Synthesis and in vitro evaluation of spirobenzovesamicols as potential 11C-PET tracer alternatives to [18F]FEOBV for vesicular acetylcholine transporter (VAChT) imaging
Abstract Background Through its central role in neurotransmission, the vesicular acetylcholine transporter (VAChT) is an increasingly valuable target for positron emission tomography (PET). VAChT ligands have been mostly derived from the vesamicol structure, but with limitations in available labelli...
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SpringerOpen
2025-02-01
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| Series: | EJNMMI Radiopharmacy and Chemistry |
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| Online Access: | https://doi.org/10.1186/s41181-025-00327-w |
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| author | Hugo Helbert Winnie Deuther-Conrad Michel de Haan Barbara Wenzel Gert Luurtsema Wiktor Szymanski Peter Brust Rudi A. J. O. Dierckx Ben L. Feringa Philip H. Elsinga |
| author_facet | Hugo Helbert Winnie Deuther-Conrad Michel de Haan Barbara Wenzel Gert Luurtsema Wiktor Szymanski Peter Brust Rudi A. J. O. Dierckx Ben L. Feringa Philip H. Elsinga |
| author_sort | Hugo Helbert |
| collection | DOAJ |
| description | Abstract Background Through its central role in neurotransmission, the vesicular acetylcholine transporter (VAChT) is an increasingly valuable target for positron emission tomography (PET). VAChT ligands have been mostly derived from the vesamicol structure, but with limitations in available labelling methods and selectivity for VAChT against σ receptors being a common pitfall of such compounds, the development of selective VAChT tracers remains a challenge. Modern labelling techniques, in this case the [11C]MeLi cross-coupling methodology, expands labelling opportunities, allowing to explore novel vesamicol-based structures as potential PET-tracers. Results A series of vesamicol derivatives was synthesized and their binding towards VAChT, σ1 and σ2 receptors assessed. Of all compound tested, (-)-2-methylspirobenzovesamicol ((-)-4) was the most promising with a 16 ± 4 nM affinity towards VAChT, a 29-fold weaker affinity for σ1 receptors and negligible binding (> 1 μM) towards σ2 receptors. The radiolabelling was performed from the corresponding bromide using a [11C]MeLi cross-coupling protocol, yielding 2-[11C]methylspirobenzovesamicol in 32–37% RCY. New in vitro binding data is also made available for (-)-FEOBV with human-sourced σ1 receptors, revealing a 300-fold stronger affinity for VAChT compared to σ receptors. Conclusion (-)-2-methylspirobenzovesamicol was identified as a potent and selective VAChT ligand, with moderate to low affinity for σ receptors, and its racemate was radiolabeled in good radiochemical yields with Carbon-11. At this stage, [11C]-methyl-2-methylspirobenzovesamicol appears a promising 11C-PET tracer for VAChT imaging. |
| format | Article |
| id | doaj-art-dba9bf3ba504410ba72af904cee79819 |
| institution | Kabale University |
| issn | 2365-421X |
| language | English |
| publishDate | 2025-02-01 |
| publisher | SpringerOpen |
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| series | EJNMMI Radiopharmacy and Chemistry |
| spelling | doaj-art-dba9bf3ba504410ba72af904cee798192025-02-09T13:00:39ZengSpringerOpenEJNMMI Radiopharmacy and Chemistry2365-421X2025-02-0110111310.1186/s41181-025-00327-wSynthesis and in vitro evaluation of spirobenzovesamicols as potential 11C-PET tracer alternatives to [18F]FEOBV for vesicular acetylcholine transporter (VAChT) imagingHugo Helbert0Winnie Deuther-Conrad1Michel de Haan2Barbara Wenzel3Gert Luurtsema4Wiktor Szymanski5Peter Brust6Rudi A. J. O. Dierckx7Ben L. Feringa8Philip H. Elsinga9Department of Nuclear Medicine and Molecular Imaging, University of Groningen, University Medical Center GroningenDepartment of Neuroradiopharmaceuticals, Institute of Radiopharmaceutical Cancer Research, Research Site Leipzig, Helmholtz-Zentrum Dresden-RossendorfDepartment of Nuclear Medicine and Molecular Imaging, University of Groningen, University Medical Center GroningenDepartment of Neuroradiopharmaceuticals, Institute of Radiopharmaceutical Cancer Research, Research Site