The major hypothesis guiding this research is that modular low- molecular weight ligands, specific for the surface of prostate epithelial cells, will be clinically useful reagents for prostate cancer. As prostate-targeting agents, low-molecular weight (less than or equal to 1,100 M.W.) ligands offer several advantages including rapid biodistribution, excellent tissue/tumor penetration, and ease of conjugation to imaging reagents. The long range goal of this research is to improve prostate cancer detection, and guided therapy, by developing novel radiocintigraphic and magnetic resonance imaging (MRI) reagents. The R21 phase of the proposal describes a phage display screening approach for finding prostate-and prostate cancer-specific ligands. Some ligands will be directed against two previously described prostate-specific cell surface proteins, prostate- specific membrane antigen (PSMA) and prostate stem cell antigen (PSCA). The R21 proposal also describes a phage display screening approach to find ligands with differential binding to metastatic prostate cancer cells over normal prostate epithelial cells. The final phase of the R21 focuses on using peptide libraries incorporating D- and unnatural amino acids to optimize ligands for biochemical properties such as solubility, protease- resistance and modularity. Modularity should permit conjugation of prostate-specific ligands to contrast agents for nuclear medicine and MRI scanning, without loss of prostate-specific binding. The R33 phase of the proposal aims to create, and to optimize, novel imaging reagents by conjugation of radiopharmaceuticals (for radioscintigrpahy) and ferromagnetic particles (for MRI) to the prostate-specific, low-molecular weight ligands developed during the R21. A systematic development scheme including in vitro optimization, in vivo biodistribution and pharmacokinetics, and in vivo three-dimensional imaging is described. Prostate cancer models in rats, and normal prostate models in dogs, will be imaged in vivo by nuclear medicine and Mri approaches. In collaboration with industry, we describe two new 3T-compatible endorectal coils, one of which permits image-guided biopsy of the prostate. In conjunction with the novel imaging reagents, these coils should permit improved contrast of the prostate gland, and should permit analysis of aging-related effects on the performance of our technology. We believe that prostate- specific, low-molecular weight ligands will someday be clinically useful reagents for improved prostate cancer detection and guided therapy.
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