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

• DOI: 10.1007/s00259-019-04399-0
• Publication Date: 2019-06-28T07:11:53Z
• Authors: Sandra Sanabria B...; 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. Weimer
• Keywords: Adult; Aged, 80 and over; Male; Fluorine Radioisotopes; Brain; Neurofibrillary Tangles; Middle Aged; Macaca mulatta; Sensitivity and Specificity; 3. Good health; Mice, Inbred C57BL; Kinetics; Mice; 03 medical and health sciences; 0302 clinical medicine; Alzheimer Disease; Positron-Emission Tomography; Animals; Humans; Female; Radiopharmaceuticals; Aged; Protein Binding

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