Tools for the preparation of peptide-based radioligands

在过去的几年中，用于诊断和治疗各种癌症的放射性肽的发展取得了显着的增长。肽基配体具有许多吸引人的特点，包括相对容易通过固相技术制备和利用天然和非天然氨基酸的化学多样性。在上一个资助期间，我使用基于盒式系统实施了新的强大的快速自动化净化工艺，用于回旋加速器常规生产放射性金属，如99mTc， 64Cu， 89Zr和68Ga。此外，我的实验室最近开发了一种方便的方法，通过使用已建立的和新的双功能螯合剂（BFC）功能化，用放射性金属标记肽和抗体，用于64Cu， 89Zr 68Ga。在我早期工作的连续性中，本提案推进了新兴和极有前途的放射性金属的发展，例如用于PET成像的45Ti （t½=3.08h）和119Sb (t½=38.2h)，这是一种可以提供高治疗指数的俄歇电子发射体，与第二代BFCs一起。我还提出了一种改进的聚合物支持的18f -放射性标记程序，用于制备各种18f -假基和18f -放射性肽。我的长期目标是开发一系列创新工具-放射性金属，BFC，聚合物辅助18f标记-这将提高基于肽的放射性配体的标记，摩尔活性和/或稳定性。除了开发一个强大的替代合成工具和程序库，致力于肽偶联物的制备和放射性标记，我的计划将为设计新的放射性药物提供基础，这将扩大医疗条件的数量，可以从诊断PET成像和靶向放疗中受益。本文提出的研究还将允许培训HQPs，这些HQPs将在一个重要的研究领域拥有合成化学、放射性标记、生物医学成像和放射治疗的独特技能组合。这个基础科学项目对我来说是一个独特的机会，可以开发分子工具，用于微调用于治疗应用的相关放射性标记肽的各种生物特性。

Tools for the preparation of peptide-based radioligands Over the past few years, the development of radiopeptides for diagnostic and therapeutic applications in diverse cancers has seen a significant growth. Peptide-based ligands provide many attractive features, including relative ease of preparation by solid phase techniques and accessible chemical diversity utilizing natural and unnatural amino acids. During the last funding period, I implemented new and robust fast-automated purification processes using cassette-based systems for a routine production of radiometals such as 99mTc, 64Cu, 89Zr and 68Ga by cyclotron. As well, convenient approaches to label peptides and antibodies with radiometals via functionalization with both established and novel bifunctional chelators (BFC) were recently developed in my laboratory for 64Cu, 89Zr 68Ga. In continuity with my earlier work, the present proposal advances the development of emerging and highly promising radiometals, such as 45Ti (t½=3.08h) for PET imaging, and 119Sb (t½=38.2h), an Auger-electron emitter that could offer a high therapeutic index along with a second generation of BFCs. I also propose an improved polymer-supported 18F-radiolabelling procedure for the preparation of a variety of 18F-prosthetic groups and 18F-radiopeptides. My long-term objective is to develop an arsenal of innovative tools-radiometals, BFC, polymer-assisted 18F-labelling-that will improve the labelling, molar activity and/or stability of peptide-based radioligands. In addition to developing an arsenal of powerful alternative synthetic tools and procedures dedicated to the preparation and radiolabelling of peptide conjugates, my program will provide a base for the design of new radiopharmaceuticals that will enlarge the number of medical conditions that can benefit from diagnostic PET imaging and targeted radiotherapy. The research proposed herein will also permit the training of HQPs that will possess a unique combination of skills from synthetic chemistry, radiolabelling, biomedical imaging and radiotherapy in an important field of research. This fundamental science program is a unique opportunity for me to develop molecular tools designed to fine-tune the various biological properties of relevant radiolabelled-peptides used for theranostic applications.