? For cellular and molecular imaging to gain clinical utility beyond the standard probes used in nuclear medicine and the few experimental trials that employ super-paramagnetic nanoparticles, a practical, biocompatible system that employs signal amplification to improve sensitivity is needed. Use of gene reporter/probe systems is becoming recognized as the best way not only to track the movement or activation of cells but also to study protein-protein interactions and other aspects of signal transduction non-invasively. A survey of the field shows that the gene reporter/probe systems that have been developed to date lack either bio-compatibility due to immunogenicity, suffer from relatively low sensitivity, are already widely expressed throughout normal tissues endogenously or are incapable of reliably sequestering the imaging agent within the cell in a high-affinity interaction. For those reasons we have chosen to embark upon a focused, interdisciplinary program to build and test a sensitive, multimodality gene reporter/probe system based on the prostate specific membrane antigen (PSMA). PSMA is ideally suited to becoming a gene reporter/probe system because it is a human, transmembrane protein that has a highly restricted expression pattern, which will limit background signal, and because the corresponding optical, magnetic resonance and nuclear imaging probes are remarkably simple to synthesize. Most germane to this application, however, is the fact that PSMA possesses enzymatic and transporter activities, and we intend to exploit those features to develop a high-sensitivity reporter/probe system. Specifically, we will 1) construct a dual enzymatic plasmid that will produce firefly luciferase concurrently with PSMA, 2) synthesize select, fluorescent, high-affinity probes to PSMA, 3) prepare enzymatic PSMA-based reporter substrates that will be both fluorescent and radioactive and 4) validate this system in vitro and in vivo. Because the high-affinity probes do not serve as substrates, we will be able to compare their ability to those of the enzymatic probes for detection of cellular events, essentially producing a variety of probes with different pharmacokinetics and sensitivities for different indications. We believe that the PSMA gene reporter/probe system will represent a clinically translatable alternative to those that currently exist and that because of the enzymatic and transporter capabilities of PSMA, the system will also be of significantly enhanced sensitivity. ? ?
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