Chemical Technology for Imaging Agent Discovery

这项NSERC发现资助提案旨在开发化学技术，将成像剂设计推向全新的创新方向。我们将探索在发现过程中包含成像组分（放射性同位素和荧光染料）的合成和配体评估方法，而不是将成像组分作为事后的传统方法。为此，我们的实验室利用药物化学技术，但进行了关键修改，将氟或放射性金属纳入结构中。肽化学仍然是我们的方法的核心，并提供了独特的结构构象，我们将模仿使用radiometals和形成控制nanoarchitecture.In这个发现补助金申请，我们提出了一些新的技术，适用于显像剂的发现，凝聚在显像剂发现的化学技术的纲领性主题。这些都是基础化学发现，有可能被应用到未来的发展，成像剂的诊断和治疗相关的许多生物靶标。1)我们建议开发一种金属配合物，该配合物能够成为荧光或放射性同位素标记的成像剂，并允许细胞分析和体内成像之间的相关性。2)肽通常含有对受体结合至关重要的转角区域。我们建议使用放射性金属在肽中创建转弯模拟物，从而创建金属折叠体，其中放射性金属对配体构象和受体结合至关重要。3)基于片段的药物设计是一种新的药物发现方法，我们建议将其用于成像剂发现，其中放射性同位素成像组分是正在评估的片段的一部分。这将是第一个基于片段的发现用于开发PET成像剂的例子。4)单珠单化合物（OBOC）文库筛选是一种有效的方法，用于评估数百万种潜在的癌症靶向肽。我们现在提出开发含氟的OBOC文库，使得通过这种方法发现的靶特异性肽将具有已经存在于分子中的成像组分，并且以允许容易的放射化学开发的方式。5)我们建议创建合成蛋白质架构作为开发生物相容性，化学控制的纳米探针的一种手段。这种产生纳米颗粒成像剂的方法将允许受控的结构，这对于纳米探针尺寸和生物行为的微调至关重要。

This NSERC discovery grant proposal seeks to develop chemical technology that moves imaging agent design in entirely new and innovative directions. We will explore methods of synthesis and ligand evaluation that is inclusive of imaging components (radioisotopes and fluorescent dyes) during the discovery process, instead of the traditional approach of conjugating an imaging component as an afterthought. To do this, our lab utilizes medicinal chemistry techniques but with key modifications to incorporate fluorine or radiometals within structures. Peptide chemistry remains central to our approach and provides unique structural conformations that we will mimic using radiometals and for the formation of controlled nanoarchitectures.In this discovery grant application we propose a number of techniques that are novel as applied to imaging agent discovery, coalescing around the programmatic theme of chemical technology for imaging agent discovery. These are fundamental chemistry discoveries that have the potential to be applied to the future development of imaging agents for many biological targets of diagnostic and therapeutic relevance. 1) We propose the development of a metal complex that is capable of being either a fluorescent or radioisotope labelled imaging agent and allows for the correlation between cell analysis and imaging in vivo. 2) Peptides often contain turn regions that are critical for receptor binding. We propose using radiometals to create turn mimics in peptides, thereby creating metal foldamers, where the radiometal is critical for ligand conformation and receptor binding. 3) Fragment based drug design is a new approach to drug discovery that we propose to adapt for imaging agent discovery, where a radioisotope imaging component is part of the fragments being evaluated. This will be the first example of fragment-based discovery for developing PET imaging agents. 4) One-bead one-compound (OBOC) library screening is an effective method for evaluating millions of potential peptides for cancer targeting. We now propose to develop fluorine containing OBOC libraries so that target specific peptides discovered through this approach will have the imaging component already present in the molecule and in a fashion that will allow for easy radiochemistry development. 5) We propose the creation of synthetic protein architectures as a means of developing biocompatible, chemically controlled nanoprobes. This approach to creating nanoparticle imaging agents will allow for a controlled architecture which is critical for the fine tuning of nanoprobe size and biological behaviour.