Search of conformation-specific PET probe

• Project/Area Number: 16K15570
• Research Category: Grant-in-Aid for Challenging Exploratory Research
• Allocation Type: Multi-year Fund
• Research Field: Radiation science
• Research Institution: Tohoku Medical and Pharmaceutical University
• Principal Investigator: OKAMURA Nobuyuki 東北医科薬科大学, 医学部, 教授 (40361076)
• Project Period (FY): 2016-04-01 – 2019-03-31
• Project Status: Completed (Fiscal Year 2018)
• Budget Amount: ¥3,510,000 (Direct Cost: ¥2,700,000、Indirect Cost: ¥810,000); Fiscal Year 2018: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2017: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2016: ¥650,000 (Direct Cost: ¥500,000、Indirect Cost: ¥150,000)
• Keywords: 分子イメージング / αシヌクレイン / PET / イメージング / PETプローブ / 脳神経疾患 / 痴呆 / 放射線

Outline of Final Research Achievements

To develop a PET probe for in vivo monitoring of misfolded protein accumulation, we tested the binding and pharmacokinetic properties of our library compounds and found a series of novel compound that can clearly stain Lewy bodies. A candidate compound (Cpd.365) showed excellent blood-brain barrier permeability in mice. Autoradiography using postmortem human brain samples showed strong binding of 18F-labeled compound to α-synuclein rich brain sections, although the binding selectivity of this compound was insufficient for selective α-synuclein probe.

Academic Significance and Societal Importance of the Research Achievements

プローブが実用化され、パーキンソン病などのミスフォールディングの脳内蓄積を生体で非侵襲的に計測できれば、多様な神経変性疾患の早期診断のためのスクリーニング法となる。また新たな治療評価系としても活用でき新規治療薬開発と連動させるによって疾患の撲滅へ向けた第一歩となる。

