Advertisement

[18F]GTP1 (Genentech Tau Probe 1), a radioligand for detecting neurofibrillary tangle tau pathology in Alzheimer’s disease

  • Sandra Sanabria Bohórquez
  • Jan Marik
  • Annie Ogasawara
  • Jeff N. Tinianow
  • Herman S. Gill
  • Olivier Barret
  • Gilles Tamagnan
  • David Alagille
  • Gai Ayalon
  • Paul Manser
  • Thomas Bengtsson
  • Michael Ward
  • Simon-Peter Williams
  • Geoffrey A. Kerchner
  • John P. Seibyl
  • Kenneth Marek
  • Robby M. WeimerEmail author
Original Article
Part of the following topical collections:
  1. Translational research

Abstract

Objective

Neurofibrillary tangles (NFTs), consisting of intracellular aggregates of the tau protein, are a pathological hallmark of Alzheimer’s disease (AD). Here we report the identification and initial characterization of Genentech Tau Probe 1 ([18F]GTP1), a small-molecule PET probe for imaging tau pathology in AD patients.

Methods

Autoradiography using human brain tissues from AD donors and protein binding panels were used to determine [18F]GTP1 binding characteristics. Stability was evaluated in vitro and in vivo in mice and rhesus monkey. In the clinic, whole-body imaging was performed to assess biodistribution and dosimetry. Dynamic [18F]GTP1 brain imaging and input function measurement were performed on two separate days in 5 β-amyloid plaque positive (Aβ+) AD and 5 β-amyloid plaque negative (Aβ-) cognitive normal (CN) participants. Tracer kinetic modeling was applied and reproducibility was evaluated. SUVR was calculated and compared to [18F]GTP1-specific binding parameters derived from the kinetic modeling. [18F]GTP1 performance in a larger cross-sectional group of 60 Aβ+ AD participants and ten (Aβ- or Aβ+) CN was evaluated with images acquired 60 to 90 min post tracer administration.

Results

[18F]GTP1 exhibited high affinity and selectivity for tau pathology with no measurable binding to β-amyloid plaques or MAO-B in AD tissues, or binding to other tested proteins at an affinity predicted to impede image data interpretation. In human, [18F]GTP1 exhibited favorable dosimetry and brain kinetics, and no evidence of defluorination. [18F]GTP1-specific binding was observed in cortical regions of the brain predicted to contain tau pathology in AD and exhibited low (< 4%) test-retest variability. SUVR measured in the 60 to 90-min interval post injection correlated with tracer-specific binding (slope = 1.36, r2 = 0.98). Furthermore, in a cross-sectional population, the degree of [18F]GTP1-specific binding increased with AD severity and could differentiate diagnostic cohorts.

Conclusions

[18F]GTP1 is a promising PET probe for the study of tau pathology in AD.

Keywords

Alzheimer’s disease Tau PET imaging [18F]GTP1 Kinetic modeling 

Notes

Acknowledgements

The authors would like to thank Alex de Crespigny, Flavia Brunstein, Edward Teng, Kristin Wildsmith, Corinne Foo-Atkins, Reina Fuji, Gautham Rao, Michael Keeley, and Beth Blankemeier for their support and contribution to this work.

Compliance with ethical standards

Research involving human participants and/or animals.

Informed consent.

Conflict of interest

All authors are paid employees of either Genentech Inc., or Invicro LLC and all work was funded by Genentech Inc.

Ethical approval

All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki Declaration and its later amendments or comparable ethical standards.

All applicable international, national, and/or institutional guidelines for the care and use of animals were followed.

