Imaging neurofibrillary tangles and astrogliosis for the clarification of the pathogenesis of Alzheimer's disease

• Project/Area Number: 18H02771
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Single-year Grants
• Section: 一般
• Review Section: Basic Section 52040:Radiological sciences-related
• Research Institution: Tohoku Medical and Pharmaceutical University
• Principal Investigator: 岡村 信行 東北医科薬科大学, 医学部, 教授 (40361076)
• Project Period (FY): 2018-04-01 – 2023-03-31
• Project Status: Granted (Fiscal Year 2020)
• Budget Amount: ¥16,900,000 (Direct Cost: ¥13,000,000、Indirect Cost: ¥3,900,000); Fiscal Year 2020: ¥2,080,000 (Direct Cost: ¥1,600,000、Indirect Cost: ¥480,000); Fiscal Year 2019: ¥7,930,000 (Direct Cost: ¥6,100,000、Indirect Cost: ¥1,830,000); Fiscal Year 2018: ¥2,730,000 (Direct Cost: ¥2,100,000、Indirect Cost: ¥630,000)
• Keywords: アルツハイマー病 / アストロサイト / タウ / PET

Outline of Annual Research Achievements

活性化したアストロサイトやミクログリアによってもたらされる神経炎症は、神経変性疾患の発病機序の一つとして示唆されてきた。反応性アストロサイトの非侵襲的イメージングは、アルツハイマー病の新規治療薬開発における画像バイオマーカーとして期待できる。本年度は反応性アストロサイトに高発現するモノアミン酸化酵素B（MAO-B）を標的とした新規PETプローブを実用化するため、候補化合物の前臨床評価を実施した。新規プローブ候補化合物SMBT-1はMAO-Bへの高い結合親和性を示した。またMAO-Aやその他の酵素、受容体、トランスポーターなどとの結合親和性は低く、老人斑や神経原線維変化などのミスフォールディング蛋白病変への結合性も認めなかった。SMBT-1の18F標識体は、マウスへの静脈内投与後に[18F]THK5351を上回る優れた体内動態を示した。またSMBT-1は急性毒性試験において臨床応用可能な安全域を有していた。
アルツハイマー病における神経原線維変化を検出するタウPETプローブの開発が国内外で進められてきたが、既存のプローブにはオフターゲット結合が存在し、体内動態も満足な性能が得られていない。そこでタウ病理像への選択性に優れた新規PETプローブを開発するため、化合物の探索を行った。その結果、タウ病変に対して優れた結合親和性、結合選択性を示す新規化合物群を新たに見出した。その化合物の一つは既存のタウPETプローブよりも優れた体内動態特性を示し、有力なタウPETプローブの候補化合物と考えられた。今後、周辺化合物の評価を行い、化合物の最適化を進める予定である。

Current Status of Research Progress

2: Research has progressed on the whole more than it was originally planned.

Reason

反応性アストロサイトを検出する新規プローブに関しては当初の予定通り、前臨床評価を完了し、実用化間近の段階にある。また次世代タウプローブの開発においても有力なプローブ候補化合物の発見に至っており、順調に進行している。

Strategy for Future Research Activity

反応性アストロサイトを画像化するPETプローブはモノアミン酸化酵素B（MAO-B）を標的としている。In vivoでのプローブの結合選択性を評価するためにはMAO-B阻害薬を用いたブロッキング研究が必要とされるため、海外での臨床研究を実施する計画である。次世代タウプローブに関してはすでに基本骨格が固まっており、側鎖の構造の改変によって更なる高性能化を図る予定である。

