This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. My lab focuses on the development of new radiopharmaceuticals and new MR contrast agents to detect and characterize common clinical conditions. There are three major efforts. First, the development of non-invasive imaging methods for early diagnosis of beta cell associated metabolic diseases, including type 1 and type 2 diabetes (T1D and T2D), has recently drawn interest from the molecular imaging community and clinical investigators. Due to the challenges imposed by the location of the pancreas, the sparsely dispersed beta cell population within the pancreas, and the poor understanding of the pathogenesis of the diseases, clinical diagnosis of beta cell abnormalities is still limited. Thus, 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. It is noteworthy that 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. Second, bone lesions in metastatic cancer are common. This project is focused on the synthesis of novel macrocyclic bone-seeking agents with methylenephosphonate or bisphosphonate motif and their applications to noninvasive imaging of bone metastases. Currently the diagnostic imaging of bone metastases is commonly performed with 99mTc-MDP (methylene bisphosphonate). Due to the lack of high specificity and sensitivity, 99mTc-MDP bone scan is often aided by other imaging modalities, such as radiography, MRI, CT, PET scans, and/or bone marrow biopsy, for a final diagnosis. Recent pharmacological investigations have revealed that the mechanism of bisphosphonate anti-resorption effects on bone metastases involves two steps: bisphosphonates bind to hydroxyapatite bone mineral surface and subsequently are internalized by osteoclasts selectively where they inhibit the osteoclastic activity. The long retention of bisphosphonates with hydroxyapatite in the first step of the mechanism limits the specificity and sensitivity of a 99mTc-MDP bone scan for early detection of bone metastases due to the limited in vivo stability of the complex and the short half-life of 99mTc (t1/2 = 6.01 h). Based upon the pharmacological mechanism of bisphosphonates, we propose to address the hypothesis that the sensitivity and specificity of bone metastasis detection will be significantly improved if bone-seeking macrocyclic tetraamine complexes can be utilized for multimodality imaging diagnosis of bone metastases . It is well-known that macrocyclic chelators form kinetically more stable metal complexes than acyclic ligands.
The specific aims are proposed as follows: 1) To synthesize and characterize bone-seeking macrocyclic chelators with a methylene-phosphonate or bisphosphonate motif and investigate their coordination chemistry with Cu(II), Lu(III), and Gd(III). 2) To prepare and evaluate 64Cu and 177Lu labeled complexes as PET/SPECT imaging agents specifically for the detection and in situ monitoring of bone metastases Third, we are investigating new methods to image prostate cancer. The goal of this project is to synthesize and characterize PSMA-targeted nano-conjugates;evaluate in vivo behavior of the nanoconjugates in normal and prostate tumor bearing mice;and apply the nanoconjugates to noninvasive MRI/PET imaging of prostate cancer. In the United States, prostate cancer (PCa) has been consistently the second leading cause of cancer-related deaths of men. Therefore it is of great significance to develop new techniques for the non-invasive detection of PCa with high sensitivity and specificity. However, the most commonly used PET radiopharmaceutical, 18F-FDG, is not quite successful at identifying PCa (until PCa becomes metastatic) as it is in the detection of other tumors because of the low glycolytic rate of PCa and high background due to the normal excretion of 18F-FDG through urine. To date, the role of PET in prostate cancer has not been established. The goal of this proposal is to explore a new approach that will combine the advantages of MRI and PET for the diagnostic imaging and staging of PCa. We propose to dope positron-emitting isotopes to superparamagnetic iron oxide nanoparticle to make nanosized dual MRI/PET probes for the detection of PCa by multi-modality (anatomical MRI plus functional PET) molecular imaging approaches, so that the sensitivity and specificity of PCa diagnosis could be significantly improved. In this proposal, we choose arsenic-74 due to its low endpoint positron energy (0.94 MeV) that provides higher spatial resolution of PET, and its relatively long half-life (17.77 days) that allows us to carry out the procedures of making the dual-modality imaging probes. In perspective, the long half-life also allows global delivery of such imaging probes. Two prostate specific membrane antigen (PSMA) targeting molecules (a new PSMA monoclonal antibody and a novel PSMA-targeting RNA aptamer) will be used to construct the PSMA-targeted nano-conjugates. Three animal models (intra-femoral, subcutaneous, and orthotopic) using two prostate cancer cell lines, C4-2 and PC-3 cells, will be used for the imaging probe evaluations in this proposal, because C4-2 is an androgen responsive cell expressing PSMA and PC-3 is PSMA-devoid AIPCa cell that will serve as negative control.
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