Investigation of an 18F-labelled Imidazopyridotriazine for Molecular Imaging of Cyclic Nucleotide Phosphodiesterase 2A
Specific radioligands for in vivo visualization and quantification of cyclic nucleotide phosphodiesterase 2A (PDE2A) by positron emission tomography (PET) are increasingly gaining interest in brain research. Herein we describe the synthesis, the 18F-labelling as well as the biological evaluation of...
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MDPI AG
2018-03-01
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| author | Susann Schröder Barbara Wenzel Winnie Deuther-Conrad Rodrigo Teodoro Mathias Kranz Matthias Scheunemann Ute Egerland Norbert Höfgen Detlef Briel Jörg Steinbach Peter Brust |
| author_facet | Susann Schröder Barbara Wenzel Winnie Deuther-Conrad Rodrigo Teodoro Mathias Kranz Matthias Scheunemann Ute Egerland Norbert Höfgen Detlef Briel Jörg Steinbach Peter Brust |
| author_sort | Susann Schröder |
| collection | DOAJ |
| description | Specific radioligands for in vivo visualization and quantification of cyclic nucleotide phosphodiesterase 2A (PDE2A) by positron emission tomography (PET) are increasingly gaining interest in brain research. Herein we describe the synthesis, the 18F-labelling as well as the biological evaluation of our latest PDE2A (radio-)ligand 9-(5-Butoxy-2-fluorophenyl)-2-(2-([18F])fluoroethoxy)-7-methylimidazo[5,1-c]pyrido[2,3-e][1,2,4]triazine (([18F])TA5). It is the most potent PDE2A ligand out of our series of imidazopyridotriazine-based derivatives so far (IC50 hPDE2A = 3.0 nM; IC50 hPDE10A > 1000 nM). Radiolabelling was performed in a one-step procedure starting from the corresponding tosylate precursor. In vitro autoradiography on rat and pig brain slices displayed a homogenous and non-specific binding of the radioligand. Investigation of stability in vivo by reversed-phase HPLC (RP-HPLC) and micellar liquid chromatography (MLC) analyses of plasma and brain samples obtained from mice revealed a high fraction of one main radiometabolite. Hence, we concluded that [18F]TA5 is not appropriate for molecular imaging of PDE2A neither in vitro nor in vivo. Our ongoing work is focusing on further structurally modified compounds with enhanced metabolic stability. |
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| last_indexed | 2024-12-12T01:47:06Z |
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| spelling | doaj.art-df2b6a0b9d3d4755a29a5f00617e36292022-12-22T00:42:33ZengMDPI AGMolecules1420-30492018-03-0123355610.3390/molecules23030556molecules23030556Investigation of an 18F-labelled Imidazopyridotriazine for Molecular Imaging of Cyclic Nucleotide Phosphodiesterase 2ASusann Schröder0Barbara Wenzel1Winnie Deuther-Conrad2Rodrigo Teodoro3Mathias Kranz4Matthias Scheunemann5Ute Egerland6Norbert Höfgen7Detlef Briel8Jörg Steinbach9Peter Brust10Department of Neuroradiopharmaceuticals, Institute of Radiopharmaceutical Cancer Research, Helmholtz-Zentrum Dresden-Rossendorf, Leipzig 04318, GermanyDepartment of Neuroradiopharmaceuticals, Institute of Radiopharmaceutical Cancer Research, Helmholtz-Zentrum Dresden-Rossendorf, Leipzig 04318, GermanyDepartment of Neuroradiopharmaceuticals, Institute of Radiopharmaceutical Cancer Research, Helmholtz-Zentrum Dresden-Rossendorf, Leipzig 04318, GermanyDepartment of Neuroradiopharmaceuticals, Institute of Radiopharmaceutical Cancer Research, Helmholtz-Zentrum Dresden-Rossendorf, Leipzig 04318, GermanyDepartment of Neuroradiopharmaceuticals, Institute of Radiopharmaceutical Cancer Research, Helmholtz-Zentrum Dresden-Rossendorf, Leipzig 04318, GermanyDepartment of Neuroradiopharmaceuticals, Institute of