TARGETED RESPONSIVE MR AND PET AGENTS FOR BETA-CELL IMAGING

这个子项目是利用由NIH/NCRR资助的中心拨款提供的资源的许多研究子项目之一。子项目和调查员(PI)可能从另一个NIH来源获得了主要资金，因此可能会出现在其他CRISE条目中。列出的机构是针对中心的，而不一定是针对调查员的机构。这是由杜克大学的克里斯·纽加德领导的悬而未决的PPG拨款续签中的第二个项目。其目标是将项目1中描述的贝塔细胞代谢策略和胰岛靶向核心与最先进的成像试剂技术相结合，创建用于体内贝塔细胞分子成像的新型PET和MR试剂。我们的目标是开发一种显像剂，不仅针对体内的胰岛β细胞，而且通过功能激活来响应胰岛细胞的新陈代谢。在进行动物实验之前，我们首先将开发一个平台，用于对培养的大鼠β细胞和分离的大鼠胰岛进行高分辨率磁共振和PET成像，并使用这项技术来筛选氧化还原敏感的PET试剂和氧化还原敏感的PARACEST试剂在β细胞中的包埋情况。通过对胰岛素瘤INS 832/1细胞和分离的大鼠胰岛进行噬菌体展示平移鉴定的多聚肽，将对特定靶向β细胞的制剂进行概念验证研究。鉴于这些多肽或Core B中确定的其他多肽，我们将开发一种有效的标记方法，将18F或基于Cyclen的配体连接到所有靶向多肽上，以创建MR(基于pH敏感的Gd3+试剂、基于PARACEST的锌离子和葡萄糖传感器)和PET试剂(18F和64Cu)，以测量a)β细胞质量和b)β细胞功能。最终目标是将AIMS 1和AIMS 2的技术结合起来，创造出目标明确、反应灵敏的MR和PET试剂，不仅能报告β细胞质量，还能提供β细胞功能的成像指标。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. This is Project #2 in a pending PPG grant renewal led by Chris Newgard of Duke University. The goal is to merge the beta - cell metabolic strategies described in Project #1 and islet targeting core with state-of-the-art imaging agent technologies to create novel PET and MR agents for molecular imaging of the beta-cell in vivo. Our goal is to develop imaging agents that not only target the pancreatic beta-cell in vivo but also respond to beta-cell metabolism by functional activation. Before moving to animal experiments, we will initially develop a platform for both high resolution MR and PET imaging of cultured rat beta-cells and isolated rat islets and use this technology to screen for entrapment of redox sensitive PET agents and redox sensitive PARACEST agents in beta-cells. Proof of concept studies on agents that specifically target beta -cells will be performed using multimeric peptides identified by phage display panning of insulinoma INS 832/1 cells and isolated rat islets. Given these peptides or others identified in Core B, we will develop an efficient labeling approach to attach either 18F or cyclen-based ligands to all targeting peptides to create MR (pH sensitive Gd3+-based agents, PARACEST-based Zn2+ and glucose sensors) and PET agents (both 18F and 64Cu) to measure a) beta-cell mass and b) beta-cell function. A final aim is to combine the technologies of aims 1 & 2 to create targeted & responsive MR and PET agents that not only report beta-cell mass but also provide an imaging index of beta-cell function.