Comparison of the binding characteristics of [18F]THK-523 and other amyloid imaging tracers to Alzheimer’s disease pathology

  • Ryuichi Harada
  • Nobuyuki Okamura
  • Shozo Furumoto
  • Tetsuro Tago
  • Masahiro Maruyama
  • Makoto Higuchi
  • Takeo Yoshikawa
  • Hiroyuki Arai
  • Ren Iwata
  • Yukitsuka Kudo
  • Kazuhiko Yanai
Original Article



Extensive deposition of senile plaques and neurofibrillary tangles in the brain is a pathological hallmark of Alzheimer’s disease (AD). Although several PET imaging agents have been developed for in vivo detection of senile plaques, no PET probe is currently available for selective detection of neurofibrillary tangles in the living human brain. Recently, [18F]THK-523 was developed as a potential in vivo imaging probe for tau pathology. The purpose of this study was to compare the binding properties of [18F]THK-523 and other amyloid imaging agents, including PiB, BF-227 and FDDNP, to synthetic protein fibrils and human brain tissue.


In vitro radioligand binding assays were conducted using synthetic amyloid β42 and K18ΔK280-tau fibrils. Nonspecific binding was determined by the addition of unlabelled compounds at a concentration of 2 μM. To examine radioligand binding to neuropathological lesions, in vitro autoradiography was conducted using sections of AD brain.


[18F]THK-523 showed higher affinity for tau fibrils than for Aβ fibrils, whereas the other probes showed a higher affinity for Aβ fibrils. The autoradiographic analysis indicated that [18F]THK-523 accumulated in the regions containing a high density of tau protein deposits. Conversely, PiB and BF-227 accumulated in the regions containing a high density of Aβ plaques.


These findings suggest that the unique binding profile of [18F]THK-523 can be used to identify tau deposits in AD brain.


PET probes Tau Amyloid Alzheimer’s disease 



This study was supported by the Industrial Technology Research Grant Program of the NEDO in Japan, Health and Labor Sciences Research Grants from the Ministry of Health, Labor, and Welfare of Japan, and Grant-in-Aid for Scientific Research (B) (23390297).

Supplementary material

259_2012_2261_MOESM2_ESM.pdf (143 kb)
ESM 1 Supplementary figure. HPLC profiles of [11C]PiB, [18F]FDDNP, [11C]BF-227, [18F]BF-227, and [18F]THK-523. HPLC conditions: Column: Intersil ODS-4 (5 μm, 4.6 × 150 mm), CH3CN/NaH2PO4 (20 mM) = 50/50, UV at 254 nm for PiB, 65/35, at 254 nm for FDDNP, 55/45 at 400 nm for BF-227, and 50/50, at 360 nm for THK-523, 2.0 mL/min for [11C]BF-227, 1.5 mL/min for the others. The UV peaks within around 2 min were DMSO and ascorvic acid because the solutions contain DMSO as a solvent and ascorvic acid to prevent radioactive decomposition. The slight difference in retention time between the radioactive peak and the UV peak is due to the configuration of the detector system (PDF 142 kb)


