鼠腦部的VMAT2有著極佳的偵測能力。胰臟方面過去認為胰臟造影的高背景源於非特異性結合,本研究推論為外分泌細胞的大量的特異性結合所致,由於外分泌細胞存在數量龐大的低親和力結合位,因此氟-18-FP-(+)-DTBZ於胰島細胞偵測的運用方面則還需要進一步的評估。
C-11 or F-18 labeled tetrabenazine derivatives targeting vesicular monoamine transporters (VMAT2), a potential biomarker for beta cell mass (BCM), have shown some promising results. In the present study we examined the binding characteristics of F-18-FP-(+)-DTBZ, a potential PET tracer for BCM imaging, in rat pancreas and rat brain, respectively.
Exocrine and islet cells were isolated from Sprague-Dawley rats. Membrane homogenates prepared from pancreatic exocrine and islet cells as well as from brain striatum and hypothalamus regions were used for in vitro binding studies. In vitro and ex vivo autoradiography studies with F-18-FP-(+)-DTBZ were performed on brain and pancreas sections. Islet beta cells were confirmed via immunohistochemistry with anti-insulin antibody.
Excellent binding affinities of F-18-FP-(+)-DTBZ were observed in rat striatum and hypothalamus homogenates with Kd values of 0.19 and 0.25 nM, respectively (Bmax= 45.0 and 5.0 fmol/mg protein). Islet cell homogenates, however, showed two saturable binding sites (site A: Kd = 6.76 nM, Bmax = 60 fmol/mg protein; site B: Kd = 241 nM, Bmax =1,500 fmol/mg protein). Similar B sites were also observed in exocrine cells (Kd = 209 nM). In vitro autoradiography of F-18-FP-(+)-DTBZ using frozen sections of rat pancreas in optimum conditions showed labeling of islets, as evidenced by co-localization with anti-insulin antibody. Ex vivo VMAT2 pancreatic autoradiography in the rat however was not successful, in contrast to the excellent ex vivo autoradiography of VMAT2 binding sites in the brain.
F-18-FP-(+)-DTBZ is an excellent imaging agent for mapping VMAT2 sites in rat brain and specifically binds islet cells in vitro and post-mortem. Additional optimization may be required to achieve ex vivo islet beta cell labeling in rats.
致謝-v-
中文摘要 -vii-
Abstract -ix-
目錄 -xi-
圖目錄 -xvi-
表目錄 -xix-
第一章 前言- 1 -
1.1 囊泡單胺轉運體 (vesicular monoamine transporter;VMAT)- 1 -
1.1.1 第一型囊泡單胺轉運體 (VMAT1) - 2 -
1.1.2 第二型囊泡單胺轉運體 (VMAT2) - 3 -
