芬布芬 (Fenbufen)的衍生物4-([1,1'-biphenyl]-4-yl)-N-octyl-4 -oxobutanamide 為一鍋化液相平行合成後篩選之具有癌細胞毒殺潛力的藥物。因此透過將其放射性標幟後進行動物造影，用以了解芬布芬衍生物於動物體內之分布情形。
利用市售藥品1-chlorooctan-8-ol經由兩步合成甲苯磺醯化前驅物8-(1,3-dioxoisoindolin-2-yl)octyl 4-methyl benzenesulfonate (2)，總產率為50 %，經由放射化學標幟後，再進行去保護以及醯胺鍵耦合反應用以合成出4-([1,1'-biphenyl]-4-yl)-N-(8- [18F]fluorooctyl)-4- oxobutanamide ([18F] FOFA 12)，放射化學產率為13 %，放射化學純度為99 %，比放射活度為22 GBq/ μmol。
[18F] FOFA 12在體外試驗中會累積在C6 glioma cell和fibroblast cell中，且由PET影像得知 [18F] FOFA 12會累積在具有C6 glioma大鼠的腦腫瘤位置，然而由於 [18F] FOFA 12在骨頭組織上有顯著的活度累積，也標示出 [18F] FOFA 12可能存在著穩定性方面的問題。

According to our previous research, the analog of fenbufen, 4-([1,1'-biphenyl]-4-yl)-N-octyl-4–oxobutanamide, was discovered through in situ parallel synthesis , which become a potential drug for cancer cell cytotoxicity. By means of radio-labeling, we could understand the distribution of fenbufen analog in tumor animal model.
By using 1-chlorooctan-8-ol as a starting material, via two steps synthesis, with chemical yield 50 %, we may synthesized the toluenesulfonate ester compound, 8-(1,3-dioxoisoindolin-2-yl)octyl 4-methyl benzenesulfonate (2) as precursor of radiofluorination.
[18F] FOFA 12, was prepared from precursor tosylate (2), followed with further deprotection and amide bond formation. Under this synthetic pathway, [18F] FOFA 12, was prepared with a radiochemical yield of 13 %, a specific activity 22 GBq/ μmol and radiochemical purity of 99 %.
In vitro cell uptake experiment showed that [18F] FOFA 12 will accumulate in C6 glioma cell and fibroblast cell. Positron emission tomography (PET) imaging also provided an evident accumulation of [18F] FOFA 12 at the lesion of brain tumor of C6 glioma rats. Instability of [18F] FOFA 12 was marked because of a significant accumulation of radioactivity in the bone tissues

摘要 6
Abstract 7
縮寫對照表 11
第一章 緒論 13
1.1 藥物開發 (Drug discovery) 13
1.2 舊藥新用 (New uses for old drugs) 16
1.2.1非類固醇抗發炎藥物 (Non- steroidal anti-inflammatory drugs, NSAIDs) 19
1.2.2芬布芬 (Fenbufen) 23
1.3 環氧合酶 (COX)的生物機轉及前列腺素 (prostanoid)合成 25
1.3.1前列腺素的合成途徑 25
1.3.2前列腺素內過氧化合物合酶 (PGHSs) 25
1.3.3環氧合酶反應機構 (COX reaction) 28
1.3.4環氧合酶活性與過氧化物 (peroxides)相關的活化 30
1.3.5前列腺素F合成酶 (Prostaglandin F synthases, PGFSs) 31
1.4 分子影像 (Molecular imaging, MI) 36
1.4.1正子造影 (positron-emission tomography, PET) 38
1.4.2 Fluorine-18 (F-18)放射性同位素 39
1.4.3 FDA核准正子造影藥物 (FDA approved PET drugs) 41
第二章 合成目標 43
第三章 結果與討論 45
3. 1非放射性實驗結果與討論 45
3. 1. 1非放射性化合物 (12)逆合成分析 45
3. 1. 2製備2-(8-hydroxyoctyl)isoindoline-1,3-dione (1) 46
3. 1. 3製備8-(1,3-dioxoisoindolin-2-yl)octyl-methylbenzenesulfonate (2) 47
3. 1. 4經由(2)製備2-(8-fluorooctyl)isoindoline-1,3-dione (3) 49
3. 1. 5 經由 (3)製備8-fluorooctan-1-amine (5) 50
3. 1. 6 經由(5)製備4-([1,1'-biphenyl]-4-yl)-N-(8-fluorooctyl) -4-oxobutan-amide (FOFA) (12) 52
3. 2放射性實驗結果與討論 53
