Fluorescent non-peptidic RGD mimetics with high selectivity for αVβ3 vs αIIbβ3 integrin receptor: novel probes for in vivo optical imaging.

Integrins are heterodimeric transmembrane protein receptors consisting of different α and β subunits. α(v)β(3) integrins are overexpressed on many tumor cells and tumor-associated angiogenic vessels, whereas α(IIb)β(3) is a receptor for, e.g., fibrinogen and mediates platelet aggregation. In this study, a near-infrared fluorescent imaging probe has been designed and synthesized by conjugating fluorescent dyes to a non-peptidic, pharmacophore-based ligand, based on a molecular modeling design approach. Affinity values were determined, and in vitro cell binding assays and preliminary in vivo xenograft studies in nude mice were performed to evaluate target binding. Competition assays revealed excellent binding and selectivity to α(v)β(3) compared to that for α(IIb)β(3). In vitro, the probe showed high target binding on α(v)β(3)-positive M-21 cells and negligible binding to α(v)β(3)-negative MCF-7 cells. In vivo, the tracer is able to image target expression in U-87 xenografts with a maximum signal-to-noise ratio (SNR) of 2.5:1 at 24 h after injection.