Fluorescent Non-peptidic RGD Mimetics with High Selectivity for αVβ3 vs αIIbβ3 Integrin Receptor: Novel Probes for in Vivo Optical Imaging
| Autor: | Günter Haufe, Michael Schäfers, Anke Hahnenkamp, Burkhard Riemann, Michel Eisenblätter, Christoph Bremer, Carsten Höltke, Wael Alsibai |
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| Rok vydání: | 2014 |
| Předmět: |
Diagnostic Imaging
Integrin Mice Nude Platelet Glycoprotein GPIIb-IIIa Complex Ligands In vivo Cell Line Tumor Drug Discovery Animals Receptor Fluorescent Dyes Integrin alphaVbeta3 biology Chemistry Molecular biology In vitro Cell culture biology.protein Heterografts Molecular Medicine Female Pharmacophore Glioblastoma Neoplasm Transplantation |
| Zdroj: | Journal of Medicinal Chemistry. 57:9971-9982 |
| ISSN: | 1520-4804 0022-2623 |
| DOI: | 10.1021/jm501197c |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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