This subproject is one of many research subprojects utilizing theresources provided by a Center grant funded by NIH/NCRR. The subproject andinvestigator (PI) may have received primary funding from another NIH source,and thus could be represented in other CRISP entries. The institution listed isfor 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 (headed by Kathlynn Brown) with state-of-the-art imaging agent technologies to create novel PET and MR agents for molecular imaging of the -cell in vivo. Our goal is to develop imaging agents that not only target the pancreatic -cell in vivo but also respond to -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 -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 -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, PARACEST-based Zn2+ and glucose sensors) and PET agents (both 18F and 64Cu) to measure a) -cell mass and b) -cell 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 -cell mass but also provide an imaging index of -cell function. With the recent technical innovations of imaging modalities, molecular imaging is gaining more and more attention in the fields of basic biomedical sciences and clinical research and practice. Indeed, non-invasive imaging techniques are revolutionizing the understanding of diseases at the cellular and molecular levels. Among the current available imaging modalities, tomographic nuclear imaging approaches, especially positron emission tomography (PET), have demonstrated their significant importance and promising potential in applications of molecular imaging probes due to the superior sensitivity and specificity in diverse subjects, and the ability to quantitatively analyze the regions of interest. In collaboration with Dr. Dean Sherry, Dr. Sun's radiochemistry laboratory is interested in the design and in vivo evaluation of a series of hybrid agents featuring both radiometal bifunctional chelators and bisphosphonates (commonly used in the treatment of bone metastasis) for multi-modality (BLI/ MRI/SPECT/PET) detection of bone metastasis and the monitoring of radiotherapeutic/palliative treatment. Additionally, we are developing collaborations with the Advanced Imaging center to study intermediary metabolism by PET. One such project 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. In this project, Drs. Sherry and Sun will create novel PET and MR agents for molecular imaging of the b-cell in vivo with state-of-the-art imaging agent technologies. Prior to animal experiments, a platform will be developed for both high resolution MR and PET imaging of isolated rat islets and this technology will be used to screen for entrapped hypoxia 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 on isolated rat islets using a peptide (MSKSPEEGRATVQPSTQPHY) isolated from panning of glucose low-responding insulinoma INS 832/1 cells. With this, or similar peptides, either an 18F-labeled group or cyclen-based ligands will be added to the N-terminal amino position of all targeting peptides to create a library of targeted MR agents (both Gd3+ and PARACEST based) and targeted PET agents (both 18F and 64Cu) for measuring b-cell mass. In a related project, Dr. Sun's laboratory will synthesize [b-18F]-fluoropropionate as a tracer of pyruvate cycling for to test the hypothesis that [b-18F]-fluoropropionate will accumulate at significantly higher levels in -cells than a-cells. If the technique works in isolated islet experiments, it will then be quickly translated to in vivo studies in small animals. This is a relatively easy hypothesis to test and, if proven correct, could provide a powerful, convenient way to image b-cell function by PET. The ultimate aim is to create targeted and responsive MR and PET agents that not only report b-cell mass but also provide an imaging index of b-cell function. It is noteworthy that the UT Southwestern Medical Center has planned to purchase a cyclotron to facilitate PET imaging studies and radiotracer developments. Construction is nearly complete on the Advanced Imaging Research Center (AIRC), which will house a 2,000 sq ft space on the first floor designated for a comprehensive PET chemistry laboratory. Once complete, Dr. Sun's laboratory will occupy this new space and begin to work closely with the faculty of the AIRC on in vivo metabolism. A novel project of potentially high impact is to administer [1-11C]acetate and [2-11C]acetate simultaneously in an attempt to tease out in vivo fluxes intersecting in the TCA cycle. Preliminary modeling by Dr. Jeffrey indicate that by placing the label in both the C1 and C2 positions of acetate, the temporal pattern of 11CO2 generation will be sufficiently sophisticated for mathematical modeling to reveal metabolic fluxes such as citrate synthase. Preliminary experiment will be performed in rat hearts perfused with [1-11C]acetate and [2-11C]acetate, and the perfusate will be analyzed via the gamma counts for hot CO2 production. Unfortunately a synthetic route for [2-11C]acetate has not been reported, therefore Dr. Sun will develop a synthetic route for [2-11C]acetate production prior to experimentation (one does exist for [1-11C]acetate). Obviously, Dr. Sun will extend his research with 18F and 11C to other metabolic substrates once the cyclotron is in place, giving PET chemistry an active role in the collaborative projects supported by this Research Resource grant.
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