3.2.1放射性化合物 (12)逆合成分析 53
3. 2. 2製備2-(8-[18F]fluorooctyl)isoindoline-1,3-dione ([18F] 3) 53
3. 2. 3製備8-[18F]fluorooctan-1-amine ([18F]5) 57
3. 2. 4製備4-([1,1'-biphenyl]-4-yl)-N-(8-[18F]fluorooctyl) -4-oxobutanamide ([18F] FOFA 12) 61
3. 3生物實驗 75
3.3.1神經膠質瘤細胞和纖維母細胞對於 [18F] FOFA 12的細胞累積結果 75
3.3.2動物造影 77
第四章 實驗步驟 80
4.1 通用性實驗方法、材料與儀器 80
4.2非放射性實驗合成步驟 83
4.2.1 製備 2-(8-hydroxyoctyl)isoindoline-1,3-dione (1) 83
4.2.2 經由TsCl製備8-(1,3-dioxoisoindolin-2-yl)octyl 4-methyl benzenesulfonate (2) 85
4.2.3 經由Ts2O製備8-(1,3-dioxoisoindolin-2-yl)octyl 4-methylbenzenesulfonate (2) 88
4.2.4 製備2-(8-fluorooctyl)isoindoline-1,3-dione (3) 做為標準品 90
4.2.5 經由 (2)製備2-(8-fluorooctyl)isoindoline-1,3-dione (3) 93
4.2.6 製備8-fluorooctan-1-amine (5) 96
4.2.7 經由 (5)製備4-([1,1'-biphenyl]-4-yl)-N-(8-fluorooctyl) -4-oxobutanamide (FOFA 12) 99
4.3 放射性化合物 (12)之實驗合成步驟 102
4.3.1製備4-([1,1'-biphenyl]-4-yl)-N-(8-[18F]fluorooctyl) -4-oxobutanamide ([18F]FOFA 12) 102
4.4 生物實驗 105
4.4.1 細胞累積實驗 ([18F] FOFA 12) 105
4.4.2 動物造影 ([18F] FOFA 12) 106
第五章 結論 107
參考文獻 109
附錄 126

1. Bunnage, M. E., Getting pharmaceutical R&D back on target. Nature Chemical Biology 2011, 7 (6), 335-9
2. Hoelder, S.; Clarke, P. A.; Workman, P., Discovery of small molecule cancer drugs: successes, challenges and opportunities. Molecular Oncology 2012, 6 (2), 155-76.
3. Swinney, D. C.; Anthony, J., How were new medicines discovered? Nature Rreviews Drug Discovery 2011, 10 (7), 507-19.
4. Collins, I.; Workman, P., New approaches to molecular cancer therapeutics. Nature Chemical Biology 2006, 2 (12), 689-700.
5. Willmann, J. K.; van Bruggen, N.; Dinkelborg, L. M.; Gambhir, S. S., Molecular imaging in drug development. Nature Reviews Drug Discovery 2008, 7 (7), 591-607.
6. Ashburn, T. T.; Thor, K. B., Drug repositioning: identifying and developing new uses for existing drugs. Nature Reviews Drug Discovery 2004, 3 (8), 673-83.
7. Kola, I.; Landis, J., Can the pharmaceutical industry reduce attrition rates? Nature Reviews Drug Discovery 2004, 3 (8), 711-5.
8. Sasaki, T.; Koivunen, J.; Ogino, A.; Yanagita, M.; Nikiforow, S.; Zheng, W.; Lathan, C.; Marcoux, J. P., A novel ALK secondary mutation and EGFR signaling cause resistance to ALK kinase inhibitors. Cancer. Res 2011, 71 (18), 6051-60.
9. Roskoski, R., Jr., Anaplastic lymphoma kinase (ALK): structure, oncogenic activation, and pharmacological inhibition. Pharmacological Research 2013, 68 (1), 68-94.
10. Poulikakos, P. I.; Persaud, Y.; Janakiraman, M.; Kong, X. J.; Ng, C.; Moriceau, G., RAF inhibitor resistance is mediated by dimerization of aberrantly spliced BRAF(V600E). Nature 2011, 480 (7377), 387-U144.
11. Bollag, G.; Tsai, J.; Zhang, J.; Zhang, C.; Ibrahim, P.; Nolop, K.; Hirth, P., Vemurafenib: the first drug approved for BRAF-mutant cancer. Nature reviews Drug Discovery 2012, 11 (11), 873-86.
