Abstract
A number of Bruton's tyrosine kinase (BTK) inhibitors are currently in development, yet it has been difficult to visualize BTK expression and pharmacological inhibition in vivo in real time. We synthesized a fluorescent, irreversible BTK binder based on the drug Ibrutinib and characterized its behavior in cells and in vivo. We show a 200 nM affinity of the imaging agent, high selectivity, and irreversible binding to its target following initial washout, resulting in surprisingly high target-to-background ratios. In vivo, the imaging agent rapidly distributed to BTK expressing tumor cells, but also to BTK-positive tumor-associated host cells.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, U.S. Gov't, Non-P.H.S.
MeSH terms
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Adenine / analogs & derivatives
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Agammaglobulinaemia Tyrosine Kinase
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Animals
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Binding Sites
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Cell Line, Tumor
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Gene Expression
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Genes, Reporter
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Heterografts
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Humans
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Lymphoma / diagnosis
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Lymphoma / metabolism
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Mice
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Models, Molecular
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Molecular Conformation
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Molecular Imaging*
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Piperidines
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Protein Binding
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Protein Kinase Inhibitors / chemistry
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Protein Kinase Inhibitors / metabolism*
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Protein Kinase Inhibitors / pharmacology
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Protein-Tyrosine Kinases / antagonists & inhibitors
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Protein-Tyrosine Kinases / chemistry
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Protein-Tyrosine Kinases / metabolism*
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Pyrazoles / chemistry
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Pyrazoles / metabolism
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Pyrazoles / pharmacology
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Pyrimidines / chemistry
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Pyrimidines / metabolism
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Pyrimidines / pharmacology
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Single-Cell Analysis*
Substances
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Piperidines
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Protein Kinase Inhibitors
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Pyrazoles
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Pyrimidines
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ibrutinib
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Protein-Tyrosine Kinases
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Agammaglobulinaemia Tyrosine Kinase
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BTK protein, human
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Btk protein, mouse
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Adenine