Leipzig, Helmholtz-Zentrum Dresden-RossendorfDepartment of Nuclear Medicine and Molecular Imaging, University of Groningen, University Medical Center GroningenDepartment of Nuclear Medicine and Molecular Imaging, University of Groningen, University Medical Center GroningenDepartment of Neuroradiopharmaceuticals, Institute of Radiopharmaceutical Cancer Research, Research Site Leipzig, Helmholtz-Zentrum Dresden-RossendorfDepartment of Nuclear Medicine and Molecular Imaging, University of Groningen, University Medical Center GroningenStratingh Institute for Chemistry, University of GroningenDepartment of Nuclear Medicine and Molecular Imaging, University of Groningen, University Medical Center GroningenAbstract Background Through its central role in neurotransmission, the vesicular acetylcholine transporter (VAChT) is an increasingly valuable target for positron emission tomography (PET). VAChT ligands have been mostly derived from the vesamicol structure, but with limitations in available labelling methods and selectivity for VAChT against σ receptors being a common pitfall of such compounds, the development of selective VAChT tracers remains a challenge. Modern labelling techniques, in this case the [11C]MeLi cross-coupling methodology, expands labelling opportunities, allowing to explore novel vesamicol-based structures as potential PET-tracers. Results A series of vesamicol derivatives was synthesized and their binding towards VAChT, σ1 and σ2 receptors assessed. Of all compound tested, (-)-2-methylspirobenzovesamicol ((-)-4) was the most promising with a 16 ± 4 nM affinity towards VAChT, a 29-fold weaker affinity for σ1 receptors and negligible binding (> 1 μM) towards σ2 receptors. The radiolabelling was performed from the corresponding bromide using a [11C]MeLi cross-coupling protocol, yielding 2-[11C]methylspirobenzovesamicol in 32–37% RCY. New in vitro binding data is also made available for (-)-FEOBV with human-sourced σ1 receptors, revealing a 300-fold stronger affinity for VAChT compared to σ receptors. Conclusion (-)-2-methylspirobenzovesamicol was identified as a potent and selective VAChT ligand, with moderate to low affinity for σ receptors, and its racemate was radiolabeled in good radiochemical yields with Carbon-11. At this stage, [11C]-methyl-2-methylspirobenzovesamicol appears a promising 11C-PET tracer for VAChT imaging.https://doi.org/10.1186/s41181-025-00327-wVAChT11C-PET tracerSpirobenzovesamicol[18F]FEOBV[11C]MeLi |
| spellingShingle | Hugo Helbert Winnie Deuther-Conrad Michel de Haan Barbara Wenzel Gert Luurtsema Wiktor Szymanski Peter Brust Rudi A. J. O. Dierckx Ben L. Feringa Philip H. Elsinga Synthesis and in vitro evaluation of spirobenzovesamicols as potential 11C-PET tracer alternatives to [18F]FEOBV for vesicular acetylcholine transporter (VAChT) imaging EJNMMI Radiopharmacy and Chemistry VAChT 11C-PET tracer Spirobenzovesamicol [18F]FEOBV [11C]MeLi |
| title | Synthesis and in vitro evaluation of spirobenzovesamicols as potential 11C-PET tracer alternatives to [18F]FEOBV for vesicular acetylcholine transporter (VAChT) imaging |
| title_full | Synthesis and in vitro evaluation of spirobenzovesamicols as potential 11C-PET tracer alternatives to [18F]FEOBV for vesicular acetylcholine transporter (VAChT) imaging |
| title_fullStr | Synthesis and in vitro evaluation of spirobenzovesamicols as potential 11C-PET tracer alternatives to [18F]FEOBV for vesicular acetylcholine transporter (VAChT) imaging |
| title_full_unstemmed | Synthesis and in vitro evaluation of spirobenzovesamicols as potential 11C-PET tracer alternatives to [18F]FEOBV for vesicular acetylcholine transporter (VAChT) imaging |
| title_short | Synthesis and in vitro evaluation of spirobenzovesamicols as potential 11C-PET tracer alternatives to [18F]FEOBV for vesicular acetylcholine transporter (VAChT) imaging |
| title_sort | synthesis and in vitro evaluation of spirobenzovesamicols as potential 11c pet tracer alternatives to 18f feobv for vesicular acetylcholine transporter vacht imaging |
| topic | VAChT 11C-PET tracer Spirobenzovesamicol [18F]FEOBV [11C]MeLi |
| url | https://doi.org/10.1186/s41181-025-00327-w |
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