The development of a GPR44 targeting radioligand [11C]AZ12204657 for in vivo assessment of beta cell mass
Abstract Background The G-protein-coupled receptor 44 (GPR44) is a beta cell-restricted target that may serve as a marker for beta cell mass (BCM) given the development of a suitable PET ligand. Methods The binding characteristics of the selected candidate, AZ12204657, at human GPR44 were determined...
| Main Authors: | , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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SpringerOpen
2018-12-01
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| Series: | EJNMMI Research |
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| Online Access: | http://link.springer.com/article/10.1186/s13550-018-0465-6 |
| _version_ | 1819074337826668544 |
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| author | Mahabuba Jahan Peter Johnström Ram K. Selvaraju Marie Svedberg Maria Sörhede Winzell Jenny Bernström Lee Kingston Magnus Schou Zhisheng Jia Stanko Skrtic Lars Johansson Olle Korsgren Lars Farde Christer Halldin Olof Eriksson |
| author_facet | Mahabuba Jahan Peter Johnström Ram K. Selvaraju Marie Svedberg Maria Sörhede Winzell Jenny Bernström Lee Kingston Magnus Schou Zhisheng Jia Stanko Skrtic Lars Johansson Olle Korsgren Lars Farde Christer Halldin Olof Eriksson |
| author_sort | Mahabuba Jahan |
| collection | DOAJ |
| description | Abstract Background The G-protein-coupled receptor 44 (GPR44) is a beta cell-restricted target that may serve as a marker for beta cell mass (BCM) given the development of a suitable PET ligand. Methods The binding characteristics of the selected candidate, AZ12204657, at human GPR44 were determined using in vitro ligand binding assays. AZ12204657 was radiolabeled using 11C- or 3H-labeled methyl iodide ([11C/3H]CH3I) in one step, and the conversion of [11C/3H]CH3I to the radiolabeled product [11C/3H]AZ12204657 was quantitative. The specificity of radioligand binding to GPR44 and the selectivity for beta cells were evaluated by in vitro binding studies on pancreatic sections from human and non-human primates as well as on homogenates from endocrine and exocrine pancreatic compartments. Results The radiochemical purity of the resulting radioligand [11C]AZ12204657 was > 98%, with high molar activity (MA), 1351 ± 575 GBq/μmol (n = 18). The radiochemical purity of [3H]AZ12204657 was > 99% with MA of 2 GBq/μmol. Pancreatic binding of [11C/3H]AZ12204657 was co-localized with insulin-positive islets of Langerhans in non-diabetic individuals and individuals with type 2 diabetes (T2D). The binding of [11C]AZ12204657 to GPR44 was > 10 times higher in islet homogenates compared to exocrine homogenates. In human islets of Langerhans GPR44 was co-expressed with insulin, but not glucagon as assessed by co-staining and confocal microscopy. Conclusion We radiolabeled [11C]AZ12204657, a potential PET radioligand for the beta cell-restricted protein GPR44. In vitro evaluation demonstrated that [3H]AZ12204657 and [11C]AZ12204657 selectively target pancreatic beta cells. [11C]AZ12204657 has promising properties as a marker for human BCM. |
| first_indexed | 2024-12-21T18:07:55Z |
| format | Article |
| id | doaj.art-adeebd397411476c89f34e68e0105f08 |
| institution | Directory Open Access Journal |
| issn | 2191-219X |
| language | English |
| last_indexed | 2024-12-21T18:07:55Z |
| publishDate | 2018-12-01 |
| publisher | SpringerOpen |
| record_format | Article |
| series | EJNMMI Research |
| spelling | doaj.art-adeebd397411476c89f34e68e0105f082022-12-21T18:54:53ZengSpringerOpenEJNMMI Research2191-219X2018-12-018111410.1186/s13550-018-0465-6The development of a GPR44 targeting radioligand [11C]AZ12204657 for in vivo assessment of beta cell massMahabuba Jahan0Peter Johnström1Ram K. Selvaraju2Marie Svedberg3Maria Sörhede Winzell4Jenny Bernström5Lee Kingston6Magnus Schou7Zhisheng Jia8Stanko Skrtic9Lars Johansson10Olle Korsgren11Lars Farde12Christer Halldin13Olof Eriksson14Department of Clinical Neuroscience, Center for Psychiatric Research, Karolinska Institutet, Karolinska University HospitalDepartment of Clinical Neuroscience, Center for Psychiatric Research, Karolinska Institutet, Karolinska University HospitalScience for Life Laboratory, Department of Medicinal Chemistry, Uppsala UniversityDepartment of Clinical Neuroscience, Center for Psychiatric Research, Karolinska