title: Optimized Near-IR Fluorescent Agents for in Vivo Imaging of Btk Expression.
abstract: Bruton's tyrosine kinase (Btk) is intricately involved in anti-apoptotic signaling pathways in cancer and in regulating innate immune response. A number of Btk inhibitors are in development for use in treating B-cell malignancies and certain immunologic diseases. To develop robust companion imaging diagnostics for in vivo use, we set out to explore the effects of red wavelength fluorochrome modifications of two highly potent irreversible Btk inhibitors, Ibrutinib and AVL-292. Surprisingly, we found that subtle chemical differences in the fluorochrome had considerable effects on target localization. Based on iterative designs, we developed a single optimized version with superb in vivo imaging characteristics enabling single cell Btk imaging in vivo. This agent (Ibrutinib-SiR-COOH) is expected to be a valuable chemical tool in deciphering Btk biology in cancer and host cells in vivo.
authors.affiliation: †Center for Systems Biology, Massachusetts General Hospital, 185 Cambridge Street, CPZN 5206, Boston, Massachusetts 02114, United States.
authors.forename: Eunha
authors.initials: E
authors.lastname: Kim
authors.affiliation: †Center for Systems Biology, Massachusetts General Hospital, 185 Cambridge Street, CPZN 5206, Boston, Massachusetts 02114, United States.
authors.forename: Katherine S
authors.initials: KS
authors.lastname: Yang
authors.affiliation: †Center for Systems Biology, Massachusetts General Hospital, 185 Cambridge Street, CPZN 5206, Boston, Massachusetts 02114, United States.
authors.forename: Rainer H
authors.initials: RH
authors.lastname: Kohler
authors.affiliation: †Center for Systems Biology, Massachusetts General Hospital, 185 Cambridge Street, CPZN 5206, Boston, Massachusetts 02114, United States.
authors.forename: John M
authors.initials: JM
authors.lastname: Dubach
authors.affiliation: †Center for Systems Biology, Massachusetts General Hospital, 185 Cambridge Street, CPZN 5206, Boston, Massachusetts 02114, United States.
authors.forename: Hannes
authors.initials: H
authors.lastname: Mikula
authors.affiliation: †Center for Systems Biology, Massachusetts General Hospital, 185 Cambridge Street, CPZN 5206, Boston, Massachusetts 02114, United States.|‡Department of Systems Biology, Harvard Medical School, 200 Longwood Avenue, Boston, Massachusetts 02115, United States.
authors.forename: Ralph
authors.initials: R
authors.lastname: Weissleder
mesh_terms: D000077329:Agammaglobulinaemia Tyrosine Kinase; D017209:Apoptosis / Q000187:drug effects; D001402:B-Lymphocytes / Q000166:cytology* / Q000187:drug effects / Q000201:enzymology; D005354:Fibrosarcoma / Q000188:drug therapy / Q000201:enzymology / Q000473:pathology*; D005456:Fluorescent Dyes / Q000737:chemistry*; D006801:Humans; D057054:Molecular Imaging; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors*; D015398:Signal Transduction / Q000187:drug effects; D019265:Spectroscopy, Near-Infrared / Q000379:methods*; D013601:T-Lymphocytes / Q000166:cytology* / Q000187:drug effects / Q000201:enzymology
chemical_list: D005456:Fluorescent Dyes; D047428:Protein Kinase Inhibitors; D011505:Protein-Tyrosine Kinases; D000077329:Agammaglobulinaemia Tyrosine Kinase; C000625949:BTK protein, human