High Thoroughput Development of Molecular Imaging Agents

描述(由申请人提供)： 基因组和蛋白质组学研究的最新进展为识别疾病的特定分子标记开辟了新的前景。为了开发这些标记用于生物医学成像，迫切需要高亲和力的配体。然而，分子标记的单价配体往往缺乏在体内有效靶向所需的亲和力。最近，多价药物设计已被证明可将亲和力提高几个数量级(Angew Chem 1998；37：2754-2794)。这项建议的目标是开发和测试高效、并行合成和高通量筛选多价、分子靶向磁共振成像剂的新方法。这项研究的基本假设是，可以利用多价性来获得分子标记体内成像所需的亲和力和特异性。磁性纳米颗粒是开发新的多价显像剂合成和筛选方法的理想平台，因为(I)细胞对纳米颗粒的摄取以及由此引起的松弛速率的变化，可以通过核磁共振以高通量的方式进行分析，(Ii)结合化学的最新进展允许连接具有广泛不同价态的低分子配体纳米颗粒，(Iii)磁性纳米颗粒是无毒的，适合临床开发，(Iv)因为磁性纳米颗粒可被MR高度检测，因此本建议的具体目标包括系统地合成位置编码的多价肽-纳米粒子库。使用不同的读出方法，我们还将研究高通量筛选技术，并验证这些方法。我们假设，i)大量的肽链偶联物可以通过小型化、平行合成并以高通量的方式进行筛选，ii)多价性和连接臂化学将在确定纳米粒子对细胞靶标的亲和力方面发挥重要作用，iii)由此开发的作为激活内皮细胞探针的MR试剂将扩展我们对各种重要病理状态下的内皮进行成像的能力。计划中的研究将提供关键技术，并使分子靶向显像剂的快速开发成为可能。

DESCRIPTION (provided by applicant): Recent advances in genomic and proteomic research have opened new vistas for identifying specific molecular markers of disease. In order to exploit these markers for biomedical imaging, high affinity ligands are urgently needed. Frequently, however, monovalent ligands for molecular markers lack the affinity needed for efficient targeting in vivo. Recently, multivalent drug design has been shown to increase affinity by several orders of magnitude (Angew Chem 1998;37:2754-2794). The goal of this proposal is to develop and test novel approaches for the efficient, parallel synthesis and high throughput screening of multivalent, molecularly targeted MR imaging agents. The underlying hypothesis of the proposed research is that multivalency can be utilized to obtain the affinity and specificity needed for in vivo imaging of molecular markers. Magnetic nanoparticles are an ideal platform for the development of new synthetic and screening methods for multivalent imaging agents because (i) the uptake of nanoparticles by cells, and resulting changes in relaxation rate, can be analyzed in a high throughput fashion by MRI, (ii) recent advances in conjugation chemistry allow the attachment of low molecular weight ligands nanoparticles with widely varying valencies, (iii) magnetic nanoparticles are non-toxic and amenable to clinical development, (iv) because magnetic nanoparticles are highly detectable by MR The specific aims of this proposal include systematic synthesis of positionally encoded, multivalent peptide-nanoparticle libraries. Using different read-out methods we will also investigate high throughput screening techniques and validate these approaches. We hypothesize that i) large numbers of peptidenanoparticle conjugates can be created with a miniaturized, parallel synthesis and screened in high through put fashion, ii) that multivalency and linker arm chemistry will play an important role in determining the affinity nanoparticles exhibit for cellular targets, and iii) that MR agents thus developed as probes for activated endothelial cells will expand our capabilities to image the endothelium in a variety of important pathological states. The planned research will provide critical technology and enable the rapid development of molecularly targeted imaging agents.