Development and application of new 18F-glycoconjugates for PET

PET用新型18F-糖复合物的开发及应用

• 批准号: 43168698
• 负责人: Dr. Simone Maschauer
• 金额: --
• 依托单位: Klinik und Poliklinik für Neurochirurgie
• 依托单位国家: 德国
• 项目类别: Research Grants
• 财政年份: 2007
• 资助国家: 德国
• 起止时间: 2006-12-31 至 2017-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/43168698?language=en
• 关键词: Development; application; new; 18F; glycoconjugates

Positron emission tomography (PET) is established in clinical and experimental molecular imaging. However, so far there are only a few 18F-labeled peptide radiopharmaceuticals that are used in human PET studies and clinical trials. This is particularly ascribed to their time-consuming and demanding radiosyntheses. In the previous funding period glycosylazide precursors were successfully developed that are suitable for the efficient click chemistry-based strategy of concomitant 18F-labeling and glycosylation of alkynyl-functionalized peptides. Using this method, a variety of 18F- glycosylated biomolecules (e.g. avb3-affine RGD peptides, neurotensin peptoids, NPY derivatives, and also non-peptide ligands for the neurotensin receptor and the endothelin receptor-A) have been prepared and characterized in vitro and in vivo as highly affine and selective PET tracers. We could show that glycosylation itself and the position of the fluorine substitution in the glycosyl residues largely determined the biodistribution of glycoconjugates in vivo, as demonstrated on a series of glycosylated RGD peptides. Moreover, we showed that glycosylation has a positive influence on the in-vivo stability of a non-peptidic endothelin receptor ligand when compared to its fluoroethoxy analog. Further objectives of this project are: A) the application of successfully developed 18F-glycoconjugates for PET imaging of angiogenesis in the (radio)therapy monitoring in animal models, and B) the development of subtype-selective 18F-glycosylated radioligands for the neurotensin receptor-2. C) In addition, the developed 18F-fluoroglycosylation strategy should be adapted to the radiolabeling of cells. This aims to analyze immunological approaches to cancer therapy and rapid cell-cell recognition processes with PET imaging. For this purpose, selected [18F]fluorodeoxyglucosyl azide are used for click chemistry-based labeling of cells and subjected to cell-trafficking experiments using suitable animal models for the determination of the biokinetics of the cells and the quantification of PET imaging data. The 18F-fluoroglycosylation strategy developed in this project has already been proven suitable for tracer development projects and provides, in case of successful adaptation for cell trafficking studies with PET, also an additional potential for use in preclinical imaging studies.

正电子发射断层扫描 (PET) 是在临床和实验分子成像领域建立的。然而，迄今为止，只有少数 18F 标记的肽放射性药物用于人体 PET 研究和临床试验。这尤其归因于它们耗时且要求高的放射合成。在之前的资助期间，成功开发了糖基叠氮化物前体，适用于伴随 18F 标记和炔基功能化肽糖基化的高效点击化学策略。使用这种方法，制备了多种 18F-糖基化生物分子（例如 avb3-亲和 RGD 肽、神经降压素类肽、NPY 衍生物，以及神经降压素受体和内皮素受体 A 的非肽配体），并在体外和体内表征为高度亲和性和选择性 PET 示踪剂。我们可以证明，糖基化本身和糖基残基中氟取代的位置在很大程度上决定了糖缀合物在体内的生物分布，正如一系列糖基化 RGD 肽所证明的那样。此外，我们发现，与氟乙氧基类似物相比，糖基化对非肽内皮素受体配体的体内稳定性具有积极影响。该项目的进一步目标是：A) 在动物模型的（放射）治疗监测中应用成功开发的用于血管生成 PET 成像的 18F-糖缀合物，以及 B) 开发用于神经降压素受体 2 的亚型选择性 18F-糖基化放射性配体。 C) 此外，已开发的 18F-氟糖基化策略应适应细胞的放射性标记。其目的是通过 PET 成像分析癌症治疗的免疫学方法和快速细胞识别过程。为此，选择的[18F]氟脱氧葡萄糖基叠氮化物用于基于点击化学的细胞标记，并使用合适的动物模型进行细胞运输实验，以确定细胞的生物动力学和PET成像数据的量化。该项目中开发的 18F-氟糖基化策略已被证明适用于示踪剂开发项目，并且在成功适应 PET 细胞运输研究的情况下，还提供了用于临床前成像研究的额外潜力。

项目成果

In vivo monitoring of the anti-angiogenic therapeutic effect of the pan-deacetylase inhibitor panobinostat by small animal PET in a mouse model of gastrointestinal cancers.

• DOI: 10.1016/j.nucmedbio.2015.10.003
• 发表时间: 2016
• 期刊: Nuclear medicine and biology
• 影响因子: 3.1
• 作者: S. Maschauer;S. Gahr;Muktheshwar Gandesiri;P. Tripal;R. Schneider-Stock;T. Kuwert;M. Ocker;O. Prante