Multi-Layered Valency: A Novel Design of Peptidic Imaging Agents for ??v??6

描述(申请人提供)：最近在诊断成像方面的努力不仅集中在改进解剖成像上，而且还设计了检测生命系统内分子变化的方法。免疫-PET的开创性工作展示了分子成像的力量。然而，结合疾病特异性细胞表面生物标记物的配体的数量必须扩大，以充分实现分子成像的力量。合成肽作为靶向分子将放射性同位素输送到体内靶点进行成像，引起了人们的关注。 这在一定程度上受到了筛选噬菌体展示多肽库以识别针对不同细胞类型的多肽配体的进展的刺激。然而，肽引导显像剂的洪流还没有出现。这部分是由于在噬菌体颗粒的背景之外保持多肽的亲和力和活性是困难的。此外，由于降解和快速的肾脏过滤，多肽在血液中的半衰期通常很短，这限制了它们在目标体内的积累。多聚体可以改善多肽的亲和力，增强稳定性，延长体内半衰期。尽管如此，大多数当前的多聚肽结构都不是系统设计的。我们建议使用一种新型的双功能螯合剂支架(BFCS)和一种独特的用于显示细胞靶向多肽的多聚肽支架来创建多价肽PET显像剂，其中价态可以分层。首先，我们将利用多价BFCS来呈现多聚肽。其次，我们将产生一系列可与单价BFCS偶联的多聚肽。最后，我们将把多价BFC支架与多价多肽结合起来，创建可用于PET成像的高阶多肽结构。每个分子的价态从1-8个多肽支链不等。为了开发这一探针设计，我们将使用我们实验室分离的一种与限制性表达的整合素？V？6具有高亲和力和特异性的多肽。该整合素是一些上皮源性癌症和肺纤维化的生物标记物，在这些疾病中，分子成像探针将具有广泛的临床应用价值。目标1将确定最佳价态，而目标2专注于对多肽进行化学修饰，以实现最佳的生物分布。在目标3中，我们将利用优化的探针在其他癌症和特发性肺纤维化模型中成像？V？6。该显像剂有望在实体瘤和纤维化疾病中对？V？6的分子成像产生广泛的影响。这些实验将为进入临床前和I期临床试验奠定基础。 公共卫生相关性：分子成像有可能通过检测疾病特异性标志物而不需要侵入性活组织检查来帮助诊断。我们将开发和优化一种可以与许多肿瘤和纤维化疾病中发现的标记物(V6)结合的PET分子显像剂。预计这一探查将对这些严重疾病的诊断产生广泛影响。

DESCRIPTION (provided by applicant): Recent efforts in diagnostic imaging have focused not only on improving anatomical imaging but designing approaches to detect molecular changes within a living system. Pioneering work in immuno-PET demonstrates the power of molecular imaging. However, the number of ligands that bind disease specific cell surface biomarkers must be expanded to fully realize the power of molecular imaging. Synthetic peptides have attracted attention as targeting molecules to deliver radioisotopes to in vivo targets for imaging. This has been stimulated in part by advances in screening phage-displayed peptide libraries to identify peptidic ligands that target different cell types. Yet, a flood of peptide guided imaging agents has not occurred. This is partially due to the difficulty in retaining the affinity and actiity of peptides outside of the context of the phage particle. Moreover, peptides typically have short half-lives in the blood because of degradation and rapid renal filtration, which limits their accumulation in their targets. Multimerization can improve affinity, enhance stability, and extend in vivo half-life of peptides. None-the-less, most current multimeric peptide constructs are not systematically designed. We propose to create multivalent peptidic PET imaging agents in which the valency can be layered using a novel bifunctional chelator scaffold (BFCS) and a unique multimeric peptide scaffold for displaying cell-targeting peptides. First, we will take advantage of a multivalent BFCS for multimeric peptide presentation. Second, we will generate a series of multimeric peptides that can be conjugated to a monovalent BFCS. Finally, we will combine the multivalent BFC scaffolds with the multivalent peptides to create higher order peptide structures that can be used for PET imaging. The valency will vary from 1-8 peptide branches per molecule. To develop this probe design, we will use a peptide isolated in our laboratory which binds with high affinity and specificity to the restrictively expressed integrin ?v?6. This integrin is a biomarker for a number of epithelial derived cancers and lung fibrosis, diseases in which molecular imaging probes would have wide clinical applicability. Aim 1 will identify the optimal valency while aim 2 focuses on chemically modifying the peptide to achieve optimal biodistribution. In aim 3, we will utilize the optimized probe to image ?v?6 in other cancers as well as in a model of idiopathic pulmonary fibrosis. The imaging agent is anticipated to have a wide impact on molecular imaging of ?v?6 in solid tumors and fibrotic diseases. These experiments will lay the foundation for moving into preclinical and Phase I clinical trials. PUBLIC HEALTH RELEVANCE: Molecular imaging has the potential to aid in diagnosis by detecting disease specific markers without the need for invasive biopsies. We will develop and optimize a PET-molecular imaging agent that binds to a marker (?v?6) found in many tumors and fibrotic diseases. This probe is anticipated to have a wide impact on the diagnosis of these serious diseases.