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Design, Synthesis, and Evaluation of Thienodiazepine Derivatives as Positron Emission Tomography Imaging Probes for Bromodomain and Extra-Terminal Domain Family Proteins.
Bai, Ping; Lan, Yu; Patnaik, Debasis; Wang, Hao; Liu, Yan; Chen, Zude; Yuan, Gengyang; Afshar, Sepideh; Striar, Robin; Zagaroli, Julia S; Tocci, Darcy R; Langan, Amelia G; Haggarty, Stephen J; Wang, Changning.
Affiliation
  • Bai P; Athinoula A. Martinos Center for Biomedical Imaging, Department of Radiology, Massachusetts General Hospital, Harvard Medical School, Charlestown, Massachusetts 02129, United States.
  • Lan Y; Athinoula A. Martinos Center for Biomedical Imaging, Department of Radiology, Massachusetts General Hospital, Harvard Medical School, Charlestown, Massachusetts 02129, United States.
  • Patnaik D; Chemical Neurobiology Laboratory, Center for Genomic Medicine, Department of Neurology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts 02114, United States.
  • Wang H; Athinoula A. Martinos Center for Biomedical Imaging, Department of Radiology, Massachusetts General Hospital, Harvard Medical School, Charlestown, Massachusetts 02129, United States.
  • Liu Y; Athinoula A. Martinos Center for Biomedical Imaging, Department of Radiology, Massachusetts General Hospital, Harvard Medical School, Charlestown, Massachusetts 02129, United States.
  • Chen Z; Athinoula A. Martinos Center for Biomedical Imaging, Department of Radiology, Massachusetts General Hospital, Harvard Medical School, Charlestown, Massachusetts 02129, United States.
  • Yuan G; Gordon Center for Medical Imaging, Massachusetts General Hospital, Harvard Medical School, Charlestown, Massachusetts 02129, United States.
  • Afshar S; Gordon Center for Medical Imaging, Massachusetts General Hospital, Harvard Medical School, Charlestown, Massachusetts 02129, United States.
  • Striar R; Athinoula A. Martinos Center for Biomedical Imaging, Department of Radiology, Massachusetts General Hospital, Harvard Medical School, Charlestown, Massachusetts 02129, United States.
  • Zagaroli JS; Athinoula A. Martinos Center for Biomedical Imaging, Department of Radiology, Massachusetts General Hospital, Harvard Medical School, Charlestown, Massachusetts 02129, United States.
  • Tocci DR; Athinoula A. Martinos Center for Biomedical Imaging, Department of Radiology, Massachusetts General Hospital, Harvard Medical School, Charlestown, Massachusetts 02129, United States.
  • Langan AG; Athinoula A. Martinos Center for Biomedical Imaging, Department of Radiology, Massachusetts General Hospital, Harvard Medical School, Charlestown, Massachusetts 02129, United States.
  • Haggarty SJ; Chemical Neurobiology Laboratory, Center for Genomic Medicine, Department of Neurology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts 02114, United States.
  • Wang C; Athinoula A. Martinos Center for Biomedical Imaging, Department of Radiology, Massachusetts General Hospital, Harvard Medical School, Charlestown, Massachusetts 02129, United States.
J Med Chem ; 64(19): 14745-14756, 2021 10 14.
Article in En | MEDLINE | ID: mdl-34549949
ABSTRACT
To better understand the role of bromodomain and extra-terminal domain (BET) proteins in epigenetic mechanisms, we developed a series of thienodiazepine-based derivatives and identified two compounds, 3a and 6a, as potent BET inhibitors. Further in vivo pharmacokinetic studies and analysis of in vitro metabolic stability of 6a revealed excellent brain penetration and reasonable metabolic stability. Compounds 3a and 6a were radiolabeled with fluorine-18 in two steps and utilized in positron emission tomography (PET) imaging studies in mice. Preliminary PET imaging results demonstrated that [18F]3a and [18F]6a have good brain uptake (with maximum SUV = 1.7 and 2, respectively) and binding specificity in mice brains. These results show that [18F]6a is a potential PET radiotracer that could be applied to imaging BET proteins in the brain. Further optimization and improvement of the metabolic stability of [18F]6a are still needed in order to create optimal PET imaging probes of BET family members.
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Full text: 1 Collection: 01-internacional Database: MEDLINE Main subject: Azepines / Drug Design / Molecular Probes / Positron-Emission Tomography / Protein Domains Type of study: Prognostic_studies Limits: Animals Language: En Journal: J Med Chem Journal subject: QUIMICA Year: 2021 Type: Article Affiliation country: United States
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Full text: 1 Collection: 01-internacional Database: MEDLINE Main subject: Azepines / Drug Design / Molecular Probes / Positron-Emission Tomography / Protein Domains Type of study: Prognostic_studies Limits: Animals Language: En Journal: J Med Chem Journal subject: QUIMICA Year: 2021 Type: Article Affiliation country: United States