Project Abstract Widely overexpressed in prostate cancer tissues, Prostate Specific Membrane Antigen (PSMA) has become an attractive target for both imaging and radionuclide-based therapy of prostate cancer. Despite exciting progress, PSMA-targeted therapeutic agents could pose high radiation exposure toward normal organs that express the receptor. In fact, salivary glands (SGs) are often the dose-limiting organ that determines how much radioactivity can be administered, patient eligibility, and the treatment outcome thereafter. This application addresses critical needs to reduce radiation exposure to normal organs while maintaining tumor uptake. We therefore focus on constructing PSMA derivatives aiming to protect SGs from these radiolabeled agents. In recent years, tremendous excitement has emerged over probes that can be diagnostic and therapeutic (Theranostics). These agents not only can reveal disease sites but also emit radiation that can have therapeutic effects, enabling localized and targeted treatments. Recently, the UNC team has established a trifunctionalized TVS system to streamline the workflows to develop theranostic agents (patent pending and Tripill Biotech is negotiating with UNC to license the technology). In our preliminary research, we have discovered that NOTA- UNC-PSMA2 can demonstrate 2-3 times higher tumor uptake in rodent models (compared with PSMA-617), while the SG uptake is only 1/10th of PSMA-617 at 24 h post-injection in non-human primates (NHP), potentially due to the cation binding ability of the TVS system. These encouraging results clearly demonstrated the feasibility of selectively reducing SG uptake with minimal impact on tumor uptake of PSMA-positive tumors. With the promising imaging component completed in preliminary research, in this project, Tripill Biotech will partner with Prof. Wu to validate the therapeutic potential of NOTA-UNC-PSMA2. The resulting agents will be labeled with 64Cu and 67Cu, and evaluated for stability, PSMA binding affinity, salivary gland uptake, and in vivo therapeutic efficacy. This application reflects a joint effort from a multidisciplinary team composed of experts in chemistry, drug delivery, radiochemistry, biology, clinical practice, and molecular imaging. The success of the proposed approach would solve key issues in PSMA-targeted radiotherapeutics (in this case exposure to SGs), which could greatly benefit prostate cancer management.