Comparative binding properties of the tau PET tracers THK5117, THK5351, PBB3, and T807 in postmortem Alzheimer brains
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...
| Main Authors: | , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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BMC
2017-12-01
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| Series: | Alzheimer’s Research & Therapy |
| Subjects: | |
| Online Access: | http://link.springer.com/article/10.1186/s13195-017-0325-z |
| _version_ | 1811194421091237888 |
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| author | 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 |
| author_facet | 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 |
| author_sort | Laetitia Lemoine |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-04-12T00:26:39Z |
| format | Article |
| id | doaj.art-97991f17d81047ff9c82a76f12203e66 |
| institution | Directory Open Access Journal |
| issn | 1758-9193 |
| language | English |
| last_indexed | 2024-04-12T00:26:39Z |
| publishDate | 2017-12-01 |
| publisher | BMC |
| record_format | Article |
| series | Alzheimer’s Research & Therapy |
| spelling | doaj.art-97991f17d81047ff9c82a76f12203e662022-12-22T03:55:29ZengBMCAlzheimer’s Research & Therapy1758-91932017-12-019111310.1186/s13195-017-0325-zComparative binding properties of the tau PET tracers THK5117, THK5351, PBB3, and T807 in postmortem Alzheimer brainsLaetitia Lemoine0Per-Göran Gillberg1Marie Svedberg2Vladimir Stepanov3Zhisheng Jia4Jinghai Huang5Sangram Nag6He Tian7Bernardino Ghetti8Nobuyuki Okamura9Makoto Higuchi10Christer Halldin11Agneta Nordberg12Division of Translational Alzheimer Neurobiology, Department of Neurobiology, Care Sciences and Society, Karolinska InstitutetDivision of Translational Alzheimer Neurobiology, Department of Neurobiology, Care Sciences and Society, Karolinska InstitutetDepartment of Clinical Neuroscience, Center for Psychiatric Research, Karolinska InstitutetDepartment of Clinical Neuroscience, Center for Psychiatric Research, Karolinska InstitutetDepartment of Clinical Neuroscience, Center for Psychiatric Research, Karolinska InstitutetInstitute of Fine Chemicals, East China University of Science and TechnologyDepartment of Clinical Neuroscience, Center for Psychiatric Research, Karolinska InstitutetInstitute of Fine Chemicals, East China University of Science and TechnologyDepartment of Pathology & Laboratory Medicine, Indiana University School of MedicineDivision of Pharmacology, Faculty of Medicine, Tohoku Medical and Pharmaceutical UniversityNational Institute of Radiological Sciences, National Institutes for Quantum and Radiological Science and TechnologyDepartment of Clinical Neuroscience, Center for Psychiatric Research, Karolinska InstitutetDivision of Translational Alzheimer Neurobiology, Department of Neurobiology, Care Sciences and Society, Karolinska InstitutetAbstract 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.http://link.springer.com/article/10.1186/s13195-017-0325-zAlzheimer’s diseaseTHK511711C-THK5351T807AV1451PBB3 |
| spellingShingle | 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 Comparative binding properties of the tau PET tracers THK5117, THK5351, PBB3, and T807 in postmortem Alzheimer brains Alzheimer’s Research & Therapy Alzheimer’s disease THK5117 11C-THK5351 T807 AV1451 PBB3 |
| title | Comparative binding properties of the tau PET tracers THK5117, THK5351, PBB3, and T807 in postmortem Alzheimer brains |
| title_full | Comparative binding properties of the tau PET tracers THK5117, THK5351, PBB3, and T807 in postmortem Alzheimer brains |
| title_fullStr | Comparative binding properties of the tau PET tracers THK5117, THK5351, PBB3, and T807 in postmortem Alzheimer brains |
| title_full_unstemmed | Comparative binding properties of the tau PET tracers THK5117, THK5351, PBB3, and T807 in postmortem Alzheimer brains |
| title_short | Comparative binding properties of the tau PET tracers THK5117, THK5351, PBB3, and T807 in postmortem Alzheimer brains |
| title_sort | comparative binding properties of the tau pet tracers thk5117 thk5351 pbb3 and t807 in postmortem alzheimer brains |
| topic | Alzheimer’s disease THK5117 11C-THK5351 T807 AV1451 PBB3 |
| url | http://link.springer.com/article/10.1186/s13195-017-0325-z |
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