Journal Article

18FGTP1 (Genentech Tau Probe 1), a radioligand for detecting neurofibrillary tangle tau pathology in Alzheimer’s disease

Sandra Sanabria Bohórquez, Tinianow, Jeff N, Ayalon, Gai, Ward, Michael, Kerchner, Geoffrey A, Marik, Jan, Seibyl, John P, Bengtsson, Thomas, Simon-Peter, Williams, Alagille, David, Weimer, Robby M, Tamagnan, Gilles, Gill, Herman S, Ogasawara, Annie, Barret, Olivier, Manser, Paul, Marek, Kenneth

2019

Overview

ObjectiveNeurofibrillary 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.MethodsAutoradiography 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.

• Publisher: Springer Nature B.V
• Subject: Affinity / Alzheimer's disease / Amine oxidase (flavin-containing) / Autoradiography / Binding / Brain / Cognitive ability / Cortex / Defluorination / Diagnostic systems / Dosimeters / Dosimetry / Fluorine isotopes / Image acquisition / In vivo methods and tests / Medical imaging / Modelling / Neurofibrillary tangles / Neuroimaging / Pathology / Positron emission / Positron emission tomography / Proteins / Selectivity / Senile plaques / Stability analysis / Tau protein / Tomography / β-Amyloid