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Ligand-based design of [18F]OXD-2314 for PET imaging in non-Alzheimer’s disease tauopathies

Author

Listed:
  • Anton Lindberg

    (Centre for Addiction and Mental Health)

  • Emily Murrell

    (Centre for Addiction and Mental Health
    University of Toronto)

  • Junchao Tong

    (Centre for Addiction and Mental Health)

  • N. Scott Mason

    (University of Pittsburgh)

  • Daniel Sohn

    (Oxiant Discovery)

  • Johan Sandell

    (Novandi Chemistry AB)

  • Peter Ström

    (Novandi Chemistry AB)

  • Jeffrey S. Stehouwer

    (University of Pittsburgh)

  • Brian J. Lopresti

    (University of Pittsburgh)

  • Jenny Viklund

    (Oxiant Discovery)

  • Samuel Svensson

    (Oxiant Discovery)

  • Chester A. Mathis

    (University of Pittsburgh)

  • Neil Vasdev

    (Centre for Addiction and Mental Health
    University of Toronto)

Abstract

Positron emission tomography (PET) imaging of tau aggregation in Alzheimer’s disease (AD) is helping to map and quantify the in vivo progression of AD pathology. To date, no high-affinity tau-PET radiopharmaceutical has been optimized for imaging non-AD tauopathies. Here we show the properties of analogues of a first-in-class 4R-tau lead, [18F]OXD-2115, using ligand-based design. Over 150 analogues of OXD-2115 were synthesized and screened in post-mortem brain tissue for tau affinity against [3H]OXD-2115, and in silico models were used to predict brain uptake. [18F]OXD-2314 was identified as a selective, high-affinity non-AD tau PET radiotracer with favorable brain uptake, dosimetry, and radiometabolite profiles in rats and non-human primate and is being translated for first-in-human PET studies.

Suggested Citation

  • Anton Lindberg & Emily Murrell & Junchao Tong & N. Scott Mason & Daniel Sohn & Johan Sandell & Peter Ström & Jeffrey S. Stehouwer & Brian J. Lopresti & Jenny Viklund & Samuel Svensson & Chester A. Mat, 2024. "Ligand-based design of [18F]OXD-2314 for PET imaging in non-Alzheimer’s disease tauopathies," Nature Communications, Nature, vol. 15(1), pages 1-13, December.
    • Handle: RePEc:nat:natcom:v:15:y:2024:i:1:d:10.1038_s41467-024-49258-1
    DOI: 10.1038/s41467-024-49258-1
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    as
    1. Yang Shi & Wenjuan Zhang & Yang Yang & Alexey G. Murzin & Benjamin Falcon & Abhay Kotecha & Mike Beers & Airi Tarutani & Fuyuki Kametani & Holly J. Garringer & Ruben Vidal & Grace I. Hallinan & Tammar, 2021. "Structure-based classification of tauopathies," Nature, Nature, vol. 598(7880), pages 359-363, October.
    2. Benjamin Falcon & Jasenko Zivanov & Wenjuan Zhang & Alexey G. Murzin & Holly J. Garringer & Ruben Vidal & R. Anthony Crowther & Kathy L. Newell & Bernardino Ghetti & Michel Goedert & Sjors H. W. Scher, 2019. "Novel tau filament fold in chronic traumatic encephalopathy encloses hydrophobic molecules," Nature, Nature, vol. 568(7752), pages 420-423, April.
    Full references (including those not matched with items on IDEAS)

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