2. Academic Validation
  3. Radiosynthesis and in vivo evaluation of a new positron emission tomography radiotracer targeting bromodomain and extra-terminal domain (BET) family proteins

Radiosynthesis and in vivo evaluation of a new positron emission tomography radiotracer targeting bromodomain and extra-terminal domain (BET) family proteins

  • Nucl Med Biol. 2020 May-Jun;84-85:96-101. doi: 10.1016/j.nucmedbio.2020.04.003.
Ping Bai 1,  Xiaoxia Lu 2,  Yu Lan 3,  Zude Chen 3,  Debasis Patnaik 4,  Stephanie Fiedler 3,  Robin Striar 3,  Stephen J Haggarty 4,  Changning Wang 5
Affiliations

Affiliations

  • 1 Chengdu Institute of Biology, Chinese Academy of Sciences, Chengdu 610041, PR China; Athinoula A. Martinos Center for Biomedical Imaging, Department of Radiology, Massachusetts General Hospital, Harvard Medical School, Charlestown, MA 02129, USA; University of Chinese Academy of Sciences, Beijing 100049, PR China.
  • 2 Chengdu Institute of Biology, Chinese Academy of Sciences, Chengdu 610041, PR China.
  • 3 Athinoula A. Martinos Center for Biomedical Imaging, Department of Radiology, Massachusetts General Hospital, Harvard Medical School, Charlestown, MA 02129, USA.
  • 4 Chemical Neurobiology Laboratory, Center for Genomic Medicine, Department of Neurology, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA.
  • 5 Athinoula A. Martinos Center for Biomedical Imaging, Department of Radiology, Massachusetts General Hospital, Harvard Medical School, Charlestown, MA 02129, USA. Electronic address: cwang15@mgh.harvard.edu.
PMID: 32320910 DOI: 10.1016/j.nucmedbio.2020.04.003
Abstract

Introduction: Bromodomain and extra-terminal domain (BET) family proteins play a vital role in the epigenetic regulation process by interacting with acetylated lysine (Ac-K) residues in histones. BET inhibitors have become promising candidates to treat various diseases through the inhibition of the interaction between BET bromodomains and Ac-K of histone tails. With a molecular imaging probe, noninvasive imaging such as positron emission tomography (PET) can visualize the distribution and roles of BET family proteins in vivo and enlighten our understanding of BET protein function in both healthy and diseased tissue.

Methods: We radiolabeled the potent BET inhibitor INCB054329 by N-methylation to make [11C]PB003 as a BET PET radiotracer. The bioactivity evaluation of unlabeled PB003 in vitro was performed to confirm its binding affinity for BRDs, then the PET/CT imaging in rodents was performed to evaluate the bioactivity of [11C]PB003 in vivo.

Results: In our in vitro evaluation, PB003 showed a high BET binding affinity for BRDs (Kd = 2 nM, 1.2 nM, and 1.2 nM for BRD2, BRD3, and BRD4, respectively). In vivo PET/CT imaging demonstrated that [11C]PB003 has favorable uptake with appropriate kinetics and distributions in main peripheral organs. Besides, the blockade of [11C]PB003 binding was found in our blocking study which indicated the specificity of [11C]PB003. However, the BBB penetration and brain uptake of [11C]PB003 was limited, with only a maximum 0.2% injected dose/g at ~2 min post-injection.

Conclusion: The imaging results in rodents in vivo demonstrate that [11C]PB003 binds to BET with high selectivity and specificity and has favorable uptake in peripheral organs. However, the low brain uptake of [11C]PB003 limits the visualization of brain regions indicating the efforts are still needed to discover the new BET imaging probes for brain visualization.

Keywords

Bromodomain; Epigenetic; Imaging; PET; Radiotracer.

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