Institutet, Karolinska University HospitalBioscience, Cardiovascular Renal and Metabolism, IMED Biotech Unit, AstraZenecaDiscovery Biology, Discovery Sciences, IMED Biotech Unit, AstraZenecaEarly Chemical Development, Pharmaceutical Sciences, IMED Biotech Unit, AstraZenecaDepartment of Clinical Neuroscience, Center for Psychiatric Research, Karolinska Institutet, Karolinska University HospitalDepartment of Clinical Neuroscience, Center for Psychiatric Research, Karolinska Institutet, Karolinska University HospitalInnovation Strategies & External Liaison, Pharmaceutical Technology & Development, AstraZenecaGMED Diabetes, Global Medicines Development, AstraZenecaDepartment of Immunology, Genetics and Pathology, Division of Immunology, Uppsala UniversityDepartment of Clinical Neuroscience, Center for Psychiatric Research, Karolinska Institutet, Karolinska University HospitalDepartment of Clinical Neuroscience, Center for Psychiatric Research, Karolinska Institutet, Karolinska University HospitalScience for Life Laboratory, Department of Medicinal Chemistry, Uppsala UniversityAbstract Background The G-protein-coupled receptor 44 (GPR44) is a beta cell-restricted target that may serve as a marker for beta cell mass (BCM) given the development of a suitable PET ligand. Methods The binding characteristics of the selected candidate, AZ12204657, at human GPR44 were determined using in vitro ligand binding assays. AZ12204657 was radiolabeled using 11C- or 3H-labeled methyl iodide ([11C/3H]CH3I) in one step, and the conversion of [11C/3H]CH3I to the radiolabeled product [11C/3H]AZ12204657 was quantitative. The specificity of radioligand binding to GPR44 and the selectivity for beta cells were evaluated by in vitro binding studies on pancreatic sections from human and non-human primates as well as on homogenates from endocrine and exocrine pancreatic compartments. Results The radiochemical purity of the resulting radioligand [11C]AZ12204657 was > 98%, with high molar activity (MA), 1351 ± 575 GBq/μmol (n = 18). The radiochemical purity of [3H]AZ12204657 was > 99% with MA of 2 GBq/μmol. Pancreatic binding of [11C/3H]AZ12204657 was co-localized with insulin-positive islets of Langerhans in non-diabetic individuals and individuals with type 2 diabetes (T2D). The binding of [11C]AZ12204657 to GPR44 was > 10 times higher in islet homogenates compared to exocrine homogenates. In human islets of Langerhans GPR44 was co-expressed with insulin, but not glucagon as assessed by co-staining and confocal microscopy. Conclusion We radiolabeled [11C]AZ12204657, a potential PET radioligand for the beta cell-restricted protein GPR44. In vitro evaluation demonstrated that [3H]AZ12204657 and [11C]AZ12204657 selectively target pancreatic beta cells. [11C]AZ12204657 has promising properties as a marker for human BCM.http://link.springer.com/article/10.1186/s13550-018-0465-6G-protein-coupled receptor 44 (GPR44)Beta cell imagingIslet imagingBeta cell massDiabetes |
| spellingShingle | Mahabuba Jahan Peter Johnström Ram K. Selvaraju Marie Svedberg Maria Sörhede Winzell Jenny Bernström Lee Kingston Magnus Schou Zhisheng Jia Stanko Skrtic Lars Johansson Olle Korsgren Lars Farde Christer Halldin Olof Eriksson The development of a GPR44 targeting radioligand [11C]AZ12204657 for in vivo assessment of beta cell mass EJNMMI Research G-protein-coupled receptor 44 (GPR44) Beta cell imaging Islet imaging Beta cell mass Diabetes |
| title | The development of a GPR44 targeting radioligand [11C]AZ12204657 for in vivo assessment of beta cell mass |
| title_full | The development of a GPR44 targeting radioligand [11C]AZ12204657 for in vivo assessment of beta cell mass |
| title_fullStr | The development of a GPR44 targeting radioligand [11C]AZ12204657 for in vivo assessment of beta cell mass |
| title_full_unstemmed | The development of a GPR44 targeting radioligand [11C]AZ12204657 for in vivo assessment of beta cell mass |
| title_short | The development of a GPR44 targeting radioligand [11C]AZ12204657 for in vivo assessment of beta cell mass |
| title_sort | development of a gpr44 targeting radioligand 11c az12204657 for in vivo assessment of beta cell mass |
| topic | G-protein-coupled receptor 44 (GPR44) Beta cell imaging Islet imaging Beta cell mass Diabetes |
| url | http://link.springer.com/article/10.1186/s13550-018-0465-6 |
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