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Open Access 01-12-2017 | Research

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

Authors: 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

Published in: Alzheimer's Research & Therapy | Issue 1/2017

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, B_max = 76 pmol/g; K _d2 = 1 nM, B_max = 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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Title: Comparative binding properties of the tau PET tracers THK5117, THK5351, PBB3, and T807 in postmortem Alzheimer brains
Authors: 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
Publication date: 01-12-2017
Publisher: BioMed Central
Published in: Alzheimer's Research & Therapy / Issue 1/2017
Electronic ISSN: 1758-9193
DOI: https://doi.org/10.1186/s13195-017-0325-z

At a glance: The ONWARDS insulin icodec trials

Springer Medicine

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

Abstract

Background

Methods

Results

Conclusions

At a glance: The ONWARDS insulin icodec trials

Springer Medicine

Abstract

Background

Methods

Results

Conclusions

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