Elucidation of neural network disruption mechanisms by protein specific PET imaging

2018 Fiscal Year Annual Research Report

• Project Area: Prevention of brain protein aging and dementia
• Project/Area Number: 26117003
• Research Institution: Tohoku University
• Principal Investigator: 谷内 一彦 東北大学, 医学系研究科, 教授 (50192787)
• Project Period (FY): 2014-07-10 – 2019-03-31
• Keywords: 老化 / 脳神経疾患 / 認知症 / トランスレーショナルリサーチ / イメージング

Outline of Annual Research Achievements

これまでタウオパチーを含む様々な神経変性疾患における[18F]THK-5351 PETの臨床的有用性ならびにPET画像の妥当性について検討を進めてきた。PET画像病理相関解析により、[18F]THK-5351のオフターゲットの標的はモノアミン酸化酵素B(MAO-B)であることが明らかとなり、[18F]THK-5351がタウのバイオマーカーとしての利用が難しいことが明らかとなった。そこで、[18F]THK-5351をリード化合物としてさらなる化合物の最適化を図り、オフターゲット結合を排除した選択的タウPETプローブの開発を実施した。その結果、タウに対して優れた結合親和性、結合選択性を示し、脳移行性、体内動態特性に優れる化合物[18F]STTを見出すことができた。さらに、上記の[18F]THK-5351 の臨床研究よりMAO-Bはアストログリオーシスの画像バイオマーカーの標的として有望と考えられることから、MAO-Bの高感度かつ選択的な画像化をめざして新たなPETプローブの開発を実施した。化合物合成ならびにスクリーニングを実施し、MAO-Bへの結合親和性および結合選択性に優れた新規プローブ候補化合物として[18F]SMBT-1を見出した。[18F]THK-5351とは異なり、[18F]SMBT-1はミスフォールディング蛋白への結合性が全くみられず、同化合物は[18F]THK5351を上回る優れた体内動態特性を示し、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。MAO-Bを選択的に検出する新規プローブ[18F]SMBT-1の臨床応用により、グリオーシスの高感度画像化が強く期待できる。