Research Products

• [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: Frontiers in Neuroscience Volume: 12 Pages: 585-585
  • DOI: 10.3389/fnins.2018.00585
  • Peer Reviewed / Open Access
• [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 Neurology Volume: 18 Issue: 1 Pages: 109-109
  • DOI: 10.1186/s12883-018-1115-3
  • Peer Reviewed / Open Access
• [Journal Article] Neuroimaging-pathological correlations of [(18)F]THK5351 PET in progressive supranuclear palsy (2018)
  • Author(s): Ishiki A, Furukawa K, et al.
  • Journal Title: Acta Neuropathol Commun Volume: 6 Issue: 1 Pages: 53-53
  • DOI: 10.1186/s40478-018-0556-7
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] THK5351-PETから見えてきた分子イメージングの新しい方向性 (2018)
  • Author(s): 岡村信行、原田龍一、江面道典、工藤幸司
  • Journal Title: 日本認知症学会誌 Volume: 32 Pages: 538-545
• [Journal Article] [18F]-THK5351 PET correlates with topology and symptom severity in progressive supranuclear palsy. (2018)
  • Author(s): Brendel M, Schoneckerr S, Hoglinger G, Lindner S, Havla J, Blautzik J, Sauerbeck J, Rohrer G, Zach C, Vettermann F, Lang AE, Golbe L, Nubling G, Bartenstein P, Furukawa K, Ishiki A, Botzel K, Danek A, Okamura N, Levin J, Rominger A.
  • Journal Title: Front Aging Neurosci. Volume: 9 Pages: 440-440
  • DOI: 10.3389/fnagi.2017.00440
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Correlations of (18)F-THK5351 PET with Postmortem Burden of Tau and Astrogliosis in Alzheimer Disease. (2018)
  • Author(s): Harada R, Furukawa K, et al.
  • Journal Title: J Nucl Med Volume: 59 Issue: 4 Pages: 671-674
  • DOI: 10.2967/jnumed.117.197426
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Comparative binding properties of the tau PET tracers THK5117, THK5351, PBB3, and T807 in postmortem Alzheimer brains. (2017)
  • Author(s): Lemoine L, Gillberg PG, Svedberg M, Stepanov V, Jia Z, Huang J, Nag S, Tian H, Ghetti B, Okamura N, Higuchi M, Halldin C, Nordberg A.
  • Journal Title: Alzheimers Res Ther. Volume: 9 Issue: 1 Pages: 96-96
  • DOI: 10.1186/s13195-017-0325-z
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] アルツハイマー病理を標的とした分子イメージングプローブの開発 (2017)
  • Author(s): 岡村信行、原田龍一、古本祥三、中村正帆、谷内一彦，工藤幸司
  • Journal Title: 日本薬理学雑誌 Volume: 150 Pages: 172-176
  • NAID: 130006107929
  • Peer Reviewed / Open Access
• [Journal Article] 18F-Labeled 2-Arylquinoline Derivatives for Tau Imaging: Chemical, Radiochemical, Biological and Clinical Features. (2017)
  • Author(s): Furumoto S, Tago T, Harada R, Kudo Y, Okamura N.
  • Journal Title: Curr Alzheimer Res. Volume: 14 Pages: 178-185
  • Peer Reviewed
• [Journal Article] Structure-Activity Relationship of 2-Arylquinolines as PET Imaging Tracers for Tau Pathology in Alzheimer’s Disease (2016)
  • Author(s): Tetsuro Tago, Shozo Furumoto, Nobuyuki Okamura, Ryuichi Harada, Hajime Adachi, Yoichi Ishikawa, Kazuhiko Yanai, Ren Iwata, and Yukitsuka Kudo
  • Journal Title: Journal of Nuclear Medicine Volume: 57(4) Issue: 4 Pages: 608-614
  • DOI: 10.2967/jnumed.115.166652
  • Peer Reviewed
• [Journal Article] Advances in the development of tau PET radiotracers and their clinical applications. (2016)
  • Author(s): Okamura N, Harada R, Furukawa K, Furumoto S, Tago T, Yanai K, Arai H, Kudo Y.
  • Journal Title: Ageing Res Rev. Volume: - Pages: 107-113
  • DOI: 10.1016/j.arr.2015.12.010
  • Peer Reviewed
• [Journal Article] microPET Imaging of Tau Pathology with [18F]-THK5117 in two Transgenic Mouse Models. (2016)
  • Author(s): Brendel M, Jaworska A, Probst F, Overhoff F, Korzhova V, Lindner S, Carlsen J, Bartenstein P, Harada R, Kudo Y, Haass C, van Leuven F, Okamura N, Herms J, Rominger A.
  • Journal Title: J Nucl Med Volume: 印刷中 Issue: 5 Pages: 792-798
  • DOI: 10.2967/jnumed.115.163493
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Introduction and overview of the special issue "Brain imaging and aging": The new era of neuroimaging in aging research. (2016)
  • Author(s): Furukawa K, Ishiki A, Tomita N, Onaka Y, Saito H, Nakamichi T, Hara K, Kusano Y, Ebara M, Arata Y, Sakota M, Miyazawa I, Totsune T, Okinaga S, Okamura N, Kudo Y, Arai H.
  • Journal Title: Ageing Res Rev Volume: - Pages: 1-3
  • DOI: 10.1016/j.arr.2016.02.005
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Dynamic PET measures of tau accumulation in cognitively normal older adults and Alzheimer's disease patients measured using [18F]THK-5351. (2016)
  • Author(s): Lockhart SN, Baker SL, Okamura N, Furukawa K, Ishiki A, Furumoto S, Tashiro M, Yanai K, Arai H, Kudo Y, Harada R, Tomita N, Hiraoka K, Watanuki S, Jagust WJ.
  • Journal Title: PLoS One. Volume: 11 Issue: 6 Pages: e0158460-e0158460
  • DOI: 10.1371/journal.pone.0158460
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Characterization of the radiolabeled metabolite of tau PET tracer 18F-THK5351. (2016)
  • Author(s): Harada R, Furumoto S, Tago T, Furukawa K, Ishiki A, Tomita N, Iwata R, Tashiro M, Arai H, Yanai K, Kudo Y, Okamura N.
  • Journal Title: Eur J Nucl Med Mol Imaging. Volume: 43 Issue: 12 Pages: 2211-2218
  • DOI: 10.1007/s00259-016-3453-y
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Untangling tau imaging. (2016)
  • Author(s): Villemagne VL, Okamura N, Rowe CC.
  • Journal Title: Alzheimers Dement (Amst) Volume: 4 Issue: 1 Pages: 39-42
  • DOI: 10.1016/j.dadm.2016.05.001
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] In vivo visualization of tau pathology using 18F-THK5351 PET in corticobasal syndrome. (2016)
  • Author(s): Kikuchi A, Okamura N, Hasegawa T, Harada R, Watanuki S, Funaki Y, Kobayashi M, Tano O, Baba T, Sugeno N, Oshima R, Yoshida S, Kobayashi J, Ezura M, Hiraoka K, Mugikura S, Takase K, Iwata R, Taki Y, Furukawa K, HArai H, Furumoto S, Tashiro M, Yanai K, Kudo Y, Takeda A，Aoki M.
  • Journal Title: Neurology Volume: 87 Issue: 22 Pages: 2309-2316
  • DOI: 10.1212/wnl.0000000000003375
  • Peer Reviewed
• [Presentation] Toward the development of novel imaging agents for protein misfolding diseases. (2018)
  • Author(s): Okamura N.
  • Organizer: 2018 International Conference on Neurodegenerative Disorders, CGMH
  • Int'l Joint Research / Invited
• [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
  • Invited
• [Presentation] Novel tracer development and potential application for movement disorders. (2017)
  • Author(s): Okamura N.
  • Organizer: 3rd Taiwan International Congress of Parkinson's Disease and Movement Disorders
  • Place of Presentation: 台北（台湾）
  • Year and Date: 2017-03-19
  • Int'l Joint Research / Invited
• [Presentation] 認知症を標的とした分子イメージングプローブ開発の現状 (2017)
  • Author(s): 岡村信行
  • Organizer: 第32回日本老年精神医学会
  • Invited
• [Presentation] 認知症を標的とした分子イメージングプローブ開発の現状 (2017)
  • Author(s): 岡村信行
  • Organizer: 第60回日本脳循環代謝学会学術集会
• [Book] Neuroimaging Diagnosis for Alzheimer’s Disease and Other Dementias. (2017)
  • Author(s): Okamura N.
  • Total Pages: 279
  • Publisher: Springer
  • ISBN: 9784431551331