Synthesis, radiolabeling, in vitro and in vivo evaluation of heterobivalent peptidic ligands for an improved and specific PET imaging of human breast carcinomas

异二价肽配体的合成、放射性标记、体外和体内评估，以改善人类乳腺癌的特异性 PET 成像

• 批准号: 255841900
• 负责人: Professorin Dr. Carmen Wängler
• 金额: --
• 依托单位: Institut für Klinische Radiologie und Nuklearmedizin
• 依托单位国家: 德国
• 项目类别: Research Grants
• 财政年份: 2014
• 资助国家: 德国
• 起止时间: 2013-12-31 至 2017-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/255841900?language=en
• 关键词: Synthesis; radiolabeling; vitro; vivo; evaluation

Aim of the project is the development of heterobivalent peptidic ligands that show a high affinity for both GRP (gastrin releasing peptide) as well as NPY(Y1) (neuropeptide Y1) receptors as it was shown, analyzing human biopsies, that human breast cancers and their metastases exhibit a very heterogeneous receptor expression profile while in most cases exhibiting a sufficient density of at least one of these receptors which would allow for a successful PET imaging of the lesions. Thus, a conjugate of two peptides, one binding to the GRPR and the other binding to the NPY(Y1)R, should result in a heterobivalent compound that allows for the in vivo visualization of most human breast carcinomas. This would strongly improve the specific receptor-mediated breast cancer imaging with PET.Thus, different heterodimers binding to the GRPR as well as the NPY(Y1)R will be synthesized, radiolabeled and systematically evaluated regarding their biological activity (binding affinity to both receptors, tumor cell binding and internalization) to determine structure-activity-relationships for these heterodimers and those conjugates that are suitable in an in vivo tumor imaging application.In order to show that this heterodimerization approach is able to result in radiotracers with improved in vivo tumor targeting properties and pharmacokinetics, the derivatives giving the best results in the in vitro assays will finally be evaluated in vivo in a tumor-bearing mouse model in a µPET/CT study and compared to the monomeric reference compounds.

该项目的目的是开发对GRP和GRP都具有高亲和力的异二价肽配体。（胃泌素释放肽）以及NPY（Y1）（神经肽Y1）受体，因为它是显示，分析人类活检，人乳腺癌及其转移显示出非常异质的受体表达谱，而在大多数情况下显示出足够密度的这些受体中的至少一种，对病变进行成功的PET成像因此，两种肽的缀合物，一种结合GRPR，另一种结合NPY（Y1）R，应该产生允许大多数人乳腺癌的体内可视化的异二价化合物。因此，将合成与GRPR和NPY（Y1）R结合的不同异源二聚体，放射性标记并系统地评价它们的生物学活性（对两种受体的结合亲和力，肿瘤细胞结合和内化）以确定结构-活性-为了显示这种异二聚化方法能够产生具有改善的体内肿瘤靶向性质和药代动力学的放射性示踪剂，在体外试验中获得最佳结果的衍生物最终将在µPET/CT研究的荷瘤小鼠模型中进行体内评价，并与单体参比化合物进行比较。