Research Progress Status

平成30年度が最終年度であるため、記入しない。

Strategy for Future Research Activity

平成30年度が最終年度であるため、記入しない。

Research Products

• [Int'l Joint Research] メルボルン大学(オーストラリア)
  • Country Name: AUSTRALIA
  • Counterpart Institution: メルボルン大学
• [Int'l Joint Research] ニューヨーク州立大学(米国)
  • Country Name: U.S.A.
  • Counterpart Institution: ニューヨーク州立大学
• [Int'l Joint Research] カロリンスカ医科大学(スウェーデン)
  • Country Name: SWEDEN
  • Counterpart Institution: カロリンスカ医科大学
• [Int'l Joint Research] クオピオ大学(フィンランド)
  • Country Name: FINLAND
  • Counterpart Institution: クオピオ大学
• [Int'l Joint Research] ミュンヘン大学(ドイツ)
  • Country Name: GERMANY
  • Counterpart Institution: ミュンヘン大学
• [Int'l Joint Research]
  • # of Other Countries: 1
• [Journal Article] Histamine N-Methyltransferase in the Brain. (2019)
  • Author(s): Yoshikawa T, Nakamura T, Yanai K.
  • Journal Title: Int J Mol Sci. Volume: 20 Pages: E737
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  • Peer Reviewed / Open Access
• [Journal Article] Characterization of the binding of tau imaging ligands to melanin-containing cells: putative off-target-binding site. (2019)
  • Author(s): Tago T, Toyohara J, Harada R, Furumoto S, Okamura N, Kudo Y, Takahashi-Fujigasaki J, Murayama S, Ishii K.
  • Journal Title: Ann Nucl Med. Volume: in press Pages: in press
  • DOI: 10.1007/s12149-019-01344-x.
  • Peer Reviewed
• [Journal Article] Targeting metals rescues the phenotyope in an animal model of tauopathy. (2018)
  • Author(s): Sedjahtera A, Gunawan L, Bray L, Hung LW, Parsons J, Okamura N, Villemagne VL, Yanai K, Liu XM, Chan J, Bush AI, Finkelstein DI, Barnham KJ, Cherny RA, Adlard PA,
  • Journal Title: Metallomics. Volume: 10 Pages: 1339-1347
  • DOI: 10.1039/c8mt00153g.
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Distinct Roles of Small GTPases Rac1 and Rac2 in Histamine H4 Receptor-Mediated Chemotaxis of Mast Cells. (2018)
  • Author(s): Kuramasu A, Wakabayashi M, Inui M, Yanai K
  • Journal Title: J Pharmacol Exp Ther. Volume: 367 Pages: 9-19
  • DOI: 10.1124/jpet.118.249706.
  • Peer Reviewed
• [Journal Article] Histamine elicits glutamate release from cultured astrocytes. (2018)
  • Author(s): Karpati A, Yoshikawa T, Nakamura T, Iida T, Matsuzawa T, Kitano H, Harada R, Yanai K.
  • Journal Title: J Pharmacol Sci. Volume: 137 Pages: 122-128
  • DOI: 10.1016/j.jphs.2018.05.002.
  • Peer Reviewed / Open Access
• [Journal Article] Comparison of 18F-T807 and 18F-THK5117 PET in a Mouse Model of Tau Pathology. (2018)
  • Author(s): Brendel M, Yousefi BH, Blume T, Herz M, Focke C, Deussing M, Peters F, Lindner S, von Ungern-Sternberg B, Drzezga A, Bartenstein P, Haass C, Okamura N, Herms J, Yakushev I, Rominger A.
  • Journal Title: Front Aging Neurosci. Volume: 10 Pages: 174
  • DOI: 10.3389/fnagi.2018.00174.
  • Peer Reviewed / Open Access / 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
  • DOI: 10.1186/s40478-018-0556-7.
  • Peer Reviewed / Open Access
• [Journal Article] Site-Specific Labeling of F-18 Proteins Using a Supplemented Cell-Free Protein Synthesis System and O-2-[18F]Fluoroethyl-L-Tyrosine: [18F]FET-HER2 Affibody Molecule. (2018)
  • Author(s): Yanai A, Harada R, Iwata R, Yoshikawa T, Ishikawa Y, Furumoto S, Ishida T, Yanai.
  • Journal Title: Mol Imaging Biol. Volume: in press Pages: in press
  • DOI: 10.1007/s11307-018-1266-z.
  • Peer Reviewed
• [Journal Article] Newly-Developed Positron Emission Mammography (PEM) Device for the Detection of Small Breast Cancer. (2018)
  • Author(s): Yanai A, Itoh M, Hirakawa H, Yanai K, Tashiro M, Harada R, Yoshikawa T, Yamamoto S, Ohuchi N, Ishida T
  • Journal Title: Tohoku J Exp Med. Volume: 245 Pages: 13-19
  • DOI: 10.1620/tjem.245.13.
  • Peer Reviewed / Open Access
• [Journal Article] The development and validation of tau PET tracers: current status and future directions. (2018)
  • Author(s): Okamura N, Harada, Ishiki A, Kikuchi A, Nakamura T, Kudo Y.
  • Journal Title: Clin Transl Imaging. Volume: 6 Pages: 305-316
  • DOI: 10.1007/s40336-018-0290-y.
  • Peer Reviewed / Open Access
• [Journal Article] Imaging Protein Misfolding in the Brain Using β-Sheet Ligands. (2018)
  • Author(s): Harada R, Okamura N, Furumoto S, Yanai K
  • Journal Title: Front Neurosci. Volume: 12 Pages: 585
  • DOI: 10.3389/fnins.2018.00585.
  • Peer Reviewed / Open Access
• [Journal Article] Heparan sulfate in pancreatic β-cells contributes to normal glucose homeostasis by regulating insulin secretion. (2018)
  • Author(s): Matsuzawa T, Yoshikawa T, Iida T, Karpati A, Kitano H, Harada R, Nakamura T, Sugawara A, Yamaguchi Y, Yanai K.
  • Journal Title: Biochem Biophys Res Commun. Volume: 499 Pages: 688-695
  • DOI: 10.1016/j.bbrc.2018.03.213.
  • Peer Reviewed
• [Journal Article] Visualization of ischemic stroke-related changes on 18F-THK-5351 positron emission tomography. (2018)
  • Author(s): Huang KL, Hsu JL, Lin KJ, Chang CH, Wu YM, Chang TY, Chang YJ, Liu CH, Ho MY, Wey SP, Yen TC, Okamura N, Hsiao IT, Lee TH
  • Journal Title: EJNMMI Res. Volume: 8 Pages: 62
  • DOI: 10.1186/s13550-018-0417-1.
  • Peer Reviewed / Open Access / Int'l Joint Research
