Katharina Distler , Simone Maschauer , Eduard Neu , Harald Hübner , Jürgen Einsiedel , Olaf Prante , Peter Gmeiner
{"title":"在结构指导下发现与奥曲肽受体结合的 PET 配体。","authors":"Katharina Distler , Simone Maschauer , Eduard Neu , Harald Hübner , Jürgen Einsiedel , Olaf Prante , Peter Gmeiner","doi":"10.1016/j.bmc.2024.117823","DOIUrl":null,"url":null,"abstract":"<div><p>Molecular imaging using positron emission tomography (PET) can serve as a promising tool for visualizing biological targets in the brain. Insights into the expression pattern and the <em>in vivo</em> imaging of the G protein-coupled orexin receptors OX1R and OX2R will further our understanding of the orexin system and its role in various physiological and pathophysiological processes. Guided by crystal structures of our lead compound <strong>JH112</strong> and the approved hypnotic drug suvorexant bound to OX1R and OX2R, respectively, we herein describe the design and synthesis of two novel radioligands, <strong>[</strong><sup><strong>18</strong></sup><strong>F]KD23</strong> and <strong>[</strong><sup><strong>18</strong></sup><strong>F]KD10</strong>. Key to the success of our structural modifications was a bioisosteric replacement of the triazole moiety with a fluorophenyl group. The <sup>19</sup>F-substituted analog <strong>KD23</strong> showed high affinity for the OX1R and selectivity over OX2R, while the high affinity ligand <strong>KD10</strong> displayed similar K<sub>i</sub> values for both subtypes. Radiolabeling starting from the respective pinacol ester precursors resulted in excellent radiochemical yields of 93% and 88% for <strong>[</strong><sup><strong>18</strong></sup><strong>F]KD23</strong> and <strong>[</strong><sup><strong>18</strong></sup><strong>F]KD10</strong>, respectively, within 20 min. The new compounds will be useful in PET studies aimed at subtype-selective imaging of orexin receptors in brain tissue.</p></div>","PeriodicalId":255,"journal":{"name":"Bioorganic & Medicinal Chemistry","volume":null,"pages":null},"PeriodicalIF":3.3000,"publicationDate":"2024-06-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S0968089624002372/pdfft?md5=75ec1fd3067164f133332174cec97fa8&pid=1-s2.0-S0968089624002372-main.pdf","citationCount":"0","resultStr":"{\"title\":\"Structure-guided discovery of orexin receptor-binding PET ligands\",\"authors\":\"Katharina Distler , Simone Maschauer , Eduard Neu , Harald Hübner , Jürgen Einsiedel , Olaf Prante , Peter Gmeiner\",\"doi\":\"10.1016/j.bmc.2024.117823\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<div><p>Molecular imaging using positron emission tomography (PET) can serve as a promising tool for visualizing biological targets in the brain. Insights into the expression pattern and the <em>in vivo</em> imaging of the G protein-coupled orexin receptors OX1R and OX2R will further our understanding of the orexin system and its role in various physiological and pathophysiological processes. Guided by crystal structures of our lead compound <strong>JH112</strong> and the approved hypnotic drug suvorexant bound to OX1R and OX2R, respectively, we herein describe the design and synthesis of two novel radioligands, <strong>[</strong><sup><strong>18</strong></sup><strong>F]KD23</strong> and <strong>[</strong><sup><strong>18</strong></sup><strong>F]KD10</strong>. Key to the success of our structural modifications was a bioisosteric replacement of the triazole moiety with a fluorophenyl group. The <sup>19</sup>F-substituted analog <strong>KD23</strong> showed high affinity for the OX1R and selectivity over OX2R, while the high affinity ligand <strong>KD10</strong> displayed similar K<sub>i</sub> values for both subtypes. Radiolabeling starting from the respective pinacol ester precursors resulted in excellent radiochemical yields of 93% and 88% for <strong>[</strong><sup><strong>18</strong></sup><strong>F]KD23</strong> and <strong>[</strong><sup><strong>18</strong></sup><strong>F]KD10</strong>, respectively, within 20 min. The new compounds will be useful in PET studies aimed at subtype-selective imaging of orexin receptors in brain tissue.</p></div>\",\"PeriodicalId\":255,\"journal\":{\"name\":\"Bioorganic & Medicinal Chemistry\",\"volume\":null,\"pages\":null},\"PeriodicalIF\":3.3000,\"publicationDate\":\"2024-06-28\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"https://www.sciencedirect.com/science/article/pii/S0968089624002372/pdfft?md5=75ec1fd3067164f133332174cec97fa8&pid=1-s2.0-S0968089624002372-main.pdf\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Bioorganic & Medicinal Chemistry\",\"FirstCategoryId\":\"3\",\"ListUrlMain\":\"https://www.sciencedirect.com/science/article/pii/S0968089624002372\",\"RegionNum\":3,\"RegionCategory\":\"医学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q2\",\"JCRName\":\"BIOCHEMISTRY & MOLECULAR BIOLOGY\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Bioorganic & Medicinal Chemistry","FirstCategoryId":"3","ListUrlMain":"https://www.sciencedirect.com/science/article/pii/S0968089624002372","RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q2","JCRName":"BIOCHEMISTRY & MOLECULAR BIOLOGY","Score":null,"Total":0}
Structure-guided discovery of orexin receptor-binding PET ligands
Molecular imaging using positron emission tomography (PET) can serve as a promising tool for visualizing biological targets in the brain. Insights into the expression pattern and the in vivo imaging of the G protein-coupled orexin receptors OX1R and OX2R will further our understanding of the orexin system and its role in various physiological and pathophysiological processes. Guided by crystal structures of our lead compound JH112 and the approved hypnotic drug suvorexant bound to OX1R and OX2R, respectively, we herein describe the design and synthesis of two novel radioligands, [18F]KD23 and [18F]KD10. Key to the success of our structural modifications was a bioisosteric replacement of the triazole moiety with a fluorophenyl group. The 19F-substituted analog KD23 showed high affinity for the OX1R and selectivity over OX2R, while the high affinity ligand KD10 displayed similar Ki values for both subtypes. Radiolabeling starting from the respective pinacol ester precursors resulted in excellent radiochemical yields of 93% and 88% for [18F]KD23 and [18F]KD10, respectively, within 20 min. The new compounds will be useful in PET studies aimed at subtype-selective imaging of orexin receptors in brain tissue.
期刊介绍:
Bioorganic & Medicinal Chemistry provides an international forum for the publication of full original research papers and critical reviews on molecular interactions in key biological targets such as receptors, channels, enzymes, nucleotides, lipids and saccharides.
The aim of the journal is to promote a better understanding at the molecular level of life processes, and living organisms, as well as the interaction of these with chemical agents. A special feature will be that colour illustrations will be reproduced at no charge to the author, provided that the Editor agrees that colour is essential to the information content of the illustration in question.