TARGETED RESPONSIVE MR AND PET AGENTS FOR B-CELL IMAGING

项目2的目标是融合项目1和胰岛靶向核心(核心B)的代谢策略，并与最先进的成像试剂技术相结合，创建用于活体b细胞分子成像的新型PET和MR试剂。我们的目标是开发不仅针对活体胰腺b细胞，而且通过功能激活对b细胞代谢做出反应的显像剂。在进行动物实验之前，我们将首先开发一个平台，对培养的大鼠b细胞和分离的b细胞进行高分辨率磁共振和正电子发射计算机断层扫描。 并利用这项技术筛选氧化还原敏感的PET试剂(64Cu-ATSM)和氧化还原敏感的PARACEST试剂(基于Eu3+或Tm3+的环素四胺络合物)在b细胞中的包埋情况。使用多聚体多肽进行验证 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。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)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 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) b-cell mass and b) b 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 b-cell mass but also provide an imaging index of b-cell function.