Supplementary material

259_2019_4399_MOESM1_ESM.doc (2.3 mb)
ESM 1 (DOC 2363 kb)

References

  1. 1.
    Jack CR Jr, Wiste HJ, Vemuri P, Weigand SD, Senjem ML, Zeng G, et al. Brain beta-amyloid measures and magnetic resonance imaging atrophy both predict time-to-progression from mild cognitive impairment to Alzheimer's disease. Brain. 2010;133(11):3336–48.  https://doi.org/10.1093/brain/awq277.CrossRefPubMedPubMedCentralGoogle Scholar
  2. 2.
    Bateman RJ, Xiong C, Benzinger TL, Fagan AM, Goate A, Fox NC, et al. Clinical and biomarker changes in dominantly inherited Alzheimer's disease. N Engl J Med. 2012;367(9):795–804.  https://doi.org/10.1056/NEJMoa1202753.CrossRefPubMedPubMedCentralGoogle Scholar
  3. 3.
    Chien DT, Bahri S, Szardenings AK, Walsh JC, Mu F, Su MY, et al. Early clinical PET imaging results with the novel PHF-tau radioligand [F-18]-T807. Journal of Alzheimer's disease: JAD. 2013;34(2):457–68.  https://doi.org/10.3233/JAD-122059.CrossRefPubMedGoogle Scholar
  4. 4.
    Chien DT, Szardenings AK, Bahri S, Walsh JC, Mu F, Xia C, et al. Early clinical PET imaging results with the novel PHF-tau radioligand [F18]-T808. Journal of Alzheimer's disease: JAD. 2014;38(1):171–84.  https://doi.org/10.3233/JAD-130098.CrossRefPubMedGoogle Scholar
  5. 5.
    Maruyama M, Shimada H, Suhara T, Shinotoh H, Ji B, Maeda J, et al. Imaging of tau pathology in a tauopathy mouse model and in Alzheimer patients compared to normal controls. Neuron. 2013;79(6):1094–108.  https://doi.org/10.1016/j.neuron.2013.07.037.CrossRefPubMedGoogle Scholar
  6. 6.
    Kimura Y, Endo H, Ichise M, Shimada H, Seki C, Ikoma Y, et al. A new method to quantify tau pathologies with (11)C-PBB3 PET using reference tissue voxels extracted from brain cortical gray matter. EJNMMI Res. 2016;6(1):24.  https://doi.org/10.1186/s13550-016-0182-y.CrossRefPubMedPubMedCentralGoogle Scholar
  7. 7.
    Kimura Y, Ichise M, Ito H, Shimada H, Ikoma Y, Seki C, et al. PET quantification of tau pathology in human brain with 11C-PBB3. J Nucl Med. 2015;56(9):1359–65.  https://doi.org/10.2967/jnumed.115.160127.CrossRefPubMedGoogle Scholar
  8. 8.
    Declercq L, Rombouts F, Koole M, Fierens K, Marien J, Langlois X, et al. Preclinical evaluation of (18)F-JNJ64349311, a novel PET tracer for tau imaging. J Nucl Med. 2017;58(6):975–81.  https://doi.org/10.2967/jnumed.116.185199.CrossRefPubMedGoogle Scholar
  9. 9.
    Hostetler ED, Walji AM, Zeng Z, Miller P, Bennacef I, Salinas C, et al. Preclinical characterization of 18F-MK-6240, a promising PET tracer for in vivo quantification of human neurofibrillary tangles. J Nucl Med. 2016;57(10):1599–606.  https://doi.org/10.2967/jnumed.115.171678.CrossRefPubMedGoogle Scholar
  10. 10.
    Pascoal TA, Shin M, Kang MS, Chamoun M, Chartrand D, Mathotaarachchi S, et al. In vivo quantification of neurofibrillary tangles with [18F]MK-6240. Alzheimers Res Ther. 2018;10(1):74.  https://doi.org/10.1186/s13195-018-0402-y.CrossRefPubMedPubMedCentralGoogle Scholar
  11. 11.
    Wong DF, Comley R, Kuwabara H, Rosenberg PB, Resnick SM, Ostrowitzki S, et al. First in-human PET study of 3 novel tau radiopharmaceuticals: [(11)C]RO6924963, [(11)C]RO6931643, and [(18)F]RO6958948. J Nucl Med. 2018.  https://doi.org/10.2967/jnumed.118.209916.
  12. 12.
    Gant TG. Using deuterium in drug discovery: leaving the label in the drug. J Med Chem. 2013.  https://doi.org/10.1021/jm4007998.
  13. 13.
    Jahan M, Eriksson O, Johnstrom P, Korsgren O, Sundin A, Johansson L, et al. Decreased defluorination using the novel beta-cell imaging agent [18F]FE-DTBZ-d4 in pigs examined by PET. EJNMMI Res. 2011;1(1):33.CrossRefPubMedPubMedCentralGoogle Scholar
  14. 14.
    Schou M, Halldin C, Sovago J, Pike VW, Hall H, Gulyas B, et al. PET evaluation of novel radiofluorinated reboxetine analogs as norepinephrine transporter probes in the monkey brain. Synapse. 2004;53(2):57–67.  https://doi.org/10.1002/syn.20031.CrossRefPubMedGoogle Scholar
  15. 15.
    Marik J, Tinianow JN, Ogasawara A, Liu N, Williams SP, Lyssikatos JP, et al. [18F]GTP1 - A tau-specific tracer for imaging taupathology in AD. 10th Human Amyloid Imaging; January 13–15, 2016; Miami, FL 2016. p. 49 (PE32).Google Scholar
  16. 16.
    Marik J, Lyssikatos JP, Williams SP, inventors; US Patent No. 10,076,581. Deuterated compounds and uses thereof. 2018 Sep. 18.Google Scholar
  17. 17.
