Project 2: TARGETED RESPONSIVE MR AND PET AGENTS FOR B-CELL IMAGING

项目2的目标是将项目1的代谢策略与胰岛靶向核心(核心B)和 使用最先进的显像剂技术创建用于分子成像的新型PET和MR试剂 活体内的b细胞。我们的目标是开发不仅针对活体胰腺b细胞的显像剂，而且 也通过功能激活对b细胞新陈代谢作出反应。在进行动物实验之前，我们将 初步建立培养的大鼠B细胞的高分辨率磁共振和正电子发射计算机断层成像平台 大鼠胰岛，并使用这项技术来筛选氧化还原敏感的PET试剂(64Cu-ATSM)和 B细胞中对氧化还原敏感的PARACEST试剂(基于环素的Eu3+或Tm3+四胺络合物)。证明 将使用多聚肽对特定靶向b细胞的制剂进行概念性研究 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。考虑到这些 ，我们将开发一种有效的标记方法来将18F或 以环为基础的配体到所有靶向多肽以创建MR(基于pH敏感的Gd3+试剂，基于PARACEST 锌离子和葡萄糖传感器)和PET试剂(18F和64Cu)用于测量a)b细胞质量和b)b细胞 功能。最终目标是将AIMS 1和AIMS 2的技术结合起来，创建具有针对性和响应性的MR PET试剂不仅报告b细胞质量，而且还提供b细胞功能的成像指标。

The goal of Project 2 is to merge the metabolic strategies of Project 1 and islet targeting core (Core B) and with state-of-the-art imaging agent technologies to create novel PET and MR agents for molecular imaging of the b-cell in vivo. Our goal is to develop imaging agents that not only target the pancreatic b-cell in vivo but also respond to b-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 b-cells and isolated rat islets and use this technology to screen for entrapment of redox sensitive PET agents (64Cu-ATSM) and redox sensitive PARACEST agents (cyclen-based tetraamide complexes of Eu3+ or Tm3+) in b-cells. Proof of concept studies on agents that specifically target b-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, PARACESTbased Zn2+ and glucose sensors) and PET agents (both 18F and 64Cu) to measure a) b-cell mass and b) bcell 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 b-cell mass but also provide an imaging index of b-cell function.