Heteromultivalency provides a route to increase binding avidity and to high specificity when compared to monovalent ligands. The enhanced specificity can potentially serve as a unique platform to develop diagnostics and therapeutics. To develop new imaging agents based upon multivalency, we employed heterobivalent constructs of optimized ligands. In this report, we describe synthetic methods we have developed for the preparation of heterobivalent constructs consisting of ligands targeted simultaneously to the melanocortin receptor, hMC4R, and the cholecystokinin receptors, CCK-2R. Modeling data suggest that a linker distance span of 20-50 Å is needed to crosslink these two G-protein coupled receptors (GPCRs). The two ligands were tethered with linkers of varying rigidity and length, and flexible polyethylene glycol based PEGO chain or semi-rigid [poly(Pro-Gly)] linkers were employed for this purpose. The described synthetic strategy provides a modular way to assemble ligands and linkers on solid-phase supports. Examples of heterobivalent ligands are provided to illustrate the increased binding avidity to cells that express the complementary receptors.

中文翻译：

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靶向黑皮质素和胆囊收缩素受体的异二价配体的固相合成。

与单价配体相比，异多价提供了增加结合亲和力和高特异性的途径。增强的特异性可能成为开发诊断和治疗的独特平台。为了开发基于多价的新成像剂，我们采用了优化配体的异二价构建体。在本报告中，我们描述了我们为制备异二价构建体而开发的合成方法，该构建体由同时靶向黑皮质素受体 hMC4R 和胆囊收缩素受体 CCK-2R 的配体组成。建模数据表明，交联这两种 G 蛋白偶联受体 (GPCR) 需要 20-50 Å 的接头距离跨度。这两个配体与不同刚性和长度的接头相连，为此目的，采用了基于聚乙二醇的柔性聚乙二醇链或半刚性 [poly(Pro-Gly)] 接头。所描述的合成策略提供了一种在固相支持物上组装配体和接头的模块化方法。提供了异二价配体的实例以说明对表达互补受体的细胞的结合亲合力增加。