Comparative binding properties of the tau PET tracers THK5117, THK5351, PBB3, and T807 in postmortem Alzheimer brains

Laetitia Lemoine, Per Göran Gillberg, Marie Svedberg, Vladimir Stepanov, Zhisheng Jia, Jinghai Huang, Sangram Nag, He Tian, Bernardino Ghetti, Nobuyuki Okamura, Makoto Higuchi, Christer Halldin, Agneta Nordberg

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Abstract

Background: The aim of this study was to compare the binding properties of several tau positron emission tomography tracers - THK5117, THK5351, T807 (also known as AV1451; flortaucipir), and PBB3 - head to head in the same human brain tissue. Methods: Binding assays were performed to compare the regional distribution of 3H-THK5117 and 3H-THK5351 in postmortem tissue from three Alzheimer's disease (AD) cases and three control subjects in frontal and temporal cortices as well as in the hippocampus. Competition binding assays between THK5351, THK5117, PBB3, and T807, as well as off-target binding of THK5117 and T807 toward monoamine oxidase B (MAO-B), were performed using binding assays in brain homogenates and autoradiography of three AD cases. Results: Regional binding of 3H-THK5117 and 3H-THK5351 was similar, except in the temporal cortex, which showed higher 3H-THK5117 binding. Saturation studies demonstrated two binding sites for 3H-THK5351 (K d1 = 5.6 nM, Bmax = 76 pmol/g; K d2 = 1 nM, Bmax = 40 pmol/g). Competition studies in the hippocampus between 3H-THK5351 and unlabeled THK5351, THK5117, and T807 revealed super-high-affinity sites for all three tracers (THK5351 K i = 0.1 pM; THK5117 K i = 0.3 pM; T807 K i = 0.2 pM) and an additional high-affinity site (THK5351 K i = 16 nM; THK5117 K i = 20 nM; T807 K i = 78nM). 18F-T807, 11C-THK5351, and 11C-PBB3 autoradiography of large frozen sections from three AD brains showed similar regional binding for the three tracers, with lower binding intensity for 11C-PBB3. Unlabeled THK5351 and T807 displaced 11C-THK5351 to a similar extent and a lower extent, respectively, compared with 11C-PBB3. Competition with the MAO-B inhibitor 3H-l-deprenyl was observed for THK5117 and T807 in the hippocampus (THK5117 K i = 286 nM; T807 K i = 227 nM) and the putamen (THK5117 K i = 148 nM; T807 K i = 135 nM). 3H-THK5351 binding was displaced using autoradiography competition with unlabeled THK5351 and T807 in cortical areas by 70-80% and 60-77%, respectively, in the basal ganglia, whereas unlabeled deprenyl displaced 3H-THK5351 binding by 40% in the frontal cortex and 50% in the basal ganglia. Conclusions: THK5351, THK5117, and T807 seem to target similar binding sites, but with different affinities, whereas PBB3 seems to target its own binding site. Both THK5117 and T807 demonstrated off-target binding in the hippocampus and putamen with a ten times lower binding affinity to the MAO-B inhibitor deprenyl compared with 3H-THK5351.

Original languageEnglish (US)
Article number96
JournalAlzheimer's Research and Therapy
Volume9
Issue number1
DOIs
StatePublished - Dec 11 2017

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Brain
Selegiline
Hippocampus
Monoamine Oxidase
Autoradiography
Alzheimer Disease
THK5351
Monoamine Oxidase Inhibitors
Putamen
Binding Sites
Frontal Lobe
Temporal Lobe
Basal Ganglia
Frozen Sections
Positron-Emission Tomography

Keywords

  • C-THK5351
  • Alzheimer's disease
  • autoradiography
  • AV1451
  • Deprenyl
  • PBB3
  • T807
  • Tau imaging
  • Tau PET
  • Tau PET tracers
  • THK5117

ASJC Scopus subject areas

  • Neurology
  • Clinical Neurology
  • Cognitive Neuroscience

Cite this

Comparative binding properties of the tau PET tracers THK5117, THK5351, PBB3, and T807 in postmortem Alzheimer brains. / Lemoine, Laetitia; Gillberg, Per Göran; Svedberg, Marie; Stepanov, Vladimir; Jia, Zhisheng; Huang, Jinghai; Nag, Sangram; Tian, He; Ghetti, Bernardino; Okamura, Nobuyuki; Higuchi, Makoto; Halldin, Christer; Nordberg, Agneta.

In: Alzheimer's Research and Therapy, Vol. 9, No. 1, 96, 11.12.2017.