1.2 第二型囊泡單胺轉運體的臨床意義- 5 -
1.2.1 高血壓 (Hypertensive) 與精神疾病 (Psychotic) 的治療標靶 - 5 -
1.2.2 與杭亭頓病 (Huntington’s disease) 有關之舞蹈症 (Chorea) 的治療標靶- 5 -
1.2.3 腦神經醫學影像診斷- 7 -
1.2.4 胰臟β細胞的造影- 11 -
1.3 氟-18標誌VMAT2 PET造影劑的發展 - 14 -
1.4 論文主旨- 16 -
第二章 材料與方法- 19 -
2.1 材料 - 19 -
2.2 儀器與設備- 21 -
2.3 氟-18-FP-(+)-DTBZ與大鼠腦組織之結合特性研究- 22 -
2.3.1 氟-18-FP-(+)-DTBZ與大鼠腦組織均質之結合實驗- 22 -
2.3.1.1 大鼠腦紋狀體與下視丘取樣- 22 -
2.3.1.2 大鼠腦紋狀體與下視丘組織均質化- 23 -
2.3.1.3 氟-18-FP-(+)-DTBZ與大鼠腦組織均質之飽和結合實驗 (Saturation binding assay)- 23 -
2.3.1.4 大鼠腦組織均質蛋白質定量- 25 -
2.3.2 大鼠腦組織切片之氟-18-FP-(+)-DTBZ自動輻射曝光顯影實驗 (Autoradiography)- 26 -
2.3.2.1 氟-18-FP-(+)-DTBZ大鼠腦組織體內法自動輻射曝光顯影實驗 (Ex-vivo autoradiography)- 26 -
2.3.2.2 氟-18-FP-(+)-DTBZ大鼠腦組織體外法自動輻射曝光顯影實驗 (In-vitro autoradiography)- 27 -
2.3.3 大鼠腦組織切片之免疫組織化學染色 (Immunohistochemistry stain; IHC)- 29 -
2.3.3.1 大鼠腦組織免疫組織化學染色組織冷凍切片製備- 29 -
2.3.3.2 VMAT2免疫組織化學染色- 29 -
2.4.1 氟-18-FP-(+)-DTBZ與大鼠胰臟細胞均質之結合實驗- 31 -
2.4.1.1 大鼠胰臟細胞分離- 31 -
2.4.1.2 大鼠胰臟細胞均質化 - 33 -
2.4.1.3 氟-18-FP-(+)-DTBZ與大鼠胰臟細胞均質之飽和結合實驗- 33 -
2.4.1.4 大鼠胰臟細胞均質蛋白質定量 - 35 -
2.4.2 大鼠胰臟切片之氟-18-FP-(+)-DTBZ自動輻射曝光顯影實驗- 36 -
2.4.2.1 氟-18-FP-(+)-DTBZ大鼠腦組織體內法自動輻射曝光顯影實驗 (Ex-vivo autoradiography)- 36 -
2.4.2.2 氟-18-FP-(+)-DTBZ大鼠腦組織體外法自動輻射曝光顯影實驗 (In-vitro autoradiography)- 36 -
2.4.3.1 大鼠胰臟冷凍切片製備- 38 -
2.4.3.2 大鼠胰臟免疫組織化學染色- 38 -


第三章 結果- 40 -
3-1 氟-18-FP-(+)-DTBZ與大鼠腦組織之結合特性研究- 40 -
3.1.1 氟-18-FP-(+)-DTBZ與大鼠腦組織均質之結合實驗- 40 -
3.1.1.1 大鼠腦紋狀體與下視丘取樣- 40 -
3.1.1.2 氟-18-FP-(+)-DTBZ與大鼠腦紋狀體均質之飽和結合實驗- 40 -
3.1.1.3 氟-18-FP-(+)-DTBZ與大鼠腦下視丘均質之飽和結合實驗- 40 -
3.1.2 氟-18-FP-(+)-DTBZ與大鼠腦組織切片之自動輻射曝光顯影實驗 - 42 -
3.1.2.1 氟-18-FP-(+)-DTBZ大鼠腦組織體內法自動輻射曝光顯影實驗 (Ex-vivo autoradiography)- 42 -
3.1.2.2 氟-18-FP-(+)-DTBZ大鼠腦組織體外法自動輻射曝光顯影實驗 (in-vitro autoradiography)- 42 -
3.1.3大鼠腦組織之免疫組織化學染色- 44 -
3-2 氟-18-FP-(+)-DTBZ與大鼠胰臟細胞之結合特性研究- 45 -
3.2.1 氟-18-FP-(+)-DTBZ在大鼠胰臟細胞均質之結合試驗- 45 -
3.2.1.1 大鼠胰臟細胞分離- 45 -
3.2.1.2 氟-18-FP-(+)-DTBZ與大鼠胰臟細胞均質之飽和結合實驗- 45 -
3.2.2 氟-18-FP-(+)-DTBZ與大鼠胰臟組織切片之自動輻射曝光顯影實驗 - 47 -
3.2.2.1 氟-18-FP-(+)-DTBZ大鼠胰臟體內法自動輻射曝光顯影實驗 (ex-vivo autoradiography)- 47 -
3.2.2.2 氟-18-FP-(+)-DTBZ大鼠胰臟體外法自動輻射曝光顯影實驗 (in-vitro autoradiography)- 47 -
3.2.3 大鼠胰臟組織之免疫組織化學染色- 49 -
第四章 討論- 50 -
4-1 氟-18-FP-(+)-DTBZ與大鼠組織之飽和結合試驗- 50 -
