A Promising PET Tracer for Imaging of α7 Nicotinic Acetylcholine Receptors in the Brain: Design, Synthesis, and in Vivo Evaluation of a Dibenzothiophene-Based Radioligand
Changes in the expression of α7 nicotinic acetylcholine receptors (α7 nAChRs) in the human brain are widely assumed to be associated with neurological and neurooncological processes. Investigation of these receptors in vivo depends on the availability of imaging agents such as radioactively labelled...
| Main Authors: | , , , , , , , , , , , , , , , |
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MDPI AG
2015-10-01
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| Series: | Molecules |
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| Online Access: | http://www.mdpi.com/1420-3049/20/10/18387 |
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| author | Rodrigo Teodoro Matthias Scheunemann Winnie Deuther-Conrad Barbara Wenzel Francesca Maria Fasoli Cecilia Gotti Mathias Kranz Cornelius K. Donat Marianne Patt Ansel Hillmer Ming-Qiang Zheng Dan Peters Jörg Steinbach Osama Sabri Yiyun Huang Peter Brust |
| author_facet | Rodrigo Teodoro Matthias Scheunemann Winnie Deuther-Conrad Barbara Wenzel Francesca Maria Fasoli Cecilia Gotti Mathias Kranz Cornelius K. Donat Marianne Patt Ansel Hillmer Ming-Qiang Zheng Dan Peters Jörg Steinbach Osama Sabri Yiyun Huang Peter Brust |
| author_sort | Rodrigo Teodoro |
| collection | DOAJ |
| description | Changes in the expression of α7 nicotinic acetylcholine receptors (α7 nAChRs) in the human brain are widely assumed to be associated with neurological and neurooncological processes. Investigation of these receptors in vivo depends on the availability of imaging agents such as radioactively labelled ligands applicable in positron emission tomography (PET). We report on a series of new ligands for α7 nAChRs designed by the combination of dibenzothiophene dioxide as a novel hydrogen bond acceptor functionality with diazabicyclononane as an established cationic center. To assess the structure-activity relationship (SAR) of this new basic structure, we further modified the cationic center systematically by introduction of three different piperazine-based scaffolds. Based on in vitro binding affinity and selectivity, assessed by radioligand displacement studies at different rat and human nAChR subtypes and at the structurally related human 5-HT3 receptor, we selected the compound 7-(1,4-diazabicyclo[3.2.2]nonan-4-yl)-2-fluorodibenzo-[b,d]thiophene 5,5-dioxide (10a) for radiolabeling and further evaluation in vivo. Radiosynthesis of [18F]10a was optimized and transferred to an automated module. Dynamic PET imaging studies with [18F]10a in piglets and a monkey demonstrated high uptake of radioactivity in the brain, followed by washout and target-region specific accumulation under baseline conditions. Kinetic analysis of [18F]10a in pig was performed using a two-tissue compartment model with arterial-derived input function. Our initial evaluation revealed that the dibenzothiophene-based PET radioligand [18F]10a ([18F]DBT-10) has high potential to provide clinically relevant information about the expression and availability of α7 nAChR in the brain. |
| first_indexed | 2024-12-14T22:27:34Z |
| format | Article |
| id | doaj.art-f95193d25fe04787b30478887fbd5172 |
| institution | Directory Open Access Journal |
| issn | 1420-3049 |
| language | English |
| last_indexed | 2024-12-14T22:27:34Z |
| publishDate | 2015-10-01 |
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| series | Molecules |
| spelling | doaj.art-f95193d25fe04787b30478887fbd51722022-12-21T22:45:20ZengMDPI AGMolecules1420-30492015-10-012010183871842110.3390/molecules201018387molecules201018387A Promising PET Tracer for Imaging of α7 Nicotinic Acetylcholine Receptors in the Brain: Design, Synthesis, and in Vivo Evaluation of a Dibenzothiophene-Based RadioligandRodrigo Teodoro0Matthias Scheunemann1Winnie Deuther-Conrad2Barbara Wenzel3Francesca Maria Fasoli4Cecilia Gotti5Mathias Kranz6Cornelius K. Donat7Marianne Patt8Ansel Hillmer9Ming-Qiang Zheng10Dan Peters11Jörg Steinbach12Osama Sabri13Yiyun Huang14Peter Brust15Helmholtz-Zentrum Dresden-Rossendorf, Institute of Radiopharmaceutical Cancer Research, Permoserstraße 15, Leipzig 04318, GermanyHelmholtz-Zentrum Dresden-Rossendorf, Institute of Radiopharmaceutical Cancer Research, Permoserstraße 15, Leipzig 04318, GermanyHelmholtz-Zentrum Dresden-Rossendorf, Institute of Radiopharmaceutical Cancer Research, Permoserstraße 15, Leipzig 04318, GermanyHelmholtz-Zentrum Dresden-Rossendorf, Institute of Radiopharmaceutical Cancer Research, Permoserstraße 15, Leipzig 04318, GermanyConsiglio Nazionale delle Ricerche, Institute of Neuroscience, Biometra-Institute University of Milan, Via Luigi Vanvitelli 32, Milano 20129, ItalyConsiglio Nazionale delle Ricerche, Institute of