Imaging the TGFβ type I receptor in pulmonary arterial hypertension
Abstract Transforming growth factor β (TGFβ) activity is perturbed in remodelled pulmonary vasculature of patients with pulmonary arterial hypertension (PAH), cancer, vascular diseases and developmental disorders. Inhibition of TGFβ, which signals via activin receptor-like kinase 5 (ALK5), prevents...
| Main Authors: | , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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SpringerOpen
2023-03-01
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| Series: | EJNMMI Research |
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| Online Access: | https://doi.org/10.1186/s13550-023-00966-7 |
| _version_ | 1827979403956584448 |
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| author | Lonneke Rotteveel Alex J. Poot Esther J. M. Kooijman Robert C. Schuit Ingrid Schalij Xiaoqing Sun Kondababu Kurakula Chris Happé Wissam Beaino Peter ten Dijke Adriaan A. Lammertsma Harm Jan Bogaard Albert D. Windhorst |
| author_facet | Lonneke Rotteveel Alex J. Poot Esther J. M. Kooijman Robert C. Schuit Ingrid Schalij Xiaoqing Sun Kondababu Kurakula Chris Happé Wissam Beaino Peter ten Dijke Adriaan A. Lammertsma Harm Jan Bogaard Albert D. Windhorst |
| author_sort | Lonneke Rotteveel |
| collection | DOAJ |
| description | Abstract Transforming growth factor β (TGFβ) activity is perturbed in remodelled pulmonary vasculature of patients with pulmonary arterial hypertension (PAH), cancer, vascular diseases and developmental disorders. Inhibition of TGFβ, which signals via activin receptor-like kinase 5 (ALK5), prevents progression and development of experimental PAH. The purpose of this study was to assess two ALK5 targeting positron emission tomography (PET) tracers ([11C]LR111 and [18F]EW-7197) for imaging ALK5 in monocrotaline (MCT)- and Sugen/hypoxia (SuHx)-induced PAH. Both tracers were subjected to extensive in vitro and in vivo studies. [11C]LR111 showed the highest metabolic stability, as 46 ± 2% of intact tracer was still present in rat blood plasma after 60 min. In autoradiography experiments, [11C]LR111 showed high ALK5 binding in vitro compared with controls, 3.2 and 1.5 times higher in SuHx and MCT, respectively. In addition, its binding could be blocked by SB431542, an adenosine triphosphate competitive ALK5 kinase inhibitor. However, [18F]EW-7197 showed the best in vivo results. 15 min after injection, uptake was 2.5 and 1.4 times higher in the SuHx and MCT lungs, compared with controls. Therefore, [18F]EW-7197 is a promising PET tracer for ALK5 imaging in PAH. |
| first_indexed | 2024-04-09T21:36:15Z |
| format | Article |
| id | doaj.art-d4e5834623554ec79cfeb8672ef8eb29 |
| institution | Directory Open Access Journal |
| issn | 2191-219X |
| language | English |
| last_indexed | 2024-04-09T21:36:15Z |
| publishDate | 2023-03-01 |
| publisher | SpringerOpen |
| record_format | Article |
| series | EJNMMI Research |
| spelling | doaj.art-d4e5834623554ec79cfeb8672ef8eb292023-03-26T11:17:40ZengSpringerOpenEJNMMI Research2191-219X2023-03-0113111410.1186/s13550-023-00966-7Imaging the TGFβ type I receptor in pulmonary arterial hypertensionLonneke Rotteveel0Alex J. Poot1Esther J. M. Kooijman2Robert C. Schuit3Ingrid Schalij4Xiaoqing Sun5Kondababu Kurakula6Chris Happé7Wissam Beaino8Peter ten Dijke9Adriaan A. Lammertsma10Harm Jan Bogaard11Albert D. Windhorst12Department Radiology and Nuclear Medicine(s), (Amsterdam Cardiovascular Sciences), Amsterdam UMC, VU University Medical CenterDepartment Radiology and Nuclear Medicine(s), (Amsterdam Cardiovascular Sciences), Amsterdam UMC, VU University Medical CenterDepartment Radiology and Nuclear Medicine(s), (Amsterdam