12. Luke, J. J.; Hodi, F. S., Vemurafenib and BRAF inhibition: a new class of treatment for metastatic melanoma. Clin. Cancer. Res 2012, 18 (1), 9-14.
13. Mullard, A., Drug repurposing programmes get lift off. Nature Reviews Drug Discovery 2012, 11 (7), 505-6.
14. Tobinick, E. L., The value of drug repositioning in the current pharmaceutical market. Drug news & Perspectives 2009, 22 (2), 119-25
15. Cohen, F. J., Macro trends in pharmaceutical innovation. Nature Reviews Drug Discovery 2005, 4 (1), 78-84.
16. Kaitin, K. I., Deconstructing the drug development process: the new face of innovation. Clinical Pharmacology & Therapeutics 2010, 87 (3), 356-61.
17. DiPiro, J. T.; American Society of Health-System Pharmacists., Concepts in clinical pharmacokinetics. 5th ed.; American Society of Health-System Pharmacists: Bethesda, MD, 2010; p xii, 248 p
18. Derendorf, H.; Meibohm, B., Modeling of pharmacokinetics/ pharmacodynamics (PK/PD) relationships: concepts and perspectives. Pharmaceutical Research 2001, 16 (2), 176-85.
19. Goodman, L. S.; Brunton, L. L.; Chabner, B.; Knollmann, B. r. C., Goodman & Gilman's pharmacological basis of therapeutics. 12th ed.; McGraw-Hill: New York, 2011; p 2084 p.
20. Li, Y. Y.; Jones, S. J., Drug repositioning for personalized medicine. Genome Medicine 2012, 4 (3), 27.
21. DiMasi, J. A.; Hansen, R. W.; Grabowski, H. G., The price of innovation: new estimates of drug development costs. Journal of Health Economics 2003, 22 (2), 151-85.
22. Ma, D. L.; Chan, D. S.; Leung, C. H., Drug repositioning by structure-based virtual screening. Chemical Society Reviews 2013, 42 (5), 2130-41.
23. Aronson, J. K., Old drugs--new uses. British Journal of Clinical Pharmacology 2007, 64 (5), 563-5.
24. Piazza, G. A.; Keeton, A. B.; Tinsley, H. N.; Whitt, J. D. NSAIDs: Old drugs reveal new anticancer targets. Pharmaceuticals 2010, 3, 1652-1667.
25. Cha, Y. I.; Duboris, R. N., NSAIDs and cancer prevention: targets downstream of COX-2. Annua Review of Medicine 2007, 58, 239-52
26. Ulrich, C. M.; Bigler, J.; Potter, J. D., Non-steroidal anti-inflammatory drugs for cancer prevention: promise, perils and pharmacogenetics. Nat.Rev.Cancer 2006, 6 (2), 130-140.
27. Brideau, C.; Kargman, S.; Liu, S.; Dallob, A. L.; Ehrich, E. W.; Rodger, I. W.; Chan, C. C., A human whole blood assay for clinical evaluation of biochemical efficacy of cyclooxygenase inhibitors. Inflamm Res 1996, 45 (2), 68-74.
28. Cryer, B.; Feldman, M., Cyclooxygenase-1 and cyclooxygenase-2 selectivity of widely used nonsteroidal anti-inflammatory drugs. American Journal of Medicine 1998, 104 (5), 413-421.
29. Paulose-Ram R, Hirsch R, Dillon C, et al.Prescription and non-prescription analgesic use among the US adult population: results from the third National Health and Nutrition Examination Survey (NHANES III). Pharmacoepidemiol. Drug. Saf. 2003, 12, 315–26
30. Melnikova, I., Pain market. Nature reviews Drug Discovery 2010, 9 (8), 589-90,
31. Batlouni, M., [Nonsteroidal anti-inflammatory drugs: cardiovascular, cerebrovascular and renal effects]. Arquivos Brasileiros de Cardiologia 2010, 94 (4), 556-63.
32. Cryer, B.; Feldman, M., Cyclooxygenase-1 and cyclooxygenase-2 selectivity of widely used nonsteroidal anti-inflammatory drugs. The American Journal of Medicine 1998, 104 (5), 413-21.
33. Vane, J. R.; Botting, R. M., Mechanism of action of antiinflammatory drugs. International Journal of Tissue Reactions 1998, 20 (1), 3-15
34. Antman, E. M.; DeMets, D.; Loscalzo, J., Cyclooxygenase inhibition and cardiovascular risk. Circulation 2005, 112 (5), 759-70.
