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. 2019 Sep;46(10):2077-2089.
doi: 10.1007/s00259-019-04399-0. Epub 2019 Jun 28.

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

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  9   10
Affiliations

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

Sandra Sanabria Bohórquez et al. Eur J Nucl Med Mol Imaging. 2019 Sep.

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; Kinetic modeling; Tau PET imaging; [18F]GTP1.

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