Sandra Sanabria Bohórquez1, Jan Marik2, Annie Ogasawara2, Jeff N Tinianow2, Herman S Gill2, Olivier Barret3, Gilles Tamagnan3,4, David Alagille3,4, Gai Ayalon5, Paul Manser6, Thomas Bengtsson6, Michael Ward7,8, Simon-Peter Williams2, Geoffrey A Kerchner7, John P Seibyl3, Kenneth Marek3, Robby M Weimer9,10. 1. Clinical Imaging Group, Genentech, Inc., 1 DNA Way, South San Francisco, CA, 94080, USA. 2. Department of Biomedical Imaging, Genentech, Inc., 1 DNA Way, South San Francisco, CA, 94080, USA. 3. Invicro LLC, 60 Temple St, Suite 8A, New Haven, CT, 06510, USA. 4. XingImaging, LLC, 760 Chapel Street, New Haven, CT, 06510, USA. 5. Department of Neuroscience, Genentech, Inc., 1 DNA Way, South San Francisco, CA, 94080, USA. 6. Clinical Biostatistics, Genentech, Inc., 1 DNA Way, South San Francisco, CA, 94080, USA. 7. Early Clinical Development, Genentech, Inc., 1 DNA Way, South San Francisco, CA, 94080, USA. 8. Alector, Inc., 151 Oyster Point Blvd, South San Francisco, CA, 94080, USA. 9. Department of Biomedical Imaging, Genentech, Inc., 1 DNA Way, South San Francisco, CA, 94080, USA. weimer.robby@gene.com. 10. Department of Neuroscience, Genentech, Inc., 1 DNA Way, South San Francisco, CA, 94080, USA. weimer.robby@gene.com.
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.
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 ADpatients. 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+ ADparticipants 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.
Entities:
Keywords:
Alzheimer’s disease; Kinetic modeling; Tau PET imaging; [18F]GTP1
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