4-2 氟-18-FP-(+)DTBZ與大鼠腦部與胰臟組織之自動輻射曝光顯影- 54 -
4-3 大鼠腦部與胰臟組織之免疫組織化學染色- 57 -
第五章 結論與未來展望- 59 -
5.1 研究結論- 59 -
5.2 未來展望- 61 -
參考文獻- 62 -

圖目錄
圖一、 VMAT穿膜蛋白構造圖- 73 -
圖二、 VMAT2示意圖- 73 -
圖三、 Reserpine結構式- 74 -
圖四、 Tetrabenazine (TBZ) 結構式 - 74 -
圖五、 DTBZ結構式- 75 -
圖六、 碳-11-(+)-DTBZ結構圖- 75 -
圖七, 胰臟之解剖位置與細胞組成示意圖- 76 -
圖八、 FP-(+)-DTBZ與FP-(-)-DTBZ結構式- 77 -
圖九、 氟-18-FP-(+)-DTBZ結構式- 77 -
圖十、 胰臟細胞分離: 膽管入口以血管夾夾住- 78 -
圖十一、 胰臟細胞分離: 膠原蛋白酶溶液注入情形 - 78 -
圖十二、 胰臟細胞分離: 依照細胞比重進行分離- 79 -
圖十三、 大鼠腦部的下視丘組織 (hypothalamus)- 79 -
圖十四、 取出的左腦與右腦半球下視丘組織- 80 -
圖十五、 大鼠腦部的紋狀體組織 (striatum)- 80 -
圖十六、 取出的左腦與右腦半球的紋狀體組織- 81 -
圖十七、 氟-18-FP-(+)-DTBZ與大鼠腦部紋狀體組織之飽和結合曲線圖 - 82 -
圖十八、 氟-18-FP-(+)-DTBZ與大鼠腦紋狀體組織特異性結合之Scatchard plot作圖- 83 -
圖十九、 氟-18-FP-(+)-DTBZ與大鼠腦下視丘組織之飽和結合曲線圖- 84 -
圖二十、 氟-18-FP-(+)-DTBZ與大鼠腦下視丘組織特異性結合之Scatchard plot作圖- 85 -
圖二十一、 氟-18-FP-(+)-DTBZ在大鼠腦部的體內法 (ex vivo) 自動輻射曝光顯影- 86 -
圖二十二、 氟-18-FP-(+)-DTBZ於大鼠腦部 (紋狀體切面) 之體外 (in vitro) 自動輻射曝光射顯影- 87 -
圖二十三、 正立式顯微鏡觀察兔VMAT2單株抗體於大鼠腦冠狀切片之免疫組織化學染色- 88 -
圖二十四、 分離出的胰島細胞 - 89 -
圖二十五、 分離出的外分泌細胞- 90 -
圖二十六、 FP-(+)-DTBZ抑制氟-18-FP-(+)-DTBZ與大鼠胰臟胰島細胞特異性結合百分率之競爭結合曲線- 91 -
圖二十七、 FP-(+)-DTBZ抑制氟-18-FP-(+)-DTBZ與大鼠胰臟外分泌細胞特異性結合百分率之競爭結合曲線- 92 -
圖二十八、 氟-18-FP-(+)-DTBZ與大鼠胰臟胰島細胞之飽和結合曲線- 93 -
圖二十九、 氟-18-FP-(+)-DTBZ與大鼠胰臟胰島細胞特異性結合之Scatchard plot作圖- 94 -
圖三十、 氟-18-FP-(+)-DTBZ與外分泌細胞之飽和結合曲線- 95 -
圖三十一、 氟-18-FP-(+)-DTBZ與大鼠胰臟外分泌細胞特異性結合之Scatchard plot作圖- 96 -
圖三十二、 氟-18-FP-(+)-DTBZ於大鼠胰臟之體內自動輻動曝光顯影 (ex vivo autoradiography)- 97 -
圖三十三、 氟-18-FP-(+)-DTBZ於大鼠胰臟之體外 (in vitro) 自動輻射曝光顯影- 98 -
圖三十四、 正立式顯微鏡觀察兔VMAT2多株抗體於大鼠胰臟組織切片之免疫組織化學染色與Hematoxylin的細胞核染色- 99 -
圖三十五、 正立式顯微鏡觀察兔胰島素單株抗體於大鼠胰臟胰島之免疫組織化學染色與Hematoxylin的細胞核染色- 100 -
圖三十六、 比較兔胰島素單株抗體與VMAT2多株抗體於相鄰的胰臟組織切片染色結果- 101 -
圖三十七、 相鄰大鼠胰臟切片之氟-18-FP-(+)-DTBZ自動輻射曝光 顯影與兔胰島素單株抗體免疫組織化學染色比較 - 102 -
表目錄
表一、氟-18-FP-(+)-DTBZ與大鼠腦組織之飽和結合實驗設計圖- 103 -
表二、氟-18-FP-(+)-DTBZ與大鼠胰臟細胞之飽和結合實驗設計圖- 104 -
表三、氟-18-FP-(+)-DTBZ於大鼠腦部組織與胰臟細胞之Kd值與Bmax彙整- 105 -
1. Yelin R, Schuldiner S. Vesicular neurotransmitter transporters: pharmacology, biochemistry, and molecular analysis. In: Reith ME, ed. Neurotransmitter Transporters: Structure, Function, and Regulation. 2nd ed. Totowa, NJ: Humana Press; 2002:313-354.
