Tools for the preparation of peptide-based radioligands

制备基于肽的工具 放射性配体 在过去的几年中，用于各种癌症的诊断和治疗应用的放射性肽的开发取得了显着的增长。基于肽的配体提供了许多吸引人的特征，包括通过固相技术相对容易制备以及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，我使用盒式系统实施了新的、强大的快速自动化纯化工艺，通过回旋加速器常规生产 99mTc、64Cu、89Zr 和 68Ga 等放射性金属。此外，我的实验室最近针对 64Cu、89Zr 68Ga 开发了通过使用已建立的和新型双功能螯合剂 (BFC) 进行功能化来用放射性金属标记肽和抗体的便捷方法。与我之前的工作相一致，本提案推动了新兴且极具前景的放射性金属的开发，例如用于 PET 成像的 45Ti (t½=3.08h) 和 119Sb (t½=38.2h)，这是一种俄歇电子发射体，可以与第二代 BFC 一起提供高治疗指数。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-辅基和 18F-放射性肽。 我的长期目标是开发一系列创新工具，包括放射性金属、BFC、聚合物辅助 18F 标记，这将改善基于肽的放射性配体的标记、摩尔活性和/或稳定性。 除了开发一系列强大的替代合成工具和程序专门用于肽缀合物的制备和放射性标记之外，我的项目还将为设计新的放射性药物提供基础，从而扩大可以受益于诊断性 PET 成像和靶向放射治疗的医疗状况的数量。本文提出的研究还将允许对 HQP 进行培训，这些 HQP 将在重要的研究领域中拥有合成化学、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，旨在微调用于治疗诊断应用的相关放射性标记肽的各种生物学特性。

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 toolsradiometals, BFC, polymer-assisted 18F-labellingthat 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.