[${}^{18}$f]gtp1 (genentech tau probe 1), a radioligand for detecting neurofibrillary tangle tau pathology in alzheimer's disease

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 ([${}^{18}$F]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 [${}^{18}$F]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 [${}^{18}$F]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 [${}^{18}$F]GTP1-specific binding parameters derived from the kinetic modeling. [${}^{18}$F]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. [${}^{18}$F]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, [${}^{18}$F]GTP1 exhibited favorable dosimetry and brain kinetics, and no evidence of defluorination. [${}^{18}$F]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 [${}^{18}$F]GTP1-specific binding increased with AD severity and could differentiate diagnostic cohorts. [${}^{18}$F]GTP1 is a promising PET probe for the study of tau pathology in AD.