2. Edwards RH. The transport of neurotransmitters into synaptic vesicles. Curr Opin Neurobiol 1992;2:586-594.
3. Liu Y, Peter D, Roghani A, et al. A cDNA that suppresses MPP+ toxicity encodes a vesicular amine transporter. Cell 1992;70:539-551.
4. Peter D, Finn JP, Klissak I, et al. Chromosomal localization of the human vesicular amine transporter genes. Genomics 1993;18:720-723.
5. http://edoc.hu-berlin.de/dissertationen/hoeltje-markus-2000-09-12/HTML/hoeltje-ch1.html
6. Julie M. Wilson, Stephen J. Kish, et al. The vesicular monoamine transporter, in contrast to the dopamine transporter, is not altered by chronic cocaine self-administration in the rat. J Neurosci 1996;16:3507-3510.
7. Eiden LE. The vesicular neurotransmitter transporters: current perspectives and future prospects. FASEB J 2000;14:2396-2400.
8. Erickson JD, Schafer MK, Bonner TI, et al. Distinct pharmacological properties and distribution in neurons and endocrine cells of two isoforms of the human vesicular monoamine transporter. Proc Natl Acad Sci USA 1996;93:5166-5171.
9. Weihe E, Eiden LE. Chemical neuroanatomy of the vesicular amine transporters. FASEB J. 2000;14:2435-2449.
10. Wilhelm CJ, Johnson RA, Eshleman AJ, Janowsky A. Hydrogen ion concentration differentiates effects of methamphetamine and dopamine on transporter-mediated efflux. J Neurochem 2006;96:1149-1159.
11. Peter D, Jimenez J, Liu Y, et al. The chromaffin granule and synaptic vesicle amine transporters differ in substrate recognition and sensitivity to inhibitors. J Biol Chem 1994;269:7231-7237.
12. Weihe E, Schäfer MK, Erickson JD, Eiden LE. Localization of vesicular monoamine transporter isoforms (VMAT1 and VMAT2) to endocrine cells and neurons in rat. Mol Neurosci 1994;5:149-164.
13. Jakobsen AM, Andersson P, Saglik G, et al. Differential expression of vesicular monoamine transporter (VMAT) 1 and 2 in gastrointestinal endocrine tumours. J Pathol 2001;195:463-472.
14. Anlauf M, Eissele R, Schäfer MK et al. Expression of the two isoforms of the vesicular monoamine transporter (VMAT1 and VMAT2) in the endocrine pancreas and pancreatic endocrine tumors. J Histochem Cytochem 2003;51:1027-1040.
15. Peter D, Liu Y, Sternini C, et al. Differential expression of two vesicular monoamine transporters. J Neurosci 1995;16:6179-6188.
16. Saisho Y, Harris PE, Butler AE, et al. Relationship between pancreatic vesicular monoamine transporter 2 (VMAT2) and insulin expression in human pancreas. J Mol Hist 2008; 39:543-551.
17. Maffei A, Liu Z, Witkowski P, et al. Identification of tissue-restricted transcripts in human islets. Endocrinology 2004;145:4513-4521.
18. Cohen G, Kesler N. Monoamine oxidase and mitochondrial respiration. J. Neurochem 1999;73:2310-2315.
19. Zheng G, Dwoskin LP, Crooks PA. Vesicular monoamine transporter 2: role as a novel target for drug development. AAPS J 2006;8:E682-E692.
20. Schilkraut JJ, Kety SS. Biogenic amines and emotion. Science 1967;156:21-37.
21. Chen FE, Huang J. Reserpine: a challenge for total synthesis of natural products. Chem Rev 2005;105:4671-4706.
22. Scherman D, Henry JP. Reserpine binding to bovine chromaffin granule membranes: characterization and comparison with dihydrotetrabenazine binding. Mol Pharmacol 1983;25:113-122.