Research output: Contribution to journalArticle

Lemoine, L, Gillberg, PG, Svedberg, M, Stepanov, V, Jia, Z, Huang, J, Nag, S, Tian, H, Ghetti, B, Okamura, N, Higuchi, M, Halldin, C & Nordberg, A 2017, 'Comparative binding properties of the tau PET tracers THK5117, THK5351, PBB3, and T807 in postmortem Alzheimer brains', Alzheimer's Research and Therapy, vol. 9, no. 1, 96. https://doi.org/10.1186/s13195-017-0325-z
Lemoine, Laetitia ; Gillberg, Per Göran ; Svedberg, Marie ; Stepanov, Vladimir ; Jia, Zhisheng ; Huang, Jinghai ; Nag, Sangram ; Tian, He ; Ghetti, Bernardino ; Okamura, Nobuyuki ; Higuchi, Makoto ; Halldin, Christer ; Nordberg, Agneta. / Comparative binding properties of the tau PET tracers THK5117, THK5351, PBB3, and T807 in postmortem Alzheimer brains. In: Alzheimer's Research and Therapy. 2017 ; Vol. 9, No. 1.
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abstract = "Background: The aim of this study was to compare the binding properties of several tau positron emission tomography tracers - THK5117, THK5351, T807 (also known as AV1451; flortaucipir), and PBB3 - head to head in the same human brain tissue. Methods: Binding assays were performed to compare the regional distribution of 3H-THK5117 and 3H-THK5351 in postmortem tissue from three Alzheimer's disease (AD) cases and three control subjects in frontal and temporal cortices as well as in the hippocampus. Competition binding assays between THK5351, THK5117, PBB3, and T807, as well as off-target binding of THK5117 and T807 toward monoamine oxidase B (MAO-B), were performed using binding assays in brain homogenates and autoradiography of three AD cases. Results: Regional binding of 3H-THK5117 and 3H-THK5351 was similar, except in the temporal cortex, which showed higher 3H-THK5117 binding. Saturation studies demonstrated two binding sites for 3H-THK5351 (K d1 = 5.6 nM, Bmax = 76 pmol/g; K d2 = 1 nM, Bmax = 40 pmol/g). Competition studies in the hippocampus between 3H-THK5351 and unlabeled THK5351, THK5117, and T807 revealed super-high-affinity sites for all three tracers (THK5351 K i = 0.1 pM; THK5117 K i = 0.3 pM; T807 K i = 0.2 pM) and an additional high-affinity site (THK5351 K i = 16 nM; THK5117 K i = 20 nM; T807 K i = 78nM). 18F-T807, 11C-THK5351, and 11C-PBB3 autoradiography of large frozen sections from three AD brains showed similar regional binding for the three tracers, with lower binding intensity for 11C-PBB3. Unlabeled THK5351 and T807 displaced 11C-THK5351 to a similar extent and a lower extent, respectively, compared with 11C-PBB3. Competition with the MAO-B inhibitor 3H-l-deprenyl was observed for THK5117 and T807 in the hippocampus (THK5117 K i = 286 nM; T807 K i = 227 nM) and the putamen (THK5117 K i = 148 nM; T807 K i = 135 nM). 3H-THK5351 binding was displaced using autoradiography competition with unlabeled THK5351 and T807 in cortical areas by 70-80{\%} and 60-77{\%}, respectively, in the basal ganglia, whereas unlabeled deprenyl displaced 3H-THK5351 binding by 40{\%} in the frontal cortex and 50{\%} in the basal ganglia. Conclusions: THK5351, THK5117, and T807 seem to target similar binding sites, but with different affinities, whereas PBB3 seems to target its own binding site. Both THK5117 and T807 demonstrated off-target binding in the hippocampus and putamen with a ten times lower binding affinity to the MAO-B inhibitor deprenyl compared with 3H-THK5351.",
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author = "Laetitia Lemoine and Gillberg, {Per G{\"o}ran} and Marie Svedberg and Vladimir Stepanov and Zhisheng Jia and Jinghai Huang and Sangram Nag and He Tian and Bernardino Ghetti and Nobuyuki Okamura and Makoto Higuchi and Christer Halldin and Agneta Nordberg",
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TY - JOUR

T1 - Comparative binding properties of the tau PET tracers THK5117, THK5351, PBB3, and T807 in postmortem Alzheimer brains

