| Project/Area Number |
15390014
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| Research Category |
Grant-in-Aid for Scientific Research (B)
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Research Field |
Physical pharmacy
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| Research Institution | Nagasaki University |
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Principal Investigator |
NAKAYAMA Morio Nagasaki University, Graduate School of Biomedical Sciences, Professor, 大学院・医歯薬学総合研究科, 教授 (60164373)
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| Co-Investigator(Kenkyū-buntansha) |
HARATAKE Mamoru Nagasaki University, Graduate School of Biomedical Sciences, Associate Professor, 大学院・医歯薬学総合研究科, 助教授 (40325668)
ONO Masahiro Nagasaki University, Graduate School of Biomedical Sciences, Assistant Professor, 大学院・医歯薬学総合研究科, 助手 (80336180)
MATSUDA Naoki Nagasaki University, Graduate School of Biomedical Sciences, Professor, 先導科学研究支援センター, 教授 (00304973)
ARANO Yasushi Chiba University, Graduate School of Pharmaceutical Sciences, Professor, 大学院・薬学研究院, 教授 (90151167)
SAJI Hideo Kyoto University, Graduate School of Pharmaceutical Sciences, Professor, 大学院・薬学研究科, 教授 (40115853)
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| Project Period (FY) |
2003 – 2005
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| Project Status |
Completed (Fiscal Year 2005)
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| Budget Amount *help |
¥11,700,000 (Direct Cost: ¥11,700,000)
Fiscal Year 2005: ¥1,300,000 (Direct Cost: ¥1,300,000)
Fiscal Year 2004: ¥2,300,000 (Direct Cost: ¥2,300,000)
Fiscal Year 2003: ¥8,100,000 (Direct Cost: ¥8,100,000)
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| Keywords | amyloid β protein / molecular imaging / Alzheimer's disease / PET / SPECT / flavone / アミロイド / 画像診断薬剤 / テクネチウム-99m / フラボン誘導体 / 痴呆 / 神経変性疾患 / 放射性薬剤 / 画像化 / 老人斑アミロイド / インビボ画像化 / 放射性医薬品 / 放射性金属核種 |
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| Research Abstract |
Formation and accumulation of β-amyloid (Aβ) peptide aggregates in the brain are critical factors in the development and progression of Alzheimer's disease (AD). In vivo imaging of amyloid plaques may lead to early detection of AD and monitoring the progression and effectiveness of AD treatment. In vivo imaging probes, showing high binding affinity for Aβ aggregates, and high brain penetrations, are essential for imaging of amyloid plaques in Alzheimer's disease. Recently, many agents based on Congo red and thioflavin have been reported as potential imaging agents. We have synthesized and evaluated benzofuran and stilbene derivatives labeled with ^<123>I and ^<11>C as PET and SPECT probes for imaging amyloid plaques in Alzheimer's disease. The results has prompted us to further search for effective and more practical amyloid imaging probe having a noble core structure.
It has been previously shown that some flavones may have binding affinity to amyloid plaques in research into the mecha
… More
nism behind the anti-amyloidogenic activity of flavones. In this study, a series of flavone derivatives was designed and synthesized. Preparation of radioiodinated flavone was carried out by an iododestannylation reaction catalyzed by hydrogen peroxide. The log PC value of these flavones varied from 1.9 to 2.7, spanning the optimum range. The binding affinities for amyloid plaques were assessed by in vitro binding assay using pre-formed synthetic Aβ aggregates. The binding affinities of some compounds for Aβ (1-40) and Aβ (1-42) aggregates varied from 13nM to 77nM. When in vitro plaque labeling was carried out using post-mortem AD brain sections, all flavones intensely stained not only, amyloid plaques, but also cerebrovascular amyloids. The in vivo pharmacokinetic properties of radioiodinated flavone derivatives were evaluated in normal mice with standard biodistribution studies. Several compounds displayed high brain uptakes ranging from 3.2 to 4.1%ID/g at 2min post injection. The radioactivity was washed out from the brain rapidly (0.5-1.9%ID/g at 30min), which is highly desirable for amyloid imaging agents. These results suggest that the classes of radioiodinated flavones may be useful candidates as potential imaging agents for amyloid plaques. Less
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