35. Grosser, T.; Fries, S.; FitzGerald, G. A., Biological basis for the cardiovascular consequences of COX-2 inhibition: therapeutic challenges and opportunities. The Journal of Clinical Investigation 2006, 116 (1), 4-15.
36. Hennekens, C. H.; Borzak, S., Cyclooxygenase-2 inhibitors and most traditional nonsteroidal anti-inflammatory drugs cause similar moderately increased risks of cardiovascular disease. Journal of Cardiovascular Pharmacology and Therapeutics 2008, 13 (1), 41-50.
37. Melnikova, I., Future of COX2 inhibitors. Nature reviews Drug Discovery 2005, 4 (6), 453-4.
38. Mukherjee, D.; Nissen, S. E.; Topol, E. J., Risk of cardiovascular events associated with selective COX-2 inhibitors. JAMA : The Journal of The American Medical Association 2001, 286 (8), 954-9.
39. Hennekens, C. H.; Borzak, S., Cyclooxygenase-2 inhibitors and most traditional nonsteroidal anti-inflammatory drugs cause similar moderately increased risks of cardiovascular disease. Journal of Cardiovascular Ppharmacology and Therapeutics 2008, 13 (1), 41-50.
40. Johannesdottir, S. A.; Chang, E. T.; Mehnert, F.; Schmidt, M.; Olesen, A. B.; Sorensen, H. T., Nonsteroidal anti-inflammatory drugs and the risk of skin cancer: a population-based case-control study. Cancer 2012, 118 (19), 4768-76.
41. Liu, J. K.; Patel, S. K.; Gillespie, D. L.; Whang, K.; Couldwell, W. T., R-flurbiprofen, a novel nonsteroidal anti-inflammatory drug, decreases cell proliferation and induces apoptosis in pituitary adenoma cells in vitro. Journal of Neuro Oncology 2012, 106 (3), 561-9.
42. Din, F. V.; Theodoratou, E.; Farrington, S. M.; Tenesa, A.; Barnetson, R. A.; Cetnarskyj, R.; Stark, L.; Porteous, M. E.; Campbell, H.; Dunlop, M. G., Effect of aspirin and NSAIDs on risk and survival from colorectal cancer. Gut 2010, 59 (12), 1670-9.
43. Baron, J. A.; Sandler, R. S.; Bresalier, R. S.; Quan, H.; Riddell, R., A randomized trial of rofecoxib for the chemoprevention of colorectal adenomas. Gastroenterology 2006, 131 (6), 1674-82.
44. Thun, M. J.; Henley, S. J.; Patrono, C., Nonsteroidal anti-inflammatory drugs as anticancer agents: mechanistic, pharmacologic, and clinical issues. Journal of the National Cancer Institute 2002, 94 (4), 252-66.
45. Chan, T. A., Nonsteroidal anti-inflammatory drugs, apoptosis, and colon-cancer chemoprevention. The Lancet Oncology 2002, 3 (3), 166-74.
46. Giardiello, F. M.; Hamilton, S. R.; Krush, A. J.; Piantadosi, S.; Hylind, L. M.; Celano, P.; Booker, S. V.; Robinson, C. R.; Offerhaus, G. J., Treatment of colonic and rectal adenomas with sulindac in familial adenomatous polyposis. The New England Journal of Medicine 1993, 328 (18), 1313-6.
47. Steinbach, G.; Lynch, P. M.; Phillips, R. K.; Wallace, M. H.; Hawk, E.; Gordon, G. B., The effect of celecoxib, a cyclooxygenase-2 inhibitor, in familial adenomatous polyposis. The New England Journal of Medicine 2000, 342 (26), 1946-52.
48. Zhang, D. Q.; Guo, Q.; Zhu, J. H.; Chen, W. C., Increase of cyclooxygenase-2 inhibition with celecoxib combined with 5-FU enhances tumor cell apoptosis and antitumor efficacy in a subcutaneous implantation tumor model of human colon cancer. World Journal of Surgical Oncology 2013, 11, 16.
49. Valcarcel, M.; Mendoza, L.; Hernandez, J. J.; Carrascal, T., Vascular endothelial growth factor regulates melanoma cell adhesion and growth in the bone marrow microenvironment via tumor cyclooxygenase-2. Journal of Translational Medicine 2011, 9, 142.
50. Fischer, S. M.; Hawk, E. T.; Lubet, R. A., Coxibs and other nonsteroidal anti-inflammatory drugs in animal models of cancer chemoprevention. Cancer. Prev. Res (Phila) 2011, 4 (11), 1728-35.