Research Products

• [Journal Article] Association of deposition of tau and amyloid-β proteins with structural connectivity changes in cognitively normal older adults and Alzheimer’s disease spectrum patients (2018)
  • Author(s): Shigemoto Y, Sone D, Maikusa N, Okamura N, Furumoto S, Kudo Y, Ogawa M, Takanno H, Yokoi Y, Sakata M, Tsukamoto T, Kato K, Sato N, Matsuda H
  • Journal Title: Brain and Behavior Volume: 8
  • DOI: 10.1002/brb3.1145
  • Peer Reviewed / Open Access
• [Journal Article] Involvement of the Precuneus/Posterior Cingulate Cortex Is Significant for the Development of Alzheimer's Disease: A Pet (Thk5351, Pib) and Resting Fmri Study. (2018)
  • Author(s): Yokoi Takamasa、Watanabe Hirohisa、Ishigaki Shinsuke、Katsuno Masahisa、Miyao Shinichi、Kato Katsuhiko、Naganawa Shinji、Harada Ryuichi、Okamura Nobuyuki、Yanai Kazuhiko、Yoshida Mari、Sobue Gen （ほか9名）
  • Journal Title: Front Aging Neurosci Volume: 10 Pages: 304-304
  • DOI: 10.3389/fnagi.2018.00304
  • Peer Reviewed / Open Access
• [Journal Article] Investigation of the quantitative accuracy of low-dose amyloid and tau PET imaging (2018)
  • Author(s): Nai YH, Watanuki S, Tashiro M, Okamura N, Watabe H.
  • Journal Title: Radiological Physics and Technology Volume: 11 Pages: 451-459
  • DOI: 10.1007/s12194-018-0485-y
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Imaging protein misfolding in the brain using β-Sheet ligands. (2018)
  • Author(s): Harada Ryuichi、Okamura Nobuyuki、Furumoto Shozo、Yanai Kazuhiko
  • Journal Title: Front Neurosci. Volume: 12 Pages: 585-585
  • DOI: 10.3389/fnins.2018.00585
  • Peer Reviewed / Open Access
• [Journal Article] Targeting metals rescues the phenotype in an animal model of tauopathy (2018)
  • Author(s): Sedjahtera Amelia、Gunawan Lydia、Bray Lisa、Hung Lin Wai、Parsons Jack、Okamura Nobuyuki、Villemagne Victor L.、Yanai Kazuhiko、Liu Xiang M.、Chan Jacky、Bush Ashley I.、Finkelstein David I.、Barnham Kevin J.、Cherny Robert A.、Adlard Paul A.
  • Journal Title: Metallomics Volume: 10 Pages: 1339-1347
  • DOI: 10.1039/c8mt00153g
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] [18F]THK-5351 PET imaging in early-stage semantic variant primary progressive aphasia: a report of two cases and a literature review. (2018)
  • Author(s): Kobayashi Ryota、Hayashi Hiroshi、Kawakatsu Shinobu、Ishiki Aiko、Okamura Nobuyuki、Arai Hiroyuki、Otani Koichi
  • Journal Title: BMC Neurol. Volume: 18 Pages: 109-109
  • DOI: 10.1186/s12883-018-1115-3
  • Peer Reviewed / Open Access
• [Journal Article] Dissociation of Tau Deposits and Brain Atrophy in Early Alzheimer’s Disease: A Combined Positron Emission Tomography/Magnetic Resonance Imaging Study (2018)
  • Author(s): Shigemoto Y, Sone D, Imabayashi E, Maikusa N, Okamura N, Furumoto S, Kudo Y, Ogawa M, Takano H, Yokoi Y, Sakata M, Tsukamoto T, Kato K, Sato N, Matsuda H.
  • Journal Title: Frontiers in Aging Neuroscience Volume: 10 Pages: 223-223
  • DOI: 10.3389/fnagi.2018.00223
  • Peer Reviewed / Open Access
• [Journal Article] Visualization of ischemic stroke-related changes on 18F-THK-5351 positron emission tomography (2018)
  • Author(s): Huang Kuo-Lun、Hsu Jung-Lung、Lin Kun-Ju、Chang Chien-Hung、Wu Yi-Ming、Chang Ting-Yu、Chang Yeu-Jhy、Liu Chi-Hung、Ho Meng-Yang、Wey Shiaw-Pyng、Yen Tzu-Chen、Okamura Nobuyuki、Hsiao Ing-Tsung、Lee Tsong-Hai
  • Journal Title: EJNMMI Research Volume: 8 Pages: 62-62
  • DOI: 10.1186/s13550-018-0417-1
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] IgLON5: A case with predominant cerebellar tau deposits and leptomeningeal inflammation (2018)
  • Author(s): Schoberl Florian、Levin Johannes、Remi Jan、Goldschagg Nicolina、Eren Ozan、Okamura Nobuyuki、Unterrainer Marcus、Rominger Axel、Albert Nathalie、Brendel Matthias
  • Journal Title: Neurology Volume: 91 Pages: 180-182
  • DOI: 10.1212/wnl.0000000000005859
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Neuroimaging-pathological correlations of [18F]THK5351 PET in progressive supranuclear palsy. (2018)