Radiopharmaceutical Cancer Research, Helmholtz-Zentrum Dresden-Rossendorf, Leipzig 04318, GermanyBioCrea GmbH, Radebeul 01445, GermanyBioCrea GmbH, Radebeul 01445, GermanyPharmaceutical/Medicinal Chemistry, Institute of Pharmacy, Faculty of Medicine, Leipzig University, Leipzig 04103, GermanyDepartment of Neuroradiopharmaceuticals, Institute of Radiopharmaceutical Cancer Research, Helmholtz-Zentrum Dresden-Rossendorf, Leipzig 04318, GermanyDepartment of Neuroradiopharmaceuticals, Institute of Radiopharmaceutical Cancer Research, Helmholtz-Zentrum Dresden-Rossendorf, Leipzig 04318, GermanySpecific radioligands for in vivo visualization and quantification of cyclic nucleotide phosphodiesterase 2A (PDE2A) by positron emission tomography (PET) are increasingly gaining interest in brain research. Herein we describe the synthesis, the 18F-labelling as well as the biological evaluation of our latest PDE2A (radio-)ligand 9-(5-Butoxy-2-fluorophenyl)-2-(2-([18F])fluoroethoxy)-7-methylimidazo[5,1-c]pyrido[2,3-e][1,2,4]triazine (([18F])TA5). It is the most potent PDE2A ligand out of our series of imidazopyridotriazine-based derivatives so far (IC50 hPDE2A = 3.0 nM; IC50 hPDE10A > 1000 nM). Radiolabelling was performed in a one-step procedure starting from the corresponding tosylate precursor. In vitro autoradiography on rat and pig brain slices displayed a homogenous and non-specific binding of the radioligand. Investigation of stability in vivo by reversed-phase HPLC (RP-HPLC) and micellar liquid chromatography (MLC) analyses of plasma and brain samples obtained from mice revealed a high fraction of one main radiometabolite. Hence, we concluded that [18F]TA5 is not appropriate for molecular imaging of PDE2A neither in vitro nor in vivo. Our ongoing work is focusing on further structurally modified compounds with enhanced metabolic stability.http://www.mdpi.com/1420-3049/23/3/556Phosphodiesterase 2A (PDE2A)secondary messengersPDE2A radioligandspositron emission tomography (PET)neuroimagingmetabolic stabilitymicellar liquid chromatography (MLC) |
| spellingShingle | Susann Schröder Barbara Wenzel Winnie Deuther-Conrad Rodrigo Teodoro Mathias Kranz Matthias Scheunemann Ute Egerland Norbert Höfgen Detlef Briel Jörg Steinbach Peter Brust Investigation of an 18F-labelled Imidazopyridotriazine for Molecular Imaging of Cyclic Nucleotide Phosphodiesterase 2A Molecules Phosphodiesterase 2A (PDE2A) secondary messengers PDE2A radioligands positron emission tomography (PET) neuroimaging metabolic stability micellar liquid chromatography (MLC) |
| title | Investigation of an 18F-labelled Imidazopyridotriazine for Molecular Imaging of Cyclic Nucleotide Phosphodiesterase 2A |
| title_full | Investigation of an 18F-labelled Imidazopyridotriazine for Molecular Imaging of Cyclic Nucleotide Phosphodiesterase 2A |
| title_fullStr | Investigation of an 18F-labelled Imidazopyridotriazine for Molecular Imaging of Cyclic Nucleotide Phosphodiesterase 2A |
| title_full_unstemmed | Investigation of an 18F-labelled Imidazopyridotriazine for Molecular Imaging of Cyclic Nucleotide Phosphodiesterase 2A |
| title_short | Investigation of an 18F-labelled Imidazopyridotriazine for Molecular Imaging of Cyclic Nucleotide Phosphodiesterase 2A |
| title_sort | investigation of an 18f labelled imidazopyridotriazine for molecular imaging of cyclic nucleotide phosphodiesterase 2a |
| topic | Phosphodiesterase 2A (PDE2A) secondary messengers PDE2A radioligands positron emission tomography (PET) neuroimaging metabolic stability micellar liquid chromatography (MLC) |
| url | http://www.mdpi.com/1420-3049/23/3/556 |
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