51. Husain, A.; Ahmad, A.; Alam, M. M.; Ajmal, M.; Ahuja, P., Fenbufen based 3-[5-(substituted aryl)-1,3,4-oxadiazol-2-yl]-1 -(biphenyl-4-yl) propan-1-ones as safer antiinflammatory and analgesic agents. European Journal of Medicinal Chemistry 2009, 44 (9), 3798-804.
52. Chiang, L. W.; Pei, K.; Chen, S. W.; Huang, H. L.; Lin, K. J.; Yen, T. C.; Yu, C. S., Combining a solution-phase derived library with in-situ cellular bioassay: prompt screening of amide-forming minilibraries using MTT assay. Chemical & Pharmaceutical Bulletin 2009, 57 (7), 714-8
53. Lin, K. I.; Yang, C. H.; Huang, C. W.; Jian, J. Y.; Huang, Y. C.; Yu, C. S., Synthesis and structure-activity relationships of fenbufen amide analogs. Molecules 2010, 15 (12), 8796-803.
54. Smith, W. L.; Urade, Y.; Jakobsson, P. J., Enzymes of the cyclooxygenase pathways of prostanoid biosynthesis. Chem. Rev 2011, 111 (10), 5821-65.
55. Farooqui, A. A.; Horrocks, L. A.; Farooqui, T., Deacylation and reacylation of neural membrane glycerophospholipids. Journal of Molecular Neuroscience : MN 2000, 14 (3), 123-35.
56. Smith, W. L.; DeWitt, D. L.; Garavito, R. M., Cyclooxygenases: structural, cellular, and molecular biology. Annual Review of Biochemistry 2000, 69, 145-82.
57. Smith, W. L., Nutritionally essential fatty acids and biologically indispensable cyclooxygenases. Trends in Biochemical Sciences 2008, 33 (1), 27-37.
58. Simmons, D. L.; Botting, R. M.; Hla, T., Cyclooxygenase isozymes: the biology of prostaglandin synthesis and inhibition. Pharmacological Reviews 2004, 56 (3), 387-437.
59. Poole, E. M.; Bigler, J.; Whitton, J.; Sibert, J. G.; Kulmacz, R. J.; Potter, J. D.; Ulrich, C. M., Genetic variability in prostaglandin synthesis, fish intake and risk of colorectal polyps. Carcinogenesis 2007, 28 (6), 1259-63.
60. Smith, W. L.; DeWitt, D. L.; Garavito, R. M., Cyclooxygenases: structural, cellular, and molecular biology. Annual Review of Biochemistry 2000, 69, 145-82.
61. Liu, J.; Seibold, S. A.; Rieke, C. J.; Song, I.; Cukier, R. I.; Smith, W. L., Prostaglandin endoperoxide H synthases: peroxidase hydroperoxide specificity and cyclooxygenase activation. The Journal of Biological Chemistry 2007, 282 (25), 18233-44.
62. Spencer, A. G.; Thuresson, E.; Otto, J. C.; Song, I.; Smith, T.; DeWitt, D. L.; Garavito, R. M.; Smith, W. L., The membrane binding domains of prostaglandin endoperoxide H synthases 1 and 2. Peptide mapping and mutational analysis. The Journal of Biological Chemistry 1999, 274 (46), 32936-42.
63. MirAfzali, Z.; Leipprandt, J. R.; McCracken, J. L.; DeWitt, D. L., Topography of the prostaglandin endoperoxide H2 synthase-2 in membranes. The Journal of Biological Chemistry 2006, 281 (38), 28354-64.
64. Raykhel, I.; Alanen, H.; Salo, K.; Jurvansuu, J.; Nguyen, V. D.; Latva-Ranta, M.; Ruddock, L., A molecular specificity code for the three mammalian KDEL receptors. The Journal of Cell Biology 2007, 179 (6), 1193-204.
65. Simmons, D. L.; Botting, R. M.; Hla, T., Cyclooxygenase isozymes: the biology of prostaglandin synthesis and inhibition. Pharmacological Reviews 2004, 56 (3), 387-437.
66. Rouzer, C. A.; Marnett, L. J., Mechanism of free radical oxygenation of polyunsaturated fatty acids by cyclooxygenases. Chem. Rev 2003, 103 (6), 2239-304.
67. Tsai, A. L.; Kulmacz, R. J., Prostaglandin H synthase: resolved and unresolved mechanistic issues. Archives of Biochemistry and Biophysics 2010, 493 (1), 103-24.
