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

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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.

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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.

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Authors and Affiliations

  1. Clinical Imaging Group, Genentech, Inc., 1 DNA Way, South San Francisco, CA, 94080, USA

    Sandra Sanabria Bohórquez

  2. Department of Biomedical Imaging, Genentech, Inc., 1 DNA Way, South San Francisco, CA, 94080, USA

    Jan Marik, Annie Ogasawara, Jeff N. Tinianow, Herman S. Gill, Simon-Peter Williams & Robby M. Weimer

  3. Invicro LLC, 60 Temple St, Suite 8A, New Haven, CT, 06510, USA

    Olivier Barret, Gilles Tamagnan, David Alagille, John P. Seibyl & Kenneth Marek

  4. XingImaging, LLC, 760 Chapel Street, New Haven, CT, 06510, USA

    Gilles Tamagnan & David Alagille

  5. Department of Neuroscience, Genentech, Inc., 1 DNA Way, South San Francisco, CA, 94080, USA

    Gai Ayalon & Robby M. Weimer

  6. Clinical Biostatistics, Genentech, Inc., 1 DNA Way, South San Francisco, CA, 94080, USA

    Paul Manser & Thomas Bengtsson

  7. Early Clinical Development, Genentech, Inc., 1 DNA Way, South San Francisco, CA, 94080, USA

    Michael Ward & Geoffrey A. Kerchner

  8. Alector, Inc., 151 Oyster Point Blvd, South San Francisco, CA, 94080, USA

    Michael Ward

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  1. Sandra Sanabria Bohórquez
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Correspondence to Robby M. Weimer.

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

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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.

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Sandra Sanabria Bohórquez and Jan Marik are co-first authors.

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Sanabria Bohórquez, S., Marik, J., Ogasawara, A. et al. [18F]GTP1 (Genentech Tau Probe 1), a radioligand for detecting neurofibrillary tangle tau pathology in Alzheimer’s disease. Eur J Nucl Med Mol Imaging 46, 2077–2089 (2019). https://doi.org/10.1007/s00259-019-04399-0

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