23. Brossi A , Lindlar H , Walter M , Schnider O . Synthesis in the emetine series, I: 2-oxohydrobenzo[a]quinolizines. Helv Chim Acta 1958;41:1793-1806.
24. Grimbergen YA, Roos RA. Therapeutic options for Huntington’s disease. Curr Opin Investig Drugs 2003;4:51-54.
25. Quinn GP, Shore PA, Brodie BB. Biochemical and pharmacological studies of RO 1-9569 (tetrabenazine), a nonindole tranquilizing agent with reserpine-like effects. J Pharmacol Exp Ther 1959;127:103-109.
26. Dalby MA. Effect of tetrabenazine on extrapyramidal movement disorders. Br Med J 1969;2:422-423.
27. Jankovic J. Tetrabenazine in the treatment of hyperkinetic movement disorders. Adv Neurol 1983;37:277-289.
28. Food and Drug Administration. FDA labeling information. 2008.
29. Huntington Study Group. Tetrabenazine as antichorea therapy in Huntington disease: a randomized controlled trial. Neurology 2006;66:366-372.
30. Kilbourn MR, Frey KA, Vander Borght T, Sherman PS. Effects of dopaminergic drug treatments on in vivo radioligand binding to brain vesicular monoamine transporters. Nucl Med Biol 1996;23:467-471.
31. Frey KA, Koeppe RA, Kilbourn MR. Imaging the vesicular monoamine transporter. Adv Neurol 2001;86:237-247.
32. Bohnen NI, Albin RL, Koeppe RA, et al. Positron emission tomography of monoaminergic vesicular binding in aging and Parkinson disease. J Cereb Blood Flow Metab 2006;26:1198-1212.
33. Lee CS, Schulzer M, de la Fuente-Fernandez R, et al. Lack of regional selectivity during the progression of Parkinson disease: implications for pathogenesis. Arch Neurol 2004;61:1920-1925.
34. Scherman D, Jaudon P, Henry JP. Characterization of the monoamine carrier of chromaffin granule membrane by binding of [2-3H]dihydrotetrabenazine. Proc Natl Acad Sci USA 1983;80:584-588.
35. DaSilva JN, Kilbourn MR, Mangner TJ. Synthesis of [11C]tetrabenazine, a vesicular monoamine uptake inhibitor, for PET imaging studies. Appl Radiat Isot 1993;44:673-676.
36. Kilbourn MR, DaSilva JN, Frey KA, Koeppe RA, Kuhl DE. In vivo imaging of vesicular monoamine transporters in human brain using [11C]tetrabenazine and positron emission tomography. J Neurochem 1993;60:2315-2318.
37. DaSilva JN, Kilbourn MR, Domino EF. In vivo imaging of monoaminergic nerve terminals in normal and MPTP-lesioned primate brain using positron emission tomography (PET) and [11C]tetrabenazine. Synapse 1993;14:128-131.
38. DaSilva JN, Carey JE, Sherman PS, Pisani TJ, Kilbourn MR. Characterization of [11C]tetrabenazine as an in vivo radioligand for the vesicular monoamine transporter. Nucl Med Biol 1994;21:151-156.
39. Kilbourn MR. PET radioligands for vesicular neurotransmitter transporters. Med Chem Res 1994;5:113-126.
40. Schwartz DE, Bruderer H, Rieder J, Brossi A. Metabolic studies of tetrabenazine, a psychotropic drug in animals and man. Biochem Pharmacol 1966;15:645-655.
41. Henry JP, Scherman D. Radioligands of the vesicular monoamine transporter and their use as markers of monoamine storage vesicles. Biochem Pharmacol 1989;38:2395-2404.
42. Scherman D, Raisman R, Ploska A, Agid Y. [3H]Dihydrotetrabenazine, a new in vitro monoaminergic probe for human brain. J Neurochem 1988;50:1131-1136.
43. Masuo Y, Pelaprat D, Scherman D, Rostene W. [3H]Dihydrotetrabenazine, a new marker for the visualization of dopaminergic denervation in the rat striatum. Neurosci Lett 1990;114:45-50.
44. Zucker M, Weizman A, Rehavi M. Characterization of high-affinity [3H]TBZOH binding to the human platelet vesicular monoamine transporter. Life Sci 2001;69:2311-2317.
45. Jewett DM, Kilbourn MR. Lee LC. A simple synthesis of [11C]dihydrotetrabenazine (DTBZ). Nucl Med Biol 1997;24:197-199.
