Chemical Technology for Imaging Agent Discovery

这项NSERC发现拨款提案旨在开发化学技术，将显像剂设计推向全新和创新的方向。我们将探索在发现过程中包含成像成分（放射性同位素和荧光染料）的合成和配体评估方法，而不是将成像成分偶联作为事后考虑的传统方法。为此，我们的实验室利用药物化学技术，但在结构中加入氟或放射性金属进行了关键修改。肽化学仍然是我们方法的核心，并提供了独特的结构构象，我们将使用放射性金属模拟并形成受控的纳米结构。***在这项发现资助申请中，我们提出了一些应用于显像剂发现的新颖技术，围绕显像剂发现的化学技术的程序性主题进行整合。这些基本的化学发现有潜力应用于成像剂的未来发展，用于诊断和治疗相关的许多生物靶点。1)我们建议开发一种金属配合物，它能够成为荧光或放射性同位素标记的显像剂，并允许细胞分析和体内成像之间的相关性。肽通常包含对受体结合至关重要的旋转区域。我们建议使用放射性金属在肽中创建旋转模拟物，从而创建金属文件夹，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，我们建议将其用于显像剂的发现，其中放射性同位素成像成分是正在评估的片段的一部分。这将是基于片段的发现开发PET显像剂的第一个例子。4)单头单化合物（OBOC）文库筛选是评价数以百万计的潜在肿瘤靶向肽的有效方法。我们现在建议开发含氟的OBOC文库，以便通过这种方法发现的目标特定肽将具有已经存在于分子中的成像成分，并且以一种易于放射化学开发的方式。5)我们建议创建合成蛋白质结构作为开发生物相容性，化学控制的纳米探针的手段。这种创建纳米颗粒显像剂的方法将允许控制结构，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.**