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 i s 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.
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