Development of a PET Probe Targeting Bromodomain and Extra-Terminal Proteins for In Vitro and In Vivo Visualization
<b>Background:</b> Bromodomain and extra-terminal (BET) proteins are critical regulators of gene transcription, as they recognize acetylated lysine residues. The BD1 bromodomain of BRD4, a member of the BET family, has emerged as a promising therapeutic target for various diseases. This...
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2024-12-01
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| author | Yongle Wang Yanli Wang Yulong Xu Hua Cheng Tewodros Mulugeta Dagnew Leyi Kang Darcy Tocci Iris Z. Shen Can Zhang Changning Wang |
| author_facet | Yongle Wang Yanli Wang Yulong Xu Hua Cheng Tewodros Mulugeta Dagnew Leyi Kang Darcy Tocci Iris Z. Shen Can Zhang Changning Wang |
| author_sort | Yongle Wang |
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| description | <b>Background:</b> Bromodomain and extra-terminal (BET) proteins are critical regulators of gene transcription, as they recognize acetylated lysine residues. The BD1 bromodomain of BRD4, a member of the BET family, has emerged as a promising therapeutic target for various diseases. This study aimed to develop and evaluate a novel C-11 labeled PET radiotracer, [<sup>11</sup>C]YL10, for imaging the BD1 bromodomain of BRD4 in vivo. <b>Methods:</b> [<sup>11</sup>C]YL10 was synthesized and evaluated for its ability to bind to the BD1 bromodomain selectively. PET imaging studies were conducted in mice to assess brain penetration, pharmacokinetics, and selectivity. In vitro autoradiography and blocking experiments were performed to confirm the tracer’s specificity for the BD1 domain. <b>Results:</b> [<sup>11</sup>C]YL10 demonstrated good brain penetration, high selectivity for the BD1 bromodomain, and favorable pharmacokinetics in initial PET imaging studies. In vitro autoradiography and blocking experiments confirmed the specific binding of [<sup>11</sup>C]YL10 to the BD1 domain of BRD4, further validating its potential as a targeted radiotracer. <b>Conclusions:</b> The development of [<sup>11</sup>C]YL10 provides a new tool for studying BRD4 bromodomains using PET imaging technology. This radiotracer offers potential advancement in the diagnosis and research of neurodegenerative diseases and related disorders involving BRD4 dysregulation. |
| format | Article |
| id | doaj-art-2f59b35c44a0494796c8a17842adb71b |
| institution | Kabale University |
| issn | 1424-8247 |
| language | English |
| publishDate | 2024-12-01 |
| publisher | MDPI AG |
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| series | Pharmaceuticals |
| spelling | doaj-art-2f59b35c44a0494796c8a17842adb71b2024-12-27T14:46:02ZengMDPI AGPharmaceuticals1424-82472024-12-011712167010.3390/ph17121670Development of a PET Probe Targeting Bromodomain and Extra-Terminal Proteins for In Vitro and In Vivo VisualizationYongle Wang0Yanli Wang1Yulong Xu2Hua Cheng3Tewodros Mulugeta Dagnew4Leyi Kang5Darcy Tocci6Iris Z. Shen7Can Zhang8Changning Wang9School of Pharmacy, Minzu University of China, Beijing 100081, ChinaAthinoula A. Martinos Center for Biomedical Imaging, Department of Radiology Massachusetts General Hospital, Harvard Medical School, Charlestown, MA 02129, USAAthinoula A. Martinos Center for Biomedical Imaging, Department of Radiology Massachusetts General Hospital, Harvard Medical School, Charlestown, MA 02129, USAAthinoula A. Martinos Center for Biomedical Imaging, Department of Radiology Massachusetts General Hospital, Harvard Medical School, Charlestown, MA 02129, USAAthinoula A. Martinos Center for Biomedical Imaging, Department of Radiology Massachusetts General Hospital, Harvard Medical School, Charlestown, MA 02129, USAAthinoula A. Martinos Center for Biomedical Imaging, Department of Radiology Massachusetts General Hospital, Harvard Medical School, Charlestown, MA 02129, USAAthinoula A. Martinos Center for Biomedical Imaging, Department of Radiology Massachusetts General Hospital, Harvard Medical School, Charlestown, MA 02129, USAAthinoula A. Martinos Center for Biomedical Imaging, Department of Radiology Massachusetts General Hospital, Harvard Medical School, Charlestown, MA 02129, USAGenetics and Aging Research Unit, Department of Neurology, McCance Center for Brain Health, Massachusetts General Institute for Neurodegenerative Disease, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02129, USAAthinoula A. Martinos Center for Biomedical Imaging, Department of Radiology Massachusetts General Hospital, Harvard Medical School, Charlestown, MA 02129, USA<b>Background:</b> Bromodomain and extra-terminal (BET) proteins are critical regulators of gene transcription, as they recognize acetylated lysine residues. The BD1 bromodomain of BRD4, a member of the BET family, has emerged as a promising therapeutic target for various diseases. This study aimed to develop and evaluate a novel C-11 labeled PET radiotracer, [<sup>11</sup>C]YL10, for imaging the BD1 bromodomain of BRD4 in vivo. <b>Methods:</b> [<sup>11</sup>C]YL10 was synthesized and evaluated for its ability to bind to the BD1 bromodomain selectively. PET imaging studies were conducted in mice to assess brain penetration, pharmacokinetics, and selectivity. In vitro autoradiography and blocking experiments were performed to confirm the tracer’s specificity for the BD1 domain. <b>Results:</b> [<sup>11</sup>C]YL10 demonstrated good brain penetration, high selectivity for the BD1 bromodomain, and favorable pharmacokinetics in initial PET imaging studies. In vitro autoradiography and blocking experiments confirmed the specific binding of [<sup>11</sup>C]YL10 to the BD1 domain of BRD4, further validating its potential as a targeted radiotracer. <b>Conclusions:</b> The development of [<sup>11</sup>C]YL10 provides a new tool for studying BRD4 bromodomains using PET imaging technology. This radiotracer offers potential advancement in the diagnosis and research of neurodegenerative diseases and related disorders involving BRD4 dysregulation.https://www.mdpi.com/1424-8247/17/12/1670bromodomainsBRD4 BD1positron emission tomographyradiotracersimaging |
| spellingShingle | Yongle Wang Yanli Wang Yulong Xu Hua Cheng Tewodros Mulugeta Dagnew Leyi Kang Darcy Tocci Iris Z. Shen Can Zhang Changning Wang Development of a PET Probe Targeting Bromodomain and Extra-Terminal Proteins for In Vitro and In Vivo Visualization Pharmaceuticals bromodomains BRD4 BD1 positron emission tomography radiotracers imaging |
| title | Development of a PET Probe Targeting Bromodomain and Extra-Terminal Proteins for In Vitro and In Vivo Visualization |
| title_full | Development of a PET Probe Targeting Bromodomain and Extra-Terminal Proteins for In Vitro and In Vivo Visualization |
| title_fullStr | Development of a PET Probe Targeting Bromodomain and Extra-Terminal Proteins for In Vitro and In Vivo Visualization |
| title_full_unstemmed | Development of a PET Probe Targeting Bromodomain and Extra-Terminal Proteins for In Vitro and In Vivo Visualization |
| title_short | Development of a PET Probe Targeting Bromodomain and Extra-Terminal Proteins for In Vitro and In Vivo Visualization |
| title_sort | development of a pet probe targeting bromodomain and extra terminal proteins for in vitro and in vivo visualization |
| topic | bromodomains BRD4 BD1 positron emission tomography radiotracers imaging |
| url | https://www.mdpi.com/1424-8247/17/12/1670 |
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