• [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, Done 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: Front Aging Neurosci. Volume: 10 Pages: 223
  • DOI: 10.3389/fnagi.2018.00223.
  • 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: Radiol Phys Technol. Volume: 11 Pages: 451-459
  • DOI: 10.1007/s12194-018-0485-y.
  • Peer Reviewed
• [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, Takano H, Yokoi Y, Sakata M, Tasukamoto T, Kato K, Sato N, Matsuda H.
  • Journal Title: Brain Behav. Volume: 8 Pages: e01145
  • DOI: 10.1002/brb3.1145.
  • Peer Reviewed / Open Access
• [Journal Article] Practical microscale one-pot radiosynthesis of 18 F-labeled probes. (2018)
  • Author(s): Iwata R, Pascali C, Terasaki K, Ishikawa Y, Furumoto S, Yanai K.
  • Journal Title: J Labelled Comp Radiopharm. Volume: 61 Pages: 540-549
  • DOI: 10.1002/jlcr.3618.
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Case of progressive supranuclear palsy detected by tau imaging with [18 F]THK-5351 before the appearance of characteristic clinical features. (2018)
  • Author(s): Shimizu S, Imabayashi E, Takenoshita N, Okamura N, Furumoto S, Kudo Y, Matsuda H, Hanyu H
  • Journal Title: Geriatr Gerontol Int. Volume: 18 Pages: 501-502
  • DOI: 10.1111/ggi.13229.
  • Peer Reviewed
• [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 J, Li Y, Pirraglia E, Okamura N, Rusinek H, de Leon MJ;
  • Journal Title: Eur J Nucl Med Mol Imaging. Volume: 45 Pages: 1596-1604
  • DOI: 10.1007/s00259-018-4040-1.
  • 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 K, Stenkrona P, Almkvist O, Stepanov V, Ferreira D, Arakawa R, Takano A, Westman E, Varrone A, Okamura N, Shimada H, Higuchi M, Halldin C, Nordberg A.
  • Journal Title: Eur J Nucl Med Mol Imaging. Volume: 45 Pages: 1605-1607
  • DOI: 10.1007/s00259-018-4012-5.
  • Peer Reviewed / 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 AM, Jaaskelainen JE, Hiltunen M, Herukka SK, Blennow K, Zetterberg H, Jokinen P, Rokka J, Helin S, Haaparanta-Solin M, Solin O, Okamura N, Kolb HC, Rinne JO
  • Journal Title: J Alzheimers Dis. Volume: 64 Pages: 171-179
  • DOI: 10.3233/JAD-180071.
  • Peer Reviewed / Int'l Joint Research
• [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 T, Watanabe H, Yamaguchi H, Bagarinao E, Masuda M, Imai K, Ogura A, Ohdake R, Kawabata K, Hara K, Riku Y, Ishigaki S, Katsuno M, Miyao S, Kato K, Naganawa S, Harada R, Okamura N, Yanai K, Yoshida M, Sobue G.
  • Journal Title: Front Aging Neurosci. Volume: 10 Pages: 304
  • DOI: 10.3389/fnagi.2018.00304.
  • Peer Reviewed / Open Access
• [Journal Article] IgLON5: A case with predominant cerebellar tau deposits and leptomeningeal inflammation. (2018)
  • Author(s): Schoberl F, Levin J, Remi J, Goldschagg N, Eren O, Okamura N, Unterrainer M, Rominger A, Albert N, Brendel M.
  • Journal Title: Neurology Volume: 91 Pages: 180-182
  • DOI: 10.1212/WNL.0000000000005859
  • 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 R, Hayashi H, Kawakatsu S, Ishiki A, Okamura N, Arai H, Otani K
  • Journal Title: BMC Neurol. Volume: 18 Pages: 109
  • DOI: 10.1186/s12883-018-1115-3.
  • Peer Reviewed / Open Access
• [Presentation] Discovery of [18F]SMBT-1: a novel selective MAO-B PET tracer for imaging astrogliosis. (2019)
  • Author(s): Ryuichi Harada
  • Organizer: Human Amyloid Imaging 2019
  • Int'l Joint Research
• [Presentation] PET imaging of neuropathology in Alzheimer’s disease. (2019)
  • Author(s): Nobuyuki OKamura
  • Organizer: 3th International Symposium on Molecular Imaging
  • Int'l Joint Research / Invited
• [Presentation] Radiolabeled proteins for the development of biopharmaceuticals (2019)
  • Author(s): 原田龍一、谷内一彦
  • Organizer: 第92回日本薬理学会年会
• [Presentation] [18F]標識アミノ酸と無細胞タンパク質合成系を用いたAffibodyの標識合成法の開発 (2019)
  • Author(s): 盛戸貴裕
  • Organizer: 第92回日本薬理学会年会
• [Presentation] Pathological corrleaes of [18F]THK-5351 in tauopathies. (2018)
  • Author(s): Ryuichi Harada
  • Organizer: WFNMB2018
  • Int'l Joint Research
• [Presentation] Potential application of 18F-THK5351 and its derivatives for PET imaging of astrogliosis in human brain. (2018)
  • Author(s): Nobuyuki OKamura
  • Organizer: AAIC2018
  • Int'l Joint Research
• [Presentation] Toward the development of novel imaging agents for protein misfolding diseases. (2018)
  • Author(s): Nobuyuki OKamura
  • Organizer: 2018 International Conference on Neurodegenerative Disorders, CGMH
  • Int'l Joint Research / Invited
• [Presentation] Development of selective tau and MAO-B PET tracers through compound optimization of 18F-THK5351 (2018)
  • Author(s): Ryuichi Harada
  • Organizer: WCP2018
  • Int'l Joint Research
• [Presentation] アンバーコドンを用いた無細胞蛋白質合成法 による新規18F標識蛋白質合成法の開発 (2018)
  • Author(s): 原田龍一
  • Organizer: 第58回日本核医学会学術総会
• [Presentation] フェルラ酸誘導体による ミスフォールディング蛋白質の凝集抑制 (2018)
  • Author(s): 原田龍一、岡村信行、谷内一彦
  • Organizer: 第69回日本薬理学会北部会
  • Invited
• [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: 原田龍一、古本祥三、工藤幸司、岡村信行
  • Industrial Property Rights Type: 特許
  • Industrial Property Number: P260496