  • Author(s): Ishiki A, Harada R, Kai H, Sato N, Totsune T, Tomita N, Watanuki S, Hiraoka K, Ishikawa Y, Funaki Y, Iwata R, Furumoto S, Tashiro M, Sasano H, Kitamoto T, Kudo Y, Yanai K, Furukawa K, Okamura N, Arai H.
  • Journal Title: Acta Neuropathol Commun. Volume: 6 Pages: 53-53
  • DOI: 10.1186/s40478-018-0556-7
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Comparison of 18F-T807 and 18F-THK5117 PET in a Mouse Model of Tau Pathology (2018)
  • Author(s): Brendel Matthias、Yousefi Behrooz H.、Blume Tanja、Herz Michael、Focke Carola、Deussing Maximilian、Peters Finn、Lindner Simon、von Ungern-Sternberg Barbara、Drzezga Alexander、Bartenstein Peter、Haass Christian、Okamura Nobuyuki、Herms Jochen、Yakushev Igor、Rominger Axel
  • Journal Title: Frontiers in Aging Neuroscience Volume: 10 Pages: 174-174
  • DOI: 10.3389/fnagi.2018.00174
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] S-[18F]THK-5117-PET and [11C]PIB-PET Imaging in Idiopathic Normal Pressure Hydrocephalus in Relation to Confirmed Amyloid-β Plaques and Tau in Brain Biopsies (2018)
  • Author(s): Leinonen V, Rauramaa T, Johansson J, Bottelbergs A, Tesseur I, van der Ark P, Pemberton D, Koivisto Anne M., Jskelinen Juha E., Hiltunen M, Herukka Sanna-Kaisa, Blennow K, Zetterberg H, Jokinen P, Rokka J, Helin S, Haaparanta-Solin M, Solin O, Okamura N, Kolb Hartmuth C., Rinne Juha O.
  • Journal Title: Journal of Alzheimer's Disease Volume: 64 Pages: 171-179
  • DOI: 10.3233/jad-180071
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Dual tracer tau PET imaging reveals different molecular targets for 11C-THK5351 and 11C-PBB3 in the Alzheimer brain (2018)
  • Author(s): Chiotis Konstantinos、Stenkrona Per、Almkvist Ove、Stepanov Vladimir、Ferreira Daniel、Arakawa Ryosuke、Takano Akihiro、Westman Eric、Varrone Andrea、Okamura Nobuyuki、Shimada Hitoshi、Higuchi Makoto、Halldin Christer、Nordberg Agneta
  • Journal Title: European Journal of Nuclear Medicine and Molecular Imaging Volume: 45 Pages: 1605-1617
  • DOI: 10.1007/s00259-018-4012-5
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Quantitative evaluation of tau PET tracers 18F-THK5351 and 18F-AV-1451 in Alzheimer’s disease with standardized uptake value peak-alignment (SUVP) normalization (2018)
  • Author(s): Chen Jingyun、Alzheimer’s Disease Neuroimaging Initiative、Li Yi、Pirraglia Elizabeth、Okamura Nobuyuki、Rusinek Henry、de Leon Mony J.
  • Journal Title: European Journal of Nuclear Medicine and Molecular Imaging Volume: 45 Pages: 1596-1604
  • DOI: 10.1007/s00259-018-4040-1
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] The development and validation of tau PET tracers: current status and future directions (2018)
  • Author(s): Okamura N, Harada R, Ishiki A, Kikuchi A, Nakamura T, Kudo Y
  • Journal Title: Clinical and Translational Imaging Volume: 6 Pages: 305-316
  • DOI: 10.1007/s40336-018-0290-y
  • Peer Reviewed / Open Access
• [Presentation] PET imaging of neuropathology in Alzheimer’s disease. (2019)
  • Author(s): Okamura Nobuyuki
  • Organizer: 3th International Symposium on Molecular Imaging, Havana, Cuba
  • Int'l Joint Research / Invited
• [Presentation] Toward the development of novel imaging agents for protein misfolding diseases. (2018)
  • Author(s): Okamura Nobuyuki
  • Organizer: 2018 International Conference on Neurodegenerative Disorders, CGMH
  • Int'l Joint Research / Invited
• [Presentation] Potential application of 18F-THK5351 and its derivatives for PET imaging of astrogliosis in human brain. (2018)
  • Author(s): Okamura Nobuyuki、Harada Ryuichi
  • Organizer: AAIC 2018
  • Int'l Joint Research
• [Presentation] 認知症の画像診断の最先端 (2018)
  • Author(s): 岡村信行、原田龍一
  • Organizer: 第33回日本老年精神医学会
  • Invited
• [Presentation] Development of PET tracers for imaging amyloid, tau and gliosis. (2018)
  • Author(s): 岡村信行、原田龍一
  • Organizer: 第58回日本核医学会学術集会
• [Patent(Industrial Property Rights)] モノアミンオキシダーゼBイメージングプローブ (2018)
  • Inventor(s): 原田龍一、古本祥三、工藤幸司、岡村信行
  • Industrial Property Rights Holder: 国立大学法人東北大学
  • Industrial Property Rights Type: 特許
  • Filing Date: 2018