title: Synthesis, in vitro, and in vivo characterization of an integrin alpha(v)beta(3)-targeted molecular probe for optical imaging of tumor.
abstract: Integrin alpha(v)beta(3) is a widely-recognized target for the development of targeted molecular probes for imaging pathological conditions. alpha(v)beta(3) is a cell-surface receptor protein that is upregulated in various pathological conditions including osteoporosis, rheumatoid arthritis, macular degeneration, and cancer. The synthesis of an alpha(v)beta(3)-targeted optical probe 7 from compound 1, and its in vitro and in vivo characterization is described. A series of aliphatic carbamate derivatives of the potent non-peptide integrin antagonist 1 was synthesized and the binding affinity to alpha(v)beta(3) was determined in both enzyme linked immunosorbent assay (ELISA) and cell adhesion inhibition assays. The hydrophobic carbamate-linked appendages improved the binding affinity of the parent compound for alpha(v)beta(3) by 2-20 times. A Boc-protected neopentyl derivative in the series is shown to have the best binding affinity to alpha(v)beta(3) (IC(50)=0.72 nM) when compared to compound 1 as well as to c-RGDfV. Optical probe 7 utilizes the neopentyl linker and demonstrates increased binding affinity and significant tumor cell uptake in vitro as well as specific tumor accumulation and retention in vivo. These results illustrate the potential of employing integrin-targeted molecular probes based on 1 to image a multitude of diseases associated with alpha(v)beta(3) overexpression.
authors.affiliation: Molecular Imaging Laboratory, Clinical Center, National Institutes of Allergies and Infectious Diseases, National Institutes of Health, 10 Center Drive, Bethesda, MD 20892, USA.
authors.forename: Christopher A
authors.initials: CA
authors.lastname: Burnett
authors.forename: Jianwu
authors.initials: J
authors.lastname: Xie
authors.forename: Jade
authors.initials: J
authors.lastname: Quijano
authors.forename: Zhimin
authors.initials: Z
authors.lastname: Shen
authors.forename: Finie
authors.initials: F
authors.lastname: Hunter
authors.forename: Monica
authors.initials: M
authors.lastname: Bur
authors.forename: King C P
authors.initials: KC
authors.lastname: Li
authors.forename: S Narasimhan
authors.initials: SN
authors.lastname: Danthi
mesh_terms: D000818:Animals; D002448:Cell Adhesion; D004797:Enzyme-Linked Immunosorbent Assay; D006801:Humans; D039302:Integrin alphaVbeta3 / Q000737:chemistry*; D009682:Magnetic Resonance Spectroscopy; D013058:Mass Spectrometry; D008856:Microscopy, Fluorescence; D015335:Molecular Probes; D009368:Neoplasm Transplantation; D009369:Neoplasms / Q000473:pathology*; D013055:Spectrophotometry, Infrared; D014407:Tumor Cells, Cultured
chemical_list: D039302:Integrin alphaVbeta3; D015335:Molecular Probes