AU - Lemoine, Laetitia

AU - Gillberg, Per Göran

AU - Svedberg, Marie

AU - Stepanov, Vladimir

AU - Jia, Zhisheng

AU - Huang, Jinghai

AU - Nag, Sangram

AU - Tian, He

AU - Ghetti, Bernardino

AU - Okamura, Nobuyuki

AU - Higuchi, Makoto

AU - Halldin, Christer

AU - Nordberg, Agneta

PY - 2017/12/11

Y1 - 2017/12/11

N2 - Background: The aim of this study was to compare the binding properties of several tau positron emission tomography tracers - THK5117, THK5351, T807 (also known as AV1451; flortaucipir), and PBB3 - head to head in the same human brain tissue. Methods: Binding assays were performed to compare the regional distribution of 3H-THK5117 and 3H-THK5351 in postmortem tissue from three Alzheimer's disease (AD) cases and three control subjects in frontal and temporal cortices as well as in the hippocampus. Competition binding assays between THK5351, THK5117, PBB3, and T807, as well as off-target binding of THK5117 and T807 toward monoamine oxidase B (MAO-B), were performed using binding assays in brain homogenates and autoradiography of three AD cases. Results: Regional binding of 3H-THK5117 and 3H-THK5351 was similar, except in the temporal cortex, which showed higher 3H-THK5117 binding. Saturation studies demonstrated two binding sites for 3H-THK5351 (K d1 = 5.6 nM, Bmax = 76 pmol/g; K d2 = 1 nM, Bmax = 40 pmol/g). Competition studies in the hippocampus between 3H-THK5351 and unlabeled THK5351, THK5117, and T807 revealed super-high-affinity sites for all three tracers (THK5351 K i = 0.1 pM; THK5117 K i = 0.3 pM; T807 K i = 0.2 pM) and an additional high-affinity site (THK5351 K i = 16 nM; THK5117 K i = 20 nM; T807 K i = 78nM). 18F-T807, 11C-THK5351, and 11C-PBB3 autoradiography of large frozen sections from three AD brains showed similar regional binding for the three tracers, with lower binding intensity for 11C-PBB3. Unlabeled THK5351 and T807 displaced 11C-THK5351 to a similar extent and a lower extent, respectively, compared with 11C-PBB3. Competition with the MAO-B inhibitor 3H-l-deprenyl was observed for THK5117 and T807 in the hippocampus (THK5117 K i = 286 nM; T807 K i = 227 nM) and the putamen (THK5117 K i = 148 nM; T807 K i = 135 nM). 3H-THK5351 binding was displaced using autoradiography competition with unlabeled THK5351 and T807 in cortical areas by 70-80% and 60-77%, respectively, in the basal ganglia, whereas unlabeled deprenyl displaced 3H-THK5351 binding by 40% in the frontal cortex and 50% in the basal ganglia. Conclusions: THK5351, THK5117, and T807 seem to target similar binding sites, but with different affinities, whereas PBB3 seems to target its own binding site. Both THK5117 and T807 demonstrated off-target binding in the hippocampus and putamen with a ten times lower binding affinity to the MAO-B inhibitor deprenyl compared with 3H-THK5351.

AB - Background: The aim of this study was to compare the binding properties of several tau positron emission tomography tracers - THK5117, THK5351, T807 (also known as AV1451; flortaucipir), and PBB3 - head to head in the same human brain tissue. Methods: Binding assays were performed to compare the regional distribution of 3H-THK5117 and 3H-THK5351 in postmortem tissue from three Alzheimer's disease (AD) cases and three control subjects in frontal and temporal cortices as well as in the hippocampus. Competition binding assays between THK5351, THK5117, PBB3, and T807, as well as off-target binding of THK5117 and T807 toward monoamine oxidase B (MAO-B), were performed using binding assays in brain homogenates and autoradiography of three AD cases. Results: Regional binding of 3H-THK5117 and 3H-THK5351 was similar, except in the temporal cortex, which showed higher 3H-THK5117 binding. Saturation studies demonstrated two binding sites for 3H-THK5351 (K d1 = 5.6 nM, Bmax = 76 pmol/g; K d2 = 1 nM, Bmax = 40 pmol/g). Competition studies in the hippocampus between 3H-THK5351 and unlabeled THK5351, THK5117, and T807 revealed super-high-affinity sites for all three tracers (THK5351 K i = 0.1 pM; THK5117 K i = 0.3 pM; T807 K i = 0.2 pM) and an additional high-affinity site (THK5351 K i = 16 nM; THK5117 K i = 20 nM; T807 K i = 78nM). 18F-T807, 11C-THK5351, and 11C-PBB3 autoradiography of large frozen sections from three AD brains showed similar regional binding for the three tracers, with lower binding intensity for 11C-PBB3. Unlabeled THK5351 and T807 displaced 11C-THK5351 to a similar extent and a lower extent, respectively, compared with 11C-PBB3. Competition with the MAO-B inhibitor 3H-l-deprenyl was observed for THK5117 and T807 in the hippocampus (THK5117 K i = 286 nM; T807 K i = 227 nM) and the putamen (THK5117 K i = 148 nM; T807 K i = 135 nM). 3H-THK5351 binding was displaced using autoradiography competition with unlabeled THK5351 and T807 in cortical areas by 70-80% and 60-77%, respectively, in the basal ganglia, whereas unlabeled deprenyl displaced 3H-THK5351 binding by 40% in the frontal cortex and 50% in the basal ganglia. Conclusions: THK5351, THK5117, and T807 seem to target similar binding sites, but with different affinities, whereas PBB3 seems to target its own binding site. Both THK5117 and T807 demonstrated off-target binding in the hippocampus and putamen with a ten times lower binding affinity to the MAO-B inhibitor deprenyl compared with 3H-THK5351.

KW - C-THK5351

KW - Alzheimer's disease

KW - autoradiography

KW - AV1451

KW - Deprenyl

KW - PBB3

KW - T807

KW - Tau imaging

KW - Tau PET

KW - Tau PET tracers

KW - THK5117

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U2 - 10.1186/s13195-017-0325-z

DO - 10.1186/s13195-017-0325-z

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