Next Step toward Optimization of GRP Receptor Avidities: Determination of the Minimal Distance between BBN(7鈥?4) Units in Peptide Homodimers

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• 作者：G. Fischer ; S. Lindner ; S. Litau ; R. Schirrmacher ; B. W盲ngler ; C. W盲ngler
• 刊名：Bioconjugate Chemistry
• 出版年：2015
• 出版时间：August 19, 2015
• 年：2015
• 卷：26
• 期：8
• 页码：1479-1483
• 全文大小：304K
• ISSN：1520-4812

文摘

As the gastrin releasing peptide receptor (GRPR) is overexpressed on several tumor types, it represents a promising target for the specific in vivo imaging of these tumors using positron emission tomography (PET). We were able to show that PESIN-based peptide multimers can result in substantially higher GRPR avidities, highly advantageous in vivo pharmacokinetics and tumor imaging properties compared to the respective monomers. However, the minimal distance between the peptidic binders, resulting in the lowest possible system entropy while enabling a concomitant GRPR binding and thus optimized receptor avidities, has not been determined so far. Thus, we aimed here to identify the minimal distance between two GRPR-binding peptides in order to provide the basis for the development of highly avid GRPR-specific PET imaging agents. We therefore synthesized dimers of the GRPR-binding bombesin analogue BBN_(7鈥?4) on a dendritic scaffold, exhibiting different distances between both peptide binders. The homodimers were further modified with the chelator NODAGA, radiolabeled with ⁶⁸Ga, and evaluated in vitro regarding their GRPR avidity. We found that the most potent of the newly developed radioligands exhibits GRPR avidity twice as high as the most potent reference compound known so far, and that a minimal distance of 62 bond lengths between both peptidic binders within the homodimer can result in concomitant peptide binding and optimal GRPR avidities. These findings answer the question as to what molecular design should be chosen when aiming at the development of highly avid homobivalent peptidic ligands addressing the GRPR.