Synthesis, in vitro, and in vivo characterization of an integrin αvβ3-targeted molecular probe for optical imaging of tumor Original Research Article

Integrin αvβ3 is a widely-recognized target for the development of targeted molecular probes for imaging pathological conditions. αvβ3 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 αvβ3-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 αvβ3 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 αvβ3 by 2–20 times. A Boc-protected neopentyl derivative in the series is shown to have the best binding affinity to αvβ3 (IC50 = 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 αvβ3 overexpression.