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。

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.