68. Kulmacz, R. J.; Wang, L. H., Comparison of hydroperoxide initiator requirements for the cyclooxygenase activities of prostaglandin H synthase-1 and -2. The Journal of Biological Chemistry 1995, 270 (41), 24019-23.
69. Karim, S. M.; Sandler, M.; Williams, E. D., Distribution of prostaglandins in human tissues. British Journal of Pharmacology and Chemotherapy 1967, 31, 340-4.
70. Kabututu, Z.; Manin, M.; Pointud, J. C.; Maruyama, T.; Nagata, N.; Lambert, S.; Lefrancois-Martinez, A. M.; Martinez, A.; Urade, Y., Prostaglandin F2alpha synthase activities of aldo-keto reductase 1B1, 1B3 and 1B7. Journal of Biochemistry 2009, 145 (2), 161-8.
71. Watanabe, K., Prostaglandin F synthase. Prostaglandins & Other Lipid Mediators 2002, 68-69, 401-7.
72. Kilunga, K. B.; Inoue, T.; Okano, Y.; Kabututu, Z.; Martin, S. K., Structural and mutational analysis of Trypanosoma brucei prostaglandin H2 reductase provides insight into the catalytic mechanism of aldo-ketoreductases. The Journal of Biological Chemistry 2005, 280 (28), 26371-82.
73. Barski, O. A.; Tipparaju, S. M.; Bhatnagar, A., The aldo-keto reductase superfamily and its role in drug metabolism and detoxification. Drug Metabolism Reviews 2008, 40 (4), 553-624.
74. Jez, J. M.; Bennett, M. J.; Schlegel, B. P.; Lewis, M.; Penning, T. M., Comparative anatomy of the aldo-keto reductase superfamily. The Biochemical Journal 1997, 326 ( Pt 3), 625-36.
75. Grimshaw, C. E., Aldose reductase: model for a new paradigm of enzymic perfection in detoxification catalysts. Biochemistry 1992, 31 (42), 10139-45.
76. Penning, T. M.; Drury, J. E., Human aldo-keto reductases: Function, gene regulation, and single nucleotide polymorphisms. Archives of Biochemistry and Biophysics 2007, 464 (2), 241-50.
77. Jin, Y.; Penning, T. M., Aldo-keto reductases and bioactivation/detoxication. Annual Review of Pharmacology and Toxicology 2007, 47, 263-92.
78. Kozma, E.; Brown, E.; Ellis, E. M.; Lapthorn, A. J., The crystal structure of rat liver AKR7A1. A dimeric member of the aldo-keto reductase superfamily. The Journal of Biological Chemistry 2002, 277 (18), 16285-93.
79. Suzuki-Yamamoto, T.; Nishizawa, M.; Fukui, M.; Okuda-Ashitaka, E.; Nakajima, T.; Ito, S.; Watanabe, K., cDNA cloning, expression and characterization of human prostaglandin F synthase. FEBS Letters 1999, 462 (3), 335-40.
80. Dozier, B. L.; Watanabe, K.; Duffy, D. M., Two pathways for prostaglandin F2 alpha synthesis by the primate periovulatory follicle. Reproduction 2008, 136 (1), 53-63.
81. Penning, T. M.; Talalay, P., Inhibition of a major NAD(P)-linked oxidoreductase from rat liver cytosol by steroidal and nonsteroidal anti-inflammatory agents and by prostaglandins. Proceedings of the National Academy of Sciences of the United States of America 1983, 80 (14), 4504-8.
82. Bauman, D. R.; Rudnick, S. I.; Szewczuk, L. M., Development of nonsteroidal anti-inflammatory drug analogs and steroid carboxylates selective for human aldo-keto reductase isoforms: potential antineoplastic agents that work independently of cyclooxygenase isozymes. Molecular Pharmacology 2005, 67 (1), 60-8.
83. Komoto, J.; Yamada, T.; Watanabe, K., Prostaglandin F2alpha formation from prostaglandin H2 by prostaglandin F synthase (PGFS): crystal structure of PGFS containing bimatoprost. Biochemistry 2006, 45 (7), 1987-96.
84. Weissleder, R.; Mahmood, U., Molecular imaging. Radiology 2001, 219 (2), 316-33.
85. Ametamey, S. M.; Honer, M.; Schubiger, P. A., Molecular imaging with PET. Chem. Rev 2008, 108 (5), 1501-16.
86. Massoud, T. F.; Gambhir, S. S., Molecular imaging in living subjects: seeing fundamental biological processes in a new light. Genes & Development 2003, 17 (5), 545-80.
87. 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 Int Ed Engl 2008, 47 (47), 8998-9033.
