Fluorescent Non-peptidic RGD Mimetics with High Selectivity for 伪V尾3 vs 伪IIb尾3 Integrin Receptor: Novel Probes for in Vivo Optical Imaging

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• 作者：Wael Alsibai ; Anke Hahnenkamp ; Michel Eisenbl盲tter ; Burkhard Riemann ; Michael Sch盲fers ; Christoph Bremer ; G眉nter Haufe ; Carsten H枚ltke
• 刊名：Journal of Medicinal Chemistry
• 出版年：2014
• 出版时间：December 11, 2014
• 年：2014
• 卷：57
• 期：23
• 页码：9971-9982
• 全文大小：637K
• ISSN：1520-4804

文摘

Integrins are heterodimeric transmembrane protein receptors consisting of different 伪 and 尾 subunits. 伪_v尾₃ integrins are overexpressed on many tumor cells and tumor-associated angiogenic vessels, whereas 伪_IIb尾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 伪_v尾₃ compared to that for 伪_IIb尾₃. In vitro, the probe showed high target binding on 伪_v尾₃-positive M-21 cells and negligible binding to 伪_v尾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.