Chemical Technology for Imaging Agent Discovery

NSERC的这项发现拨款提案寻求开发化学技术，将显像剂设计推向全新和创新的方向。我们将探索合成和配体评估的方法，包括发现过程中的成像成分(放射性同位素和荧光染料)，而不是事后才想到的传统方法，即结合成像成分。为此，我们的实验室利用了药物化学技术，但进行了关键的修改，将氟或放射性金属结合到结构中。多肽化学仍然是我们方法的核心，它提供了独特的结构构象，我们将使用放射性金属来模拟这些构象，并用于形成受控的纳米结构。*在这项发现奖申请中，我们提出了一些应用于显像剂发现的新技术，围绕着化学技术用于显像剂发现这一规划主题。这些是基本的化学发现，有可能应用于许多具有诊断和治疗意义的生物靶点的显像剂的未来发展。1)我们建议开发一种金属络合物，它能够作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。2)多肽通常含有对受体结合至关重要的转向区。我们建议使用放射性金属在多肽中创建TURN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，我们建议将其应用于显像剂的发现，其中放射性同位素成像成分是被评估的片段的一部分。这将是开发PET显像剂的第一个基于片段的发现示例。4)一珠一化合物(OBOC)文库筛选是评估数百万个潜在的肿瘤靶向多肽的有效方法。我们现在建议开发包含氟的OBOC文库，以便通过这种方法发现的目标特定多肽将具有分子中已经存在的成像成分，并且以一种允许轻松进行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的、化学控制的纳米探针的一种手段。这种制造纳米粒子显像剂的方法将允许一个受控的结构，这对于微调纳米探测器的尺寸和生物行为至关重要。**

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.**