88. Pimlott, S. L.; Sutherland, A., Molecular tracers for the PET and SPECT imaging of disease. Chemical Society Reviews 2011, 40 (1), 149-62.
89. Vallabhajosula, S.; Kothari, P. J.; Goldsmith, S. J., Fda Approval of New Drug Application (Nda) for Fludeoxyglucose F18 Injection (Fdg). J Labelled Compd Rad 2005, 48, S22-S22.
90. FDA Approves C-11-Choline for PET in Prostate Cancer. J Nucl Med 2012, 53 (12), 11n-11n.
91. Fletcher, J. W.; Djulbegovic, B.; Soares, H. P.; Siegel, B. A., Recommendations on the use of F-18-FDG PET in oncology. J Nucl Med 2008, 49 (3), 480-508.
92. Kitajima, K.; Murphy, R. C.; Nathan, M. A., Choline PET/CT for imaging prostate cancer: an update. Ann Nucl Med 2013, 27 (7), 581-91.
93. Huang, H. L.; Yeh, C. N.; Lee, W. Y.; Huang, Y. C.; Chang, K. W.; Lin, K. J.; Tien, S. F.; Su, W. C.; Yang, C. H.; Chen, J. T.; Lin, W. J.; Fan, S. S.; Yu, C. S., [123I]Iodooctyl fenbufen amide as a SPECT tracer for imaging tumors that over-express COX enzymes. Biomaterials 2013, 34 (13), 3355-65
94. Bartholoma, M. D.; Vortherms, A. R.; Hillier, S.; Ploier, B.; Joyal, J.; Babich, J.; Doyle, R. P.; Zubieta, J., Synthesis, cytotoxicity, and insight into the mode of action of Re(CO)3 thymidine complexes. ChemMedChem 2010, 5 (9), 1513-29.
95. Albert-Seifried, S.; Finlayson, C. E.; Laquai, F.; Friend, R. H.; Swager, T. M.; Kouwer, P. H.; Juricek, M.; Kitto, H. J.; Valster, S.; Nolte, R. J.; Rowan, A. E., Multichromophoric phthalocyanine-(perylenediimide)(8) molecules: a photophysical study. Chemistry 2010, 16 (33), 10021-9
96. Zhou, Z.; Tang, Y.; Whitten, D. G.; Achyuthan, K. E., New high-throughput screening protease assay based upon supramolecular self-assembly. ACS Applied Materials & Interfaces 2009, 1 (1), 162-70.
97. Harjani, J. R.; Liang, C.; Jessop, P. G., A synthesis of acetamidines. The Journal of Organic Chemistry 2011, 76 (6), 1683-91.
98. van den Berg, R. J.; Boltje, T. J.; Verhagen, C. P., An efficient synthesis of the natural tetrahydrofuran pachastrissamine starting from D-ribo-phytosphingosine. The Journal of organic Chemistry 2006, 71 (2), 836-9
99. Armarego, W. L. F.; Chai, C. L. L., Purification of laboratory chemicals. 6th ed.; Elsevier/Butterworth-Heinemann: Amsterdam ; Boston, 2009; p xvi, 743 p.
100. Venkatesan, K.; Srinivasan, K. V., A novel stereoselective synthesis of pachastrissamine (jaspine B) starting from 1-pentadecanol. Tetrahedron-Asymmetr 2008, 19 (2), 209-15.
101. Ono, M.; Suzuki, K.; Tanikawa, S.; Akita, H., First synthesis of (+)- and (-)-elvirol based on an enzymatic function. Tetrahedron-Asymmetr 2001, 12 (18), 2597-2604.
102. Kuboyama, T.; Nakahara, M.; Yoshino, M.; Cui, Y. L., Stoichiometry-focused F-18-labeling of alkyne-substituted oligodeoxynucleotides using azido([F-18]fluoromethyl)benzenes by Cu-catalyzed Huisgen reaction. Bioorganic & Medicinal Chemistry 2011, 19 (1), 249-255.
103. Gibson, M. S., Bradshaw, R. W., The Gabriel Synthesis of Primary Amine. Angew. Chem. Int. Ed 1968, 7 (12), 919-930.
104. Tewson, T. J., Synthesis of [18F]fluoroetanidazole: a potential new tracer for imaging hypoxia. Nuclear Medicine and Biology 1997, 24 (8), 755-60.