Cardiovascular Sciences), Amsterdam UMC, VU University Medical CenterDepartment Radiology and Nuclear Medicine(s), (Amsterdam Cardiovascular Sciences), Amsterdam UMC, VU University Medical CenterDepartment Pulmonary Medicine, (Amsterdam Cardiovascular Sciences), Amsterdam UMC, VU University Medical CenterDepartment Pulmonary Medicine, (Amsterdam Cardiovascular Sciences), Amsterdam UMC, VU University Medical CenterDepartment Cell and Chemical Biology, Leiden University Medical CenterDepartment Pulmonary Medicine, (Amsterdam Cardiovascular Sciences), Amsterdam UMC, VU University Medical CenterDepartment Radiology and Nuclear Medicine(s), (Amsterdam Cardiovascular Sciences), Amsterdam UMC, VU University Medical CenterDepartment Cell and Chemical Biology, Leiden University Medical CenterDepartment Radiology and Nuclear Medicine(s), (Amsterdam Cardiovascular Sciences), Amsterdam UMC, VU University Medical CenterDepartment Pulmonary Medicine, (Amsterdam Cardiovascular Sciences), Amsterdam UMC, VU University Medical CenterDepartment Radiology and Nuclear Medicine(s), (Amsterdam Cardiovascular Sciences), Amsterdam UMC, VU University Medical CenterAbstract Transforming growth factor β (TGFβ) activity is perturbed in remodelled pulmonary vasculature of patients with pulmonary arterial hypertension (PAH), cancer, vascular diseases and developmental disorders. Inhibition of TGFβ, which signals via activin receptor-like kinase 5 (ALK5), prevents progression and development of experimental PAH. The purpose of this study was to assess two ALK5 targeting positron emission tomography (PET) tracers ([11C]LR111 and [18F]EW-7197) for imaging ALK5 in monocrotaline (MCT)- and Sugen/hypoxia (SuHx)-induced PAH. Both tracers were subjected to extensive in vitro and in vivo studies. [11C]LR111 showed the highest metabolic stability, as 46 ± 2% of intact tracer was still present in rat blood plasma after 60 min. In autoradiography experiments, [11C]LR111 showed high ALK5 binding in vitro compared with controls, 3.2 and 1.5 times higher in SuHx and MCT, respectively. In addition, its binding could be blocked by SB431542, an adenosine triphosphate competitive ALK5 kinase inhibitor. However, [18F]EW-7197 showed the best in vivo results. 15 min after injection, uptake was 2.5 and 1.4 times higher in the SuHx and MCT lungs, compared with controls. Therefore, [18F]EW-7197 is a promising PET tracer for ALK5 imaging in PAH.https://doi.org/10.1186/s13550-023-00966-7TGFβ type I receptorALK5Positron emission tomographyPulmonary arterial hypertensionSuHxMCT |
| spellingShingle | Lonneke Rotteveel Alex J. Poot Esther J. M. Kooijman Robert C. Schuit Ingrid Schalij Xiaoqing Sun Kondababu Kurakula Chris Happé Wissam Beaino Peter ten Dijke Adriaan A. Lammertsma Harm Jan Bogaard Albert D. Windhorst Imaging the TGFβ type I receptor in pulmonary arterial hypertension EJNMMI Research TGFβ type I receptor ALK5 Positron emission tomography Pulmonary arterial hypertension SuHx MCT |
| title | Imaging the TGFβ type I receptor in pulmonary arterial hypertension |
| title_full | Imaging the TGFβ type I receptor in pulmonary arterial hypertension |
| title_fullStr | Imaging the TGFβ type I receptor in pulmonary arterial hypertension |
| title_full_unstemmed | Imaging the TGFβ type I receptor in pulmonary arterial hypertension |
| title_short | Imaging the TGFβ type I receptor in pulmonary arterial hypertension |
| title_sort | imaging the tgfβ type i receptor in pulmonary arterial hypertension |
| topic | TGFβ type I receptor ALK5 Positron emission tomography Pulmonary arterial hypertension SuHx MCT |
| url | https://doi.org/10.1186/s13550-023-00966-7 |
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