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

该项目的目标是开发与GRP(胃泌素释放肽)以及NPY(Y1)(神经肽Y1)受体都具有高亲和力的异二价多肽配体。分析人类活检组织表明，人类乳腺癌及其转移瘤表现出非常不同的受体表达谱，而在大多数情况下，这些受体中至少有一个具有足够的密度，这将允许对病变进行成功的PET成像。因此，两个肽的结合，一个与GRPR结合，另一个与NPY(Y1)R结合，应该会产生一种异二价化合物，从而允许大多数人类乳腺癌的体内可视化。因此，将合成不同的与GRPR以及NPY(Y1)R结合的异源二聚体，并系统地评估它们的生物活性(与两个受体的结合亲和力、肿瘤细胞结合和内化)，以确定这些异源二聚体和那些适合于体内肿瘤成像应用的结合物的结构-活性-关系。为了表明这种异二聚化方法能够产生具有改进的体内肿瘤靶向性和药代动力学的放射性示踪剂，这些在体外测试中效果最好的衍生物最终将在荷瘤小鼠模型中进行体内评估，并与单体参考化合物进行比较。

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.