Tools for peptide radiolabeling

*多肽在正电子发射断层扫描（PET）成像和肿瘤靶向方面的巨大兴趣是由于许多优点，包括小尺寸，易于制备，低毒性和低免疫原性。除此之外，将双功能螯合物（BFC）附着到肽上的能力可以极大地简化其放射性金属标记，从而使试剂盒配方成为可能。为了鉴定用于标记含有正电子放射金属（如Cu-64， Ga-68和Zr-89）的肽的改进BFC，我们建议开发一系列由多氮杂环衍生的环状BFC和由氨基酸衍生的无环BFC，并具有不同的供体基团。同样，通过直接标记肽的18f标记几乎是不可能的。由于肽18f标记包括多步骤程序，因此仍然需要适用于更快肽标记的18f标记方法。**基于令人鼓舞的初步结果，我们建议研究用F-18标记肽的硫酯连接化学。虽然这种反应是在一段时间前开发的，但它在F-18放射化学中的应用从未被研究过。我们的方法侧重于开发可切割的硫醇助剂，使用简单的反应和纯化条件，以高产量，特定活性和短反应时间（几分钟而不是几小时）获得所需的肽。我们还建议研究硫酯连接化学用于制备肽二聚体和环肽。这些肽结构更稳定，可能比相应的无环肽单体具有许多优点，例如更好的肿瘤摄取和更长的肿瘤保留时间。**目前的研究项目推进了用于正电子发射放射性金属肽标记的新型BFC的开发，基于硫酯连接化学的新合成方法，用于改进18f标记程序和开发多种肽结构。该计划的长期目标是：**开发新的工具- bfc，化学选择偶联方法，肽二聚体和环肽-将提高肽基示踪剂的标记和/或稳定性。**除了开发用于制备和放射性标记肽类似物的替代合成程序外，我们的计划将为设计新的放射性肽提供基础，这将扩大可从PET诊断成像中受益的医疗条件的数量。本文提出的研究还将允许HQP在一个重要的研究领域进行培训，该领域将拥有合成化学、放射性标记和生物医学成像等独特技能的组合。

Tools for peptide radiolabeling*The tremendous interest of peptides for positron emission tomography (PET) imaging and tumour targeting is due to the many advantages including small size, easy preparation, low toxicity and low immunogenicity. Among others, the ability to attach bifunctional chelates (BFC) to peptides can extremely simplify their labeling with radiometal to the point where kit formulations are possible. With the goal of identifying improved BFC for the labeling of peptides with positron emitting radiometals such as Cu-64, Ga-68 and Zr-89, we propose to develop a series of cyclic BFC derived from polyazacycles and acyclic BFC derived from amino acids and bearing various donor groups. As well, 18F-labeling of peptides by direct labeling is almost not possible. Since peptide 18F-labeling includes multistep procedures, there is still the need for 18F-labeling methods suitable for faster peptide labeling. **Based on encouraging preliminary results, we propose to investigate thioester ligation chemistry to label peptide with F-18. Although this reaction was developed some time ago, its application to F-18 radiochemistry has never been studied. Our approach focuses on the development of cleavable thiol auxiliaries using simple reaction and purification conditions to give the desired peptides in high yields, specific activities and short reaction times (minutes instead of hours). We also propose to investigate the thioester ligation chemistry for the preparation of peptide dimers and cyclic peptides. These peptide constructs are more stable and may present many advantages over the corresponding acyclic peptide monomer such as a superior tumor uptake and longer tumor retention. **The current research program advances the development of novel BFC for peptide-labeling with positron emitting radiometals, a new synthetic approach based on thioester ligation chemistry for an improved 18F-labeling procedure and the development of diverse peptide constructs. The long term objective of this program is:**To develop novel tools-BFC, chemoselective conjugation methods, peptide dimers and cyclic peptides-that will improve the labeling and/or stability of peptide-based tracers.**In addition to developing alternative synthetic procedures for the preparation and the radiolabeling of peptide analogs, our program will provide a base for the design of new radiopeptides that will enlarge the number of medical conditions that can benefit from diagnostic PET imaging. The research proposed herein will also permit the training of HQP in an important field of research that will possess a unique combination of skills from synthetic chemistry, radiolabelling and biomedical imaging.