Assessment of glucagon receptor occupancy by Positron Emission Tomography in non-human primates
The glucagon receptor (GCGR) is an emerging target in anti-diabetic therapy. Reliable biomarkers for in vivo activity on the GCGR, in the setting of dual glucagon-like peptide 1/glucagon (GLP-1/GCG) receptor agonism, are currently unavailable. Here, we investigated [68Ga]Ga-DO3A-S01-GCG as a biomark...
| Main Authors: | , , , , , , , , , , , , , |
|---|---|
| Other Authors: | |
| Format: | Journal Article |
| Language: | English |
| Published: |
2020
|
| Subjects: | |
| Online Access: | https://hdl.handle.net/10356/142352 |
| _version_ | 1826126898659328000 |
|---|---|
| author | Eriksson, Olof Velikyan, Irina Haack, Torsten Bossart, Martin Evers, Andreas Laitinen, Iina Larsen, Philip J. Plettenburg, Oliver Takano, Akihiro Halldin, Christer Antoni, Gunnar Johansson, Lars Pierrou, Stefan Wagner, Michael |
| author2 | Lee Kong Chian School of Medicine (LKCMedicine) |
| author_facet | Lee Kong Chian School of Medicine (LKCMedicine) Eriksson, Olof Velikyan, Irina Haack, Torsten Bossart, Martin Evers, Andreas Laitinen, Iina Larsen, Philip J. Plettenburg, Oliver Takano, Akihiro Halldin, Christer Antoni, Gunnar Johansson, Lars Pierrou, Stefan Wagner, Michael |
| author_sort | Eriksson, Olof |
| collection | NTU |
| description | The glucagon receptor (GCGR) is an emerging target in anti-diabetic therapy. Reliable biomarkers for in vivo activity on the GCGR, in the setting of dual glucagon-like peptide 1/glucagon (GLP-1/GCG) receptor agonism, are currently unavailable. Here, we investigated [68Ga]Ga-DO3A-S01-GCG as a biomarker for GCGR occupancy in liver, the tissue with highest GCGR expression, in non-human primates (NHP) by PET. [68Ga]Ga-DO3A-S01-GCG was evaluated by dynamic PET in NHPs by a dose escalation study design, where up to 67 µg/kg DO3A-S01-GCG peptide mass was co-injected. The test-retest reproducibility of [68Ga]Ga-DO3A-S01-GCG binding in liver was evaluated. Furthermore, we investigated the effect of pre-treatment with acylated glucagon agonist 1-GCG on [68Ga]Ga-DO3A-S01-GCG binding in liver. [68Ga]Ga-DO3A-S01-GCG bound to liver in vivo in a dose-dependent manner. Negligible peptide mass effect was observed for DO3A-S01-GCG doses <0.2 µg/kg. In vivo Kd for [68Ga]Ga-DO3A-S01-GCG corresponded to 0.7 µg/kg, which indicates high potency. The test-retest reproducibility for [68Ga]Ga-DO3A-S01-GCG binding in liver was 5.7 ± 7.9%. Pre-treatment with 1-GCG, an acylated glucagon agonist, resulted in a GCGR occupancy of 61.5 ± 9.1% in liver. Predicted human radiation dosimetry would allow for repeated annual [68Ga]Ga-DO3A-S01-GCG PET examinations. In summary, PET radioligand [68Ga]Ga-DO3A-S01-GCG is a quantitative biomarker of in vivo GCGR occupancy. |
| first_indexed | 2024-10-01T06:59:56Z |
| format | Journal Article |
| id | ntu-10356/142352 |
| institution | Nanyang Technological University |
| language | English |
| last_indexed | 2024-10-01T06:59:56Z |
| publishDate | 2020 |
| record_format | dspace |
| spelling | ntu-10356/1423522020-11-01T05:26:33Z Assessment of glucagon receptor occupancy by Positron Emission Tomography in non-human primates Eriksson, Olof Velikyan, Irina Haack, Torsten Bossart, Martin Evers, Andreas Laitinen, Iina Larsen, Philip J. Plettenburg, Oliver Takano, Akihiro Halldin, Christer Antoni, Gunnar Johansson, Lars Pierrou, Stefan Wagner, Michael Lee Kong Chian School of Medicine (LKCMedicine) Science::Medicine Positron Emission Tomography (PET) Glucagon Receptor (GCGR) The glucagon receptor (GCGR) is an emerging target in anti-diabetic therapy. Reliable biomarkers for in vivo activity on the GCGR, in the setting of dual glucagon-like peptide 1/glucagon (GLP-1/GCG) receptor agonism, are currently unavailable. Here, we investigated [68Ga]Ga-DO3A-S01-GCG as a biomarker for GCGR occupancy in liver, the tissue with highest GCGR expression, in non-human primates (NHP) by PET. [68Ga]Ga-DO3A-S01-GCG was evaluated by dynamic PET in NHPs by a dose escalation study design, where up to 67 µg/kg DO3A-S01-GCG peptide mass was co-injected. The test-retest reproducibility of [68Ga]Ga-DO3A-S01-GCG binding in liver was evaluated. Furthermore, we investigated the effect of pre-treatment with acylated glucagon agonist 1-GCG on [68Ga]Ga-DO3A-S01-GCG binding in liver. [68Ga]Ga-DO3A-S01-GCG bound to liver in vivo in a dose-dependent manner. Negligible peptide mass effect was observed for DO3A-S01-GCG doses <0.2 µg/kg. In vivo Kd for [68Ga]Ga-DO3A-S01-GCG corresponded to 0.7 µg/kg, which indicates high potency. The test-retest reproducibility for [68Ga]Ga-DO3A-S01-GCG binding in liver was 5.7 ± 7.9%. Pre-treatment with 1-GCG, an acylated glucagon agonist, resulted in a GCGR occupancy of 61.5 ± 9.1% in liver. Predicted human radiation dosimetry would allow for repeated annual [68Ga]Ga-DO3A-S01-GCG PET examinations. In summary, PET radioligand [68Ga]Ga-DO3A-S01-GCG is a quantitative biomarker of in vivo GCGR occupancy. Published version 2020-06-19T05:45:17Z 2020-06-19T05:45:17Z 2019 Journal Article Eriksson, O., Velikyan, I., Haack, T., Bossart, M., Evers, A., Laitinen, I., . . . Wagner, M. (2019). Assessment of glucagon receptor occupancy by Positron Emission Tomography in non-human primates. Scientific Reports, 9(1), 14960-. doi:10.1038/s41598-019-51530-0 2045-2322 https://hdl.handle.net/10356/142352 10.1038/s41598-019-51530-0 31628379 2-s2.0-85073590810 1 9 en Scientific Reports © 2019 The Author(s). This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. Te images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/. application/pdf |
| spellingShingle | Science::Medicine Positron Emission Tomography (PET) Glucagon Receptor (GCGR) Eriksson, Olof Velikyan, Irina Haack, Torsten Bossart, Martin Evers, Andreas Laitinen, Iina Larsen, Philip J. Plettenburg, Oliver Takano, Akihiro Halldin, Christer Antoni, Gunnar Johansson, Lars Pierrou, Stefan Wagner, Michael Assessment of glucagon receptor occupancy by Positron Emission Tomography in non-human primates |
| title | Assessment of glucagon receptor occupancy by Positron Emission Tomography in non-human primates |
| title_full | Assessment of glucagon receptor occupancy by Positron Emission Tomography in non-human primates |
| title_fullStr | Assessment of glucagon receptor occupancy by Positron Emission Tomography in non-human primates |
| title_full_unstemmed | Assessment of glucagon receptor occupancy by Positron Emission Tomography in non-human primates |
| title_short | Assessment of glucagon receptor occupancy by Positron Emission Tomography in non-human primates |
| title_sort | assessment of glucagon receptor occupancy by positron emission tomography in non human primates |
| topic | Science::Medicine Positron Emission Tomography (PET) Glucagon Receptor (GCGR) |
| url | https://hdl.handle.net/10356/142352 |
| work_keys_str_mv | AT erikssonolof assessmentofglucagonreceptoroccupancybypositronemissiontomographyinnonhumanprimates AT velikyanirina assessmentofglucagonreceptoroccupancybypositronemissiontomographyinnonhumanprimates AT haacktorsten assessmentofglucagonreceptoroccupancybypositronemissiontomographyinnonhumanprimates AT bossartmartin assessmentofglucagonreceptoroccupancybypositronemissiontomographyinnonhumanprimates AT eversandreas assessmentofglucagonreceptoroccupancybypositronemissiontomographyinnonhumanprimates AT laitineniina assessmentofglucagonreceptoroccupancybypositronemissiontomographyinnonhumanprimates AT larsenphilipj assessmentofglucagonreceptoroccupancybypositronemissiontomographyinnonhumanprimates AT plettenburgoliver assessmentofglucagonreceptoroccupancybypositronemissiontomographyinnonhumanprimates AT takanoakihiro assessmentofglucagonreceptoroccupancybypositronemissiontomographyinnonhumanprimates AT halldinchrister assessmentofglucagonreceptoroccupancybypositronemissiontomographyinnonhumanprimates AT antonigunnar assessmentofglucagonreceptoroccupancybypositronemissiontomographyinnonhumanprimates AT johanssonlars assessmentofglucagonreceptoroccupancybypositronemissiontomographyinnonhumanprimates AT pierroustefan assessmentofglucagonreceptoroccupancybypositronemissiontomographyinnonhumanprimates AT wagnermichael assessmentofglucagonreceptoroccupancybypositronemissiontomographyinnonhumanprimates |