Tools for the preparation of peptide-based radioligands

多肽类药物的制备工具 放射性配体 在过去的几年里，用于诊断和治疗各种癌症的放射性多肽的开发有了显著的增长。基于多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地制备，以及利用天然和非天然氨基酸获得的化学多样性。在上一次资助期间，我采用了新的和强大的快速自动净化工艺，使用基于盒式系统的系统，通过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通过已建立的和新的双功能螯合剂(BFC)功能化的放射性金属标记多肽和抗体的简便方法，用于64Cu，89Zr 68Ga。与我早期工作的连续性，本提案推动了新兴和极具前景的放射金属的开发，例如用于PET成像的45Ti(tç=3.08h)和119Sb(tç=38.2h)，这是一种可以提供高治疗指数的俄歇电子发射体，以及第二代BFCS。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-假体基团和18F-放射性多肽。 我的长期目标是开发一批创新的工具，如放射性金属、BFC、聚合物辅助的18F标记，这些工具将改善基于多肽的放射性配体的标记、摩尔活性和/或稳定性。 除了开发一系列功能强大的替代合成工具和程序，专门用于多肽结合物的制备和放射性标记外，我的计划还将为设计新的放射性药物提供基础，这些药物将扩大可受益于诊断性PET成像和靶向放射治疗的医疗条件的数量。这里提出的研究还将允许在一个重要的研究领域培训具有合成化学、放射性标记、生物医学成像和放射治疗等方面独特技能的HQP。 这个基础科学项目是我开发分子工具的一个独特机会，这些工具旨在微调用于治疗应用的相关放射性标记多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.