105. Lysek, R.; Schutz, C.; Favre, S.; O'Sullivan, A. C.; Pillonel, C.; Krulle, T., Search for alpha-glucosidase inhibitors: new N-substituted valienamine and conduramine F-1 derivatives. Bioorganic & Medicinal Chemistry 2006, 14 (18), 6255-82.
106. Piscitelli, F.; Ligresti, A.; La Regina, G.; Coluccia, A.; Morera, L., Indole-2-carboxamides as allosteric modulators of the cannabinoid CB(1) receptor. Journal of Medicinal Chemistry 2012, 55 (11), 5627-31.
107. Wu, X. P.; Boz, E.; Sirkis, A. M., Synthesis and phosphonate binding of guanidine-functionalized fluorinated amphiphiles. J Fluorine Chem 2012, 135, 292-302.
108. Harjani, J. R.; Liang, C.; Jessop, P. G., A Synthesis of Acetamidines. Journal of Organic Chemistry 2011, 76 (6), 1683-1691.
109. Gilissen, C.; Bormans, G.; de Groot, T.; Verbruggen, A., Synthesis of N-(2-[F-18]fluoroethyl)-N '-methylthiourea: a hydrogen peroxide scavenger. J Labelled Compd Rad 1998, 41 (6), 491-502.
110. Miyake, K.; Shinomiya, A.; Okada, M.; Hatakeyama, T., Usefulness of FDG, MET and FLT-PET studies for the management of human gliomas. Journal of Biomedicine & Biotechnology 2012, 2012, 205818.
111. Hatakeyama, T.; Kawai, N.; Nishiyama, Y.; Yamamoto, Y.; Sasakawa, Y., 11C-methionine (MET) and 18F-fluorothymidine (FLT) PET in patients with newly diagnosed glioma. EuropeanJournal of Nuclear Medicine and Molecular Imaging 2008, 35 (11), 2009-17.
112. Chen, W.; Cloughesy, T.; Kamdar, N.; Satyamurthy, N.; Bergsneider, M.; Liau, L.; Mischel, P.; Czernin, J.; Phelps, M. E.; Silverman, D. H., Imaging proliferation in brain tumors with 18F-FLT PET: comparison with 18F-FDG. Journal of Nuclear Medicine : official publication, Society of Nuclear Medicine 2005, 46 (6), 945-52.
113. Park, B. K.; Kitteringham, N. R.; O'Neill, P. M., Metabolism of fluorine-containing drugs. Annual Review of Pharmacology and Toxicology 2001, 41, 443-70.
114. Buiter, H. J.; van Velden, F. H.; Leysen, J. E.; Fisher, A.; Windhorst, A. D.; Lammertsma, A. A.; Huisman, M. C., Reproducible Analysis of Rat Brain PET Studies Using an Additional [(18)F]NaF Scan and an MR-Based ROI Template. International journal of molecular imaging 2012, 2012, 580717
115. Hetzel, M.; Arslandemir, C.; Konig, H. H.; Buck, A. K., F-18 NaF PET for detection of bone metastases in lung cancer: accuracy, cost-effectiveness, and impact on patient management. Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research 2003, 18 (12), 2206-14.
116. Silveira, M. B.; Soares, M. A.; Valente, E. S.; Waquil, S. S.; Ferreira, A. V., Synthesis, quality control and dosimetry of the radiopharmaceutical F-18-sodium fluoride produced at the Center for Development of Nuclear Technology - CDTN. Braz J Pharm Sci 2010, 46 (3), 563-569.
117. Fabi, A.; Vidiri, A.; Carapella, C.; Pace, A.; Occhipinti, E., Bone metastasis from glioblastoma multiforme without central nervous system relapse: a case report. Anticancer Research 2004, 24 (4), 2563-5.
118. Zhang, D. Q.; Guo, Q.; Zhu, J. H.; Chen, W. C., Increase of cyclooxygenase-2 inhibition with celecoxib combined with 5-FU enhances tumor cell apoptosis and antitumor efficacy in a subcutaneous implantation tumor model of human colon cancer. World Journal of Surgical Oncology 2013, 11, 16.
119. Valcarcel, M.; Mendoza, L.; Hernandez, J. J.; Carrascal, T.; Salado, C.; Crende, O.; Vidal-Vanaclocha, F., Vascular endothelial growth factor regulates melanoma cell adhesion and growth in the bone marrow microenvironment via tumor cyclooxygenase-2. Journal of Translational Medicine 2011, 9, 142.
120. Mendes, R. A.; Carvalho, J. F.; Waal, I., An overview on the expression of cyclooxygenase-2 in tumors of the head and neck. Oral Oncology 2009, 45 (10), e124-8