    Choi SR, Golding G, Zhuang Z, Zhang W, Lim N, Hefti F, et al. Preclinical properties of 18F-AV-45: a PET agent for Abeta plaques in the brain. J Nucl Med. 2009;50(11):1887–94.  https://doi.org/10.2967/jnumed.109.065284.CrossRefPubMedPubMedCentralGoogle Scholar
  18. 18.
    Innis RB, Cunningham VJ, Delforge J, Fujita M, Gjedde A, Gunn RN, et al. Consensus nomenclature for in vivo imaging of reversibly binding radioligands. J Cereb Blood Flow Metab. 2007;27(9):1533–9.  https://doi.org/10.1038/sj.jcbfm.9600493.CrossRefGoogle Scholar
  19. 19.
    Logan J. Graphical analysis of PET data applied to reversible and irreversible tracers. Nucl Med Biol. 2000;27(7):661–70.CrossRefPubMedGoogle Scholar
  20. 20.
    Braak H, Braak E. Neuropathological stageing of Alzheimer-related changes. Acta Neuropathol. 1991;82(4):239–59.CrossRefPubMedGoogle Scholar
  21. 21.
    Marquie M, Normandin MD, Vanderburg CR, Costantino IM, Bien EA, Rycyna LG, et al. Validating novel tau positron emission tomography tracer [F-18]-AV-1451 (T807) on postmortem brain tissue. Ann Neurol. 2015;78(5):787–800.  https://doi.org/10.1002/ana.24517.CrossRefPubMedPubMedCentralGoogle Scholar
  22. 22.
    Lammertsma AA, Hume SP. Simplified reference tissue model for PET receptor studies. NeuroImage. 1996;4(3 Pt 1):153–8.  https://doi.org/10.1006/nimg.1996.0066.CrossRefPubMedGoogle Scholar
  23. 23.
    Hedges LV, Shymansky JA, Woodworth G. A practical guide to modern methods of meta-analysis. Washington, DC: National Science Teachers Association; 1989.Google Scholar
  24. 24.
    Scholl M, Lockhart SN, Schonhaut DR, O'Neil JP, Janabi M, Ossenkoppele R, et al. PET imaging of tau deposition in the aging human brain. Neuron. 2016;89(5):971–82.  https://doi.org/10.1016/j.neuron.2016.01.028.CrossRefPubMedPubMedCentralGoogle Scholar
  25. 25.
    Jack CR Jr, Wiste HJ, Weigand SD, Therneau TM, Lowe VJ, Knopman DS, et al. Defining imaging biomarker cut points for brain aging and Alzheimer's disease. Alzheimers Dement. 2017;13(3):205–16.  https://doi.org/10.1016/j.jalz.2016.08.005.CrossRefPubMedGoogle Scholar
  26. 26.
    Landau SM, Breault C, Joshi AD, Pontecorvo M, Mathis CA, Jagust WJ, et al. Amyloid-beta imaging with Pittsburgh compound B and florbetapir: comparing radiotracers and quantification methods. J Nucl Med. 2013;54(1):70–7.  https://doi.org/10.2967/jnumed.112.109009.CrossRefPubMedGoogle Scholar
  27. 27.
    Ng KP, Pascoal TA, Mathotaarachchi S, Therriault J, Kang MS, Shin M, et al. Monoamine oxidase B inhibitor, selegiline, reduces (18)F-THK5351 uptake in the human brain. Alzheimers Res Ther. 2017;9(1):25.  https://doi.org/10.1186/s13195-017-0253-y.CrossRefPubMedPubMedCentralGoogle Scholar
  28. 28.
    Wu Y, Carson RE. Noise reduction in the simplified reference tissue model for neuroreceptor functional imaging. J Cereb Blood Flow Metab. 2002;22(12):1440–52.  https://doi.org/10.1097/01.WCB.0000033967.83623.34.CrossRefPubMedGoogle Scholar
  29. 29.
    Teng E, Ward M, Manser PT, Sanabria-Bohorquez S, Ray RD, Wildsmith KR, et al. Cross-sectional associations between [18F]GTP1 tau PET and cognition in Alzheimer's disease. Neurobiol Aging. 2019. Accepted.Google Scholar
  30. 30.
    Leuzy A, Chiotis K, Lemoine L, Gillberg PG, Almkvist O, Rodriguez-Vieitez E, et al. Tau PET imaging in neurodegenerative tauopathies-still a challenge. Mol Psychiatry. 2019.  https://doi.org/10.1038/s41380-018-0342-8.
  31. 31.
    Gobbi LC, Knust H, Korner M, Honer M, Czech C, Belli S, et al. Identification of three novel radiotracers for imaging aggregated tau in Alzheimer's disease with positron emission tomography. J Med Chem. 2017;60(17):7350–70.  https://doi.org/10.1021/acs.jmedchem.7b00632.CrossRefPubMedGoogle Scholar
  32. 32.
    Barret O, Alagille D, Sanabria S, Comley RA, Weimer RM, Borroni E, et al. Kinetic modeling of the tau PET tracer (18)F-AV-1451 in human healthy volunteers and Alzheimer disease subjects. J Nucl Med. 2017;58(7):1124–31.  https://doi.org/10.2967/jnumed.116.182881.CrossRefPubMedGoogle Scholar
  33. 33.
    Shcherbinin S, Schwarz AJ, Joshi A, Navitsky M, Flitter M, Shankle WR, et al. Kinetics of the tau PET tracer 18F-AV-1451 (T807) in subjects with normal cognitive function, mild cognitive impairment, and Alzheimer disease. J Nucl Med. 2016;57(10):1535–42.  https://doi.org/10.2967/jnumed.115.170027.CrossRefPubMedGoogle Scholar

Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2019

Authors and Affiliations

  • Sandra Sanabria Bohórquez
    • 1
  • Jan Marik
    • 2
  • Annie Ogasawara
    • 2
  • Jeff N. Tinianow
    • 2
  • Herman S. Gill
    • 2
  • Olivier Barret
    • 3
  • Gilles Tamagnan
    • 3
    • 4
  • David Alagille
    • 3
    • 4
  • Gai Ayalon
    • 5
  • Paul Manser
    • 6
  • Thomas Bengtsson
    • 6
  • Michael Ward
    • 7
    • 8
  • Simon-Peter Williams
    • 2
  • Geoffrey A. Kerchner
    • 7
  • John P. Seibyl
    • 3
  • Kenneth Marek
    • 3
  • Robby M. Weimer
    • 2
    • 5
    Email author
  1. 1.Clinical Imaging GroupGenentech, Inc.South San FranciscoUSA
  2. 2.Department of Biomedical ImagingGenentech, Inc.South San FranciscoUSA
  3. 3.Invicro LLCNew HavenUSA
  4. 4.XingImaging, LLCNew HavenUSA
  5. 5.Department of NeuroscienceGenentech, Inc.South San FranciscoUSA
  6. 6.Clinical BiostatisticsGenentech, Inc.South San FranciscoUSA
  7. 7.Early Clinical DevelopmentGenentech, Inc.South San FranciscoUSA
  8. 8.Alector, Inc.South San FranciscoUSA

Personalised recommendations