46. Kilbourn MR, Lee LC, Heeg MJ, Jewett DM. Absolute configuration of (+)-alpha-dihydrotetrabenazine, an active metabolite of tetrabenazine. Chirality 1997;9:59-62.
47. Frey KA, Koeppe RA, Kilbourn MR, et al. Presynaptic monoaminergic vesicles in Parkinson’s disease and normal aging. Ann Neurol 1996;40:873-884.
48. Brooks DJ, Frey KA, Marek KL, et al. Assessment of neuroimaging techniques as biomarkers of the progression of Parkinson's disease. Exp Neurol 2003;184: S68-S79.
49. Albin RL, Koeppe RA, Bohnen NI, et al. Increased ventral striatal monoaminergic innervation in Tourette syndrome. Neurology 2003;61:310-315.
50. Johanson CE, Frey KA, Lundahol LH, et al. Cognitive function and nigrostriatal markers in abstinent methamphetamine abusers. Psychopharmacology 2006;185: 327-338.
51. Tatsch K. Can SPET imaging of dopamine uptake sites replace PET imaging in Parkinson's disease? Eur J Nucl Med Mol Imaging 2002;29:711-714.
52. Booij J, Tissingh G, Winogrodzka A, van Royen EA. Imaging of the dopaminergic neurotransmission system using single photon emission tomography and positron emission tomography in patients with parkinsonism. Eur J Nucl Med 1999;26:171-182.
53. Tatsch K. Imaging of the dopaminergic system in parkinsonism with SPECT. Nucl Med Commun 2001; 22:819-827.
54. Brücke T, Djamshidian S, Bencsits G, Pirker W, Asenbaum S, Podreka I. SPECT and PET imaging of the dopaminergic system in Parkinson’s disease. J Neurol 2000;247 (Suppl 4):IV/2–IV/7.
55. Stoessl AJ. Neurochemical and neuroreceptor imaging with PET in Parkinson’s disease. Adv Neurol 2001;86:215-223.
56. Lee CS, Samii A, Sossi I, et al. In vivo positron emission tomographic evidence for compensatory changes in presynaptic dopaminergic nerve terminals in Parkinson’s disease. Ann Neurol 2000;47:493-503.
57. Stefan H. J. Dresel, Mei-Ping Kung, Karl Plossl, et al. Pharmacological effects of dopaminergic drugs on in vivo binding of [99mTc] TRODAT-1 to the dopamine transporters in rats. Eur J Nucl Med. 1998;25:31-39.
58. Kilbourn M, Frey K. Striatal concentrations of vesicular monoamine transporters are identical in MPTP-sensitive (C57BL/6) and -insensitive (CD-1) mouse strains. Eur J Pharmacol 1996;307:227-232.
59. Kilbourn MR, Kuszpit K, Sherman P. Rapid and differential losses of in vivo dopamine transporter (DAT) and vesicular monoamine transporter (VMAT2) radioligand binding in MPTP-treated mice. Synapse 2000;35:250-255.
60. Tedroff J, Ekesbo A, Rydin E, Långström B, Hagberg G. Regulation of dopaminergic activity in early Parkinson’s disease. Ann Neurol 1999;46:359-365.
61. Albin R, Koeppe R. Rapid loss of striatal VMAT2 binding associated with onset of Lewy body dementia. Mov Disord 2006;21:287-288.
62. Kilbourn MR. In vivo radiotracers for vesicular neurotransmitter transporters. Nucl Med Biol 1997;24:615-619.
63. Weir G, Bonner-Weir S, Leahy J. Islet mass and function in diabetes and transplantation. Diabetes 1990;39:401-405.
64. Souza F, Freeby M, Hultman K, et al. Current progress in non-invasive imaging of beta cell mass of the endocrine pancreas. Curr Med Chem 2006;13:2761-2773.
65. McCulloch DK, Koerker DJ, Kahn SE, Bonner-Weir S, Palmer JP. Correlations of in vivo beta-cell function tests with beta-cell mass and pancreatic insulin content in streptozocin-administered baboons. Diabetes 1991;40:673-679.
66. Schmitz A, Shiue CY, Feng Q, et al. Synthesis and evaluation of fluorine-18 labeled glyburide analogs as beta-cell imaging agents. Nucl Med Biol 2004;31:483-491.
