Tools for peptide radiolabeling

多肽放射性标记工具 多肽具有体积小、制备简单、毒性低、免疫原性低等优点，在正电子发射断层扫描(PET)成像和肿瘤靶向方面具有巨大的应用前景。其中，将双功能螯合物(BFC)附着到多肽上的能力可以极大地简化它们的放射性金属标记，从而使试剂盒配方成为可能。为了更好地标记具有正电子辐射的金属多肽，如铜-、镓-68和锆-89，我们提出了一系列由多氮杂环衍生的环状BFC和由氨基酸衍生的含有不同给体基团的无环BFC。同样，直接标记多肽的18F-标记几乎是不可能的。由于18F-肽标记包括多个步骤，因此仍然需要适用于更快的肽标记的18F-标记方法。 基于令人鼓舞的初步结果，我们建议研究硫酯连接化学来标记F-18多肽。虽然这一反应发展已有一段时间，但其在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裂解的硫醇辅助剂，通过简单的反应和纯化条件来获得所需的多肽，产率高，比活性高，反应时间短(几分钟而不是几小时)。我们还建议研究硫酯连接化学以制备多肽二聚体和环多肽。这些多肽结构更稳定，可能比相应的非环多肽单体具有许多优点，例如更好的肿瘤摄取和更长的肿瘤滞留时间。 目前的研究计划推进了利用正电子发射的放射性金属标记多肽的新型BFC的开发，基于硫酯连接化学的改进的18F标记程序的新的合成方法，以及各种多肽结构的开发。该计划的长期目标是： 开发新的工具--BFC、化学选择性偶联方法、多肽二聚体和环多肽--将提高多肽示踪剂的标记和/或稳定性。 除了开发制备和标记多肽类似物的替代合成程序外，我们的计划还将为设计新的放射性多肽奠定基础，这些多肽将扩大可受益于诊断PET成像的医疗条件的数量。这里提出的研究还将允许HQP在一个重要的研究领域进行培训，该领域将拥有来自合成化学、放射性标记和生物医学成像的独特技能组合。

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.