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

描述（由申请人提供）：最近在诊断成像方面的努力不仅集中在改进解剖成像上，而且还集中在设计检测生命系统内分子变化的方法上。免疫pet的开创性工作证明了分子成像的力量。然而，结合疾病特异性细胞表面生物标志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传递到体内目标进行成像引起了人们的关注。

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.