67. Hampe CS, Wallen AR, Schlosser M, Ziegler M, Sweet IR. Quantitative evaluation of a monoclonal antibody and its fragment as potential markers for pancreatic beta cell mass. Exp Clin Endocrinol Diabetes 2005;113:381-387.
68. Saisho Y, Harris PE, Butler AE, et al. Relationship between pancreatic vesicular monoamine transporter 2 (VMAT2) and insulin expression in human pancreas. J Mol Hist 2008;39:543-551.
69. Anlauf M, Eissele R, Schäfer MK, et al. Expression of the two isoforms of the vesicular monoamine transporter (VMAT1 and VMAT2) in the endocrine pancreas and pancreatic endocrine tumors. J Histochem Cytochem 2003;51:1027-1040.
70. Simpson NR, Souza F, Witkowski P, et al. Visualizing pancreatic -cell mass with [11C]DTBZ. Nucl Med Biol 2006;33:855-864.
71. Souza F, Simpson N, Raffo A, et al. Longitudinal noninvasive PET-based  cell mass estimates in a spontaneous diabetes rat model. J Clin Invest 2006;116:1506-1513.
72. Harris PE, Ferrara C, Barba P, Polito T, Freeby M, Maffei A. VMAT2 gene expression and function as it applies to imaging -cell mass. J Mol Med 2008;86:5-16.
73. Goland R, Freeby M, Parsey R, et al. 11C-Dihydrotetrabenazine PET of the pancreas in subjects with long-standing type 1 diabetes and in healthy controls. J Nucl Med 2009;50:382-389.
74. Goswami R, Ponde DE, Kung MP, Hou C, Kilbourn MR, Kung HF. Fluoroalkyl derivatives of dihydrotetrabenazine as positron emission tomography imaging agents targeting vesicular monoamine transporters. Nucl Med Biol 2006;33:685-694.
75. Kung MP, Hou C, Goswami R, Ponde DE, Kilbourn MR, Kung HF. Characterization of optically resolved 9-fluoropropyldihydrotetrabenazine as a potential PET imaging agent targeting vesicular monoamine transporters. Nucl Med Biol 2007;34:239-246.
76. Kilbourn MR, Hockley B, Lee L, et al. Pharmacokinetics of [18F]fluoroalkyl derivatives of dihydrotetrabenazine in rat and monkey brain. Nucl Med Biol 2007;34:233-237.
77. Kung MP, Hou C, Lieberman BP, et al. In vivo imaging of -cell mass in rats using 18F-FP-(+)-DTBZ: a potential PET ligand for studying diabetes mellitus. J Nucl Med 2008;49:1171-1176.
78. Kruger NJ. The Bradford method for protein quantitation. In: Walker JM, ed. The Protein Protocols Handbook. 2nd edtion. Totowa, New Jersey: Humana Press; 2002:15-21.
79. Chen MK, Kuwabara H, Zhou Y, et al.VMAT2 and dopamine neuron loss in a primate model of Parkinson’s disease. J Neurochem 2008;105:78-90.
80. Deuther-Conrad W, Wevers A, Becker G, et al. Autoradiography of 2-[18F]F-A-85380 on nicotinic acetylcholine receptors in the porcine brain In vitro. Synapse 2006;59:201-210.
81. Juang JH, Kuo CH., Hsu BR. Effects of multiple site implantation on islet transplantation. Transplant Proc 2002;34:2698-2699.
82. Naggar MM, Elayat AA, Ardawi MS, Tahir M. Isolated pancreatic islets of the rat: an immunohistochemical and morphometric study. Anat Rec 1993;237:489-497.
83. Tahir M, Elayat AA, Jalalah S, Naggar MM. Isolated pancreatic islets of the rat: an ultrastructural study. Acta Anat (Basel) 1992;145:93-100.
84. Henry JP, Scherman D. Radioligands of the vesicular monoamine transporter and their use as markers of monoamine storage vesicles. Biochem Pharmacol 1989;15:2395-2404.
85. Kilbourn M, Lee L, Vander Borght T, Jewett D, Frey K. Binding of alpha-dihydrotetrabenazine to the vesicular monoamine transporter is stereospecific. Eur J Pharmacol 1995;3:249-252.
QRCODE
 
 
 
 
 
                                                                                                                                                                                                                                                                                                                                                                                                               
第一頁 上一頁 下一頁 最後一頁 top
系統版面圖檔 系統版面圖檔