  1. 1.
    Nordberg A, Rinne JO, Kadir A, Langstrom B. The use of PET in Alzheimer disease. Nat Rev Neurol. 2010;6:78–87. doi: 10.1038/nrneurol.2009.217.PubMedCrossRefGoogle Scholar
  2. 2.
    Furumoto S, Okamura N, Iwata R, Yanai K, Arai H, Kudo Y. Recent advances in the development of amyloid imaging agents. Curr Top Med Chem. 2007;7:1773–89.PubMedCrossRefGoogle Scholar
  3. 3.
    Shoghi-Jadid K, Small GW, Agdeppa ED, Kepe V, Ercoli LM, Siddarth P, et al. Localization of neurofibrillary tangles and beta-amyloid plaques in the brains of living patients with Alzheimer disease. Am J Geriatr Psychiatry. 2002;10:24–35.PubMedGoogle Scholar
  4. 4.
    Mathis CA, Wang Y, Holt DP, Huang GF, Debnath ML, Klunk WE. Synthesis and evaluation of 11C-labeled 6-substituted 2-arylbenzothiazoles as amyloid imaging agents. J Med Chem. 2003;46:2740–54. doi: 10.1021/jm030026b.PubMedCrossRefGoogle Scholar
  5. 5.
    Klunk WE, Engler H, Nordberg A, Wang Y, Blomqvist G, Holt DP, et al. Imaging brain amyloid in Alzheimer's disease with Pittsburgh Compound-B. Ann Neurol. 2004;55:306–19. doi: 10.1002/ana.20009.PubMedCrossRefGoogle Scholar
  6. 6.
    Kudo Y, Okamura N, Furumoto S, Tashiro M, Furukawa K, Maruyama M, et al. 2-(2-[2-Dimethylaminothiazol-5-yl]ethenyl)-6- (2-[fluoro]ethoxy)benzoxazole: a novel PET agent for in vivo detection of dense amyloid plaques in Alzheimer's disease patients. J Nucl Med. 2007;48:553–61.PubMedCrossRefGoogle Scholar
  7. 7.
    Ikonomovic MD, Klunk WE, Abrahamson EE, Mathis CA, Price JC, Tsopelas ND, et al. Post-mortem correlates of in vivo PiB-PET amyloid imaging in a typical case of Alzheimer's disease. Brain. 2008;131:1630–45. doi: 10.1093/brain/awn016.PubMedCrossRefGoogle Scholar
  8. 8.
    Sperling RA, Aisen PS, Beckett LA, Bennett DA, Craft S, Fagan AM, et al. Toward defining the preclinical stages of Alzheimer's disease: recommendations from the National Institute on Aging-Alzheimer's Association workgroups on diagnostic guidelines for Alzheimer's disease. Alzheimers Dement. 2011;7:280–92. doi: 10.1016/j.jalz.2011.03.003.PubMedCrossRefGoogle Scholar
  9. 9.
    Jack Jr CR, Knopman DS, Jagust WJ, Shaw LM, Aisen PS, Weiner MW, et al. Hypothetical model of dynamic biomarkers of the Alzheimer's pathological cascade. Lancet Neurol. 2010;9:119–28. doi: 10.1016/S1474-4422(09)70299-6.PubMedCrossRefGoogle Scholar
  10. 10.
    Pike KE, Savage G, Villemagne VL, Ng S, Moss SA, Maruff P, et al. Beta-amyloid imaging and memory in non-demented individuals: evidence for preclinical Alzheimer's disease. Brain. 2007;130:2837–44. doi: 10.1093/brain/awm238.PubMedCrossRefGoogle Scholar
  11. 11.
    Okamura N, Suemoto T, Furumoto S, Suzuki M, Shimadzu H, Akatsu H, et al. Quinoline and benzimidazole derivatives: candidate probes for in vivo imaging of tau pathology in Alzheimer's disease. J Neurosci. 2005;25:10857–62. doi: 10.1523/JNEUROSCI.1738-05.2005.PubMedCrossRefGoogle Scholar
  12. 12.
    Fodero-Tavoletti MT, Okamura N, Furumoto S, Mulligan RS, Connor AR, McLean CA, et al. 18F-THK523: a novel in vivo tau imaging ligand for Alzheimer's disease. Brain. 2011;134:1089–100. doi: 10.1093/Brain/Awr038.PubMedCrossRefGoogle Scholar
  13. 13.
    Lockhart A, Lamb JR, Osredkar T, Sue LI, Joyce JN, Ye L, et al. PIB is a non-specific imaging marker of amyloid-beta (Abeta) peptide-related cerebral amyloidosis. Brain. 2007;130:2607–15. doi: 10.1093/brain/awm191.PubMedCrossRefGoogle Scholar
  14. 14.
    Burack MA, Hartlein J, Flores HP, Taylor-Reinwald L, Perlmutter JS, Cairns NJ. In vivo amyloid imaging in autopsy-confirmed Parkinson disease with dementia. Neurology. 2010;74:77–84. doi: 10.1212/WNL.0b013e3181c7da8e.PubMedCrossRefGoogle Scholar
  15. 15.
    Clark CM, Schneider JA, Bedell BJ, Beach TG, Bilker WB, Mintun MA, et al. Use of florbetapir-PET for imaging beta-amyloid pathology. JAMA. 2011;305:275–83. doi: 10.1001/jama.2010.2008.PubMedCrossRefGoogle Scholar
  16. 16.
    Wong DF, Moghekar AR, Rigamonti D, Brasic JR, Rousset O, Willis W, et al. An in vivo evaluation of cerebral cortical amyloid with [(18)F]Flutemetamol using positron emission tomography compared with parietal biopsy samples in living normal pressure hydrocephalus patients. Mol Imaging Biol. 2012. doi: 10.1007/s11307-012-0583-x.
  17. 17.
    Maeda J, Ji B, Irie T, Tomiyama T, Maruyama M, Okauchi T, et al. Longitudinal, quantitative assessment of amyloid, neuroinflammation, and anti-amyloid treatment in a living mouse model of Alzheimer's disease enabled by positron emission tomography. J Neurosci. 2007;27:10957–68. doi: 10.1523/JNEUROSCI.0673-07.2007.PubMedCrossRefGoogle Scholar