Neuroscience, Biometra-Institute University of Milan, Via Luigi Vanvitelli 32, Milano 20129, ItalyHelmholtz-Zentrum Dresden-Rossendorf, Institute of Radiopharmaceutical Cancer Research, Permoserstraße 15, Leipzig 04318, GermanyHelmholtz-Zentrum Dresden-Rossendorf, Institute of Radiopharmaceutical Cancer Research, Permoserstraße 15, Leipzig 04318, GermanyDepartment of Nuclear Medicine, University Hospital Leipzig, Liebigstraße 18, Leipzig 04103, GermanyPET Center, Yale University, P.O. Box 208048, 801 Howard Avenue, New Haven, CT 06520-8048, USAPET Center, Yale University, P.O. Box 208048, 801 Howard Avenue, New Haven, CT 06520-8048, USADan PET AB, Rosenstigen 7, Malmö SE-21619, SwedenHelmholtz-Zentrum Dresden-Rossendorf, Institute of Radiopharmaceutical Cancer Research, Permoserstraße 15, Leipzig 04318, GermanyDepartment of Nuclear Medicine, University Hospital Leipzig, Liebigstraße 18, Leipzig 04103, GermanyPET Center, Yale University, P.O. Box 208048, 801 Howard Avenue, New Haven, CT 06520-8048, USAHelmholtz-Zentrum Dresden-Rossendorf, Institute of Radiopharmaceutical Cancer Research, Permoserstraße 15, Leipzig 04318, GermanyChanges in the expression of α7 nicotinic acetylcholine receptors (α7 nAChRs) in the human brain are widely assumed to be associated with neurological and neurooncological processes. Investigation of these receptors in vivo depends on the availability of imaging agents such as radioactively labelled ligands applicable in positron emission tomography (PET). We report on a series of new ligands for α7 nAChRs designed by the combination of dibenzothiophene dioxide as a novel hydrogen bond acceptor functionality with diazabicyclononane as an established cationic center. To assess the structure-activity relationship (SAR) of this new basic structure, we further modified the cationic center systematically by introduction of three different piperazine-based scaffolds. Based on in vitro binding affinity and selectivity, assessed by radioligand displacement studies at different rat and human nAChR subtypes and at the structurally related human 5-HT3 receptor, we selected the compound 7-(1,4-diazabicyclo[3.2.2]nonan-4-yl)-2-fluorodibenzo-[b,d]thiophene 5,5-dioxide (10a) for radiolabeling and further evaluation in vivo. Radiosynthesis of [18F]10a was optimized and transferred to an automated module. Dynamic PET imaging studies with [18F]10a in piglets and a monkey demonstrated high uptake of radioactivity in the brain, followed by washout and target-region specific accumulation under baseline conditions. Kinetic analysis of [18F]10a in pig was performed using a two-tissue compartment model with arterial-derived input function. Our initial evaluation revealed that the dibenzothiophene-based PET radioligand [18F]10a ([18F]DBT-10) has high potential to provide clinically relevant information about the expression and availability of α7 nAChR in the brain.http://www.mdpi.com/1420-3049/20/10/18387α7 nAChRpharmacophorepositron emission tomographyneuroimagingfluorine-18 |
| spellingShingle | Rodrigo Teodoro Matthias Scheunemann Winnie Deuther-Conrad Barbara Wenzel Francesca Maria Fasoli Cecilia Gotti Mathias Kranz Cornelius K. Donat Marianne Patt Ansel Hillmer Ming-Qiang Zheng Dan Peters Jörg Steinbach Osama Sabri Yiyun Huang Peter Brust A Promising PET Tracer for Imaging of α7 Nicotinic Acetylcholine Receptors in the Brain: Design, Synthesis, and in Vivo Evaluation of a Dibenzothiophene-Based Radioligand Molecules α7 nAChR pharmacophore positron emission tomography neuroimaging fluorine-18 |
| title | A Promising PET Tracer for Imaging of α7 Nicotinic Acetylcholine Receptors in the Brain: Design, Synthesis, and in Vivo Evaluation of a Dibenzothiophene-Based Radioligand |
| title_full | A Promising PET Tracer for Imaging of α7 Nicotinic Acetylcholine Receptors in the Brain: Design, Synthesis, and in Vivo Evaluation of a Dibenzothiophene-Based Radioligand |
| title_fullStr | A Promising PET Tracer for Imaging of α7 Nicotinic Acetylcholine Receptors in the Brain: Design, Synthesis, and in Vivo Evaluation of a Dibenzothiophene-Based Radioligand |
| title_full_unstemmed | A Promising PET Tracer for Imaging of α7 Nicotinic Acetylcholine Receptors in the Brain: Design, Synthesis, and in Vivo Evaluation of a Dibenzothiophene-Based Radioligand |
| title_short | A Promising PET Tracer for Imaging of α7 Nicotinic Acetylcholine Receptors in the Brain: Design, Synthesis, and in Vivo Evaluation of a Dibenzothiophene-Based Radioligand |
| title_sort | promising pet tracer for imaging of α7 nicotinic acetylcholine receptors in the brain design synthesis and in vivo evaluation of a dibenzothiophene based radioligand |
| topic | α7 nAChR pharmacophore positron emission tomography neuroimaging fluorine-18 |
| url | http://www.mdpi.com/1420-3049/20/10/18387 |
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