  18. 18.
    Manook A, Yousefi BH, Willuweit A, Platzer S, Reder S, Voss A, et al. Small-animal PET imaging of amyloid-beta plaques with [11C]PiB and its multi-modal validation in an APP/PS1 mouse model of Alzheimer's disease. PLoS One. 2012;7:e31310. doi: 10.1371/journal.pone.0031310.PubMedCrossRefGoogle Scholar
  19. 19.
    Agdeppa ED, Kepe V, Liu J, Flores-Torres S, Satyamurthy N, Petric A, et al. Binding characteristics of radiofluorinated 6-dialkylamino-2-naphthylethylidene derivatives as positron emission tomography imaging probes for beta-amyloid plaques in Alzheimer's disease. J Neurosci. 2001;21:RC189.PubMedGoogle Scholar
  20. 20.
    Gallyas F. Silver staining of Alzheimer's neurofibrillary changes by means of physical development. Acta Morphol Acad Sci Hung. 1971;19:1–8.PubMedGoogle Scholar
  21. 21.
    Barghorn S, Davies P, Mandelkow E. Tau paired helical filaments from Alzheimer's disease brain and assembled in vitro are based on beta-structure in the core domain. Biochemistry. 2004;43:1694–703. doi: 10.1021/bi0357006.PubMedCrossRefGoogle Scholar
  22. 22.
    von Bergen M, Barghorn S, Muller SA, Pickhardt M, Biernat J, Mandelkow EM, et al. The core of tau-paired helical filaments studied by scanning transmission electron microscopy and limited proteolysis. Biochemistry. 2006;45:6446–57. doi: 10.1021/bi052530j.CrossRefGoogle Scholar
  23. 23.
    Fodero-Tavoletti MT, Mulligan RS, Okamura N, Furumoto S, Rowe CC, Kudo Y, et al. In vitro characterisation of BF227 binding to alpha-synuclein/Lewy bodies. Eur J Pharmacol. 2009;617:54–8. doi: 10.1016/j.ejphar.2009.06.042.PubMedCrossRefGoogle Scholar
  24. 24.
    Thompson PW, Ye L, Morgenstern JL, Sue L, Beach TG, Judd DJ, et al. Interaction of the amyloid imaging tracer FDDNP with hallmark Alzheimer's disease pathologies. J Neurochem. 2009;109:623–30. doi: 10.1111/j.1471-4159.2009.05996.x.PubMedCrossRefGoogle Scholar
  25. 25.
    Braak E, Braak H, Mandelkow EM. A sequence of cytoskeleton changes related to the formation of neurofibrillary tangles and neuropil threads. Acta Neuropathol. 1994;87:554–67.PubMedCrossRefGoogle Scholar
  26. 26.
    Thal DR, Rub U, Schultz C, Sassin I, Ghebremedhin E, Del Tredici K, et al. Sequence of Abeta-protein deposition in the human medial temporal lobe. J Neuropathol Exp Neurol. 2000;59:733–48.PubMedGoogle Scholar
  27. 27.
    Villemagne VL, Furumoto S, Fodero-Tavoletti M, Harada R, Mulligan RS, Kudo Y, et al. The challenges of tau imaging. Future Neurol. 2012;7:409–21. doi: 10.2217/fnl.12.34.CrossRefGoogle Scholar
  28. 28.
    Fodero-Tavoletti MT, Smith DP, McLean CA, Adlard PA, Barnham KJ, Foster LE, et al. In vitro characterization of Pittsburgh compound-B binding to Lewy bodies. J Neurosci. 2007;27:10365–71. doi: 10.1523/JNEUROSCI.0630-07.2007.PubMedCrossRefGoogle Scholar
  29. 29.
    Klunk WE, Lopresti BJ, Ikonomovic MD, Lefterov IM, Koldamova RP, Abrahamson EE, et al. Binding of the positron emission tomography tracer Pittsburgh compound-B reflects the amount of amyloid-beta in Alzheimer's disease brain but not in transgenic mouse brain. J Neurosci. 2005;25:10598–606. doi: 10.1523/JNEUROSCI.2990-05.2005.PubMedCrossRefGoogle Scholar
  30. 30.
    Klunk WE, Wang Y, Huang GF, Debnath ML, Holt DP, Shao L, et al. The binding of 2-(4'-methylaminophenyl)benzothiazole to postmortem brain homogenates is dominated by the amyloid component. J Neurosci. 2003;23:2086–92.PubMedGoogle Scholar
  31. 31.
    Shin J, Lee SY, Kim SH, Kim YB, Cho SJ. Multitracer PET imaging of amyloid plaques and neurofibrillary tangles in Alzheimer's disease. Neuroimage. 2008;43:236–44. doi: 10.1016/j.neuroimage.2008.07.022.PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 2012

Authors and Affiliations

  • Ryuichi Harada
    • 1
  • Nobuyuki Okamura
    • 1
  • Shozo Furumoto
    • 1
    • 2
  • Tetsuro Tago
    • 2
  • Masahiro Maruyama
    • 3
  • Makoto Higuchi
    • 3
  • Takeo Yoshikawa
    • 1
  • Hiroyuki Arai
    • 4
  • Ren Iwata
    • 2
  • Yukitsuka Kudo
    • 5
  • Kazuhiko Yanai
    • 1
  1. 1.Department of PharmacologyTohoku University School of MedicineSendaiJapan
  2. 2.Division of Radiopharmaceutical Chemistry, Cyclotron and Radioisotope CenterTohoku UniversitySendaiJapan
  3. 3.Molecular Imaging Center, National Institute of Radiological SciencesChibaJapan
  4. 4.Department of Geriatrics and Gerontology, Institute of Development, Aging and CancerTohoku UniversitySendaiJapan
  5. 5.Innovation of New Biomedical Engineering CenterTohoku UniversitySendaiJapan

Personalised recommendations