Project Summary The long-term goal of this project is to develop a theranostic (for both diagnosis and therapy) agent targeting neurotensin receptor 1 (NTSR1) for prostate cancer management. Prostate cancer is the second-leading cause of cancer deaths for men in the United States. Approximately 1 in 9 men will be diagnosed with prostate cancer in their lifetime. Despite recent developments in its diagnosis and treatments, the advanced stages of prostate cancer still have poor survival rates. In fact, patients with advanced stage prostate cancer may initially respond to hormone therapy with more than 90% rate, but they could relapse into the hormone-refractory state and generally die within 3 years. Clearly, this urgent unmet need warrants further exploration of clinically relevant molecular targets for patient screening, detection of metastatic disease, and corresponding treatment strategies. Accumulating evidence suggests that neurotensin (NTS) and neurotensin receptors (NTSRs) play key roles in prostate cancer progression. In our recent histology analysis, all examined PSMA-negative prostate cancer tissues were found to have positive NTSR1 expression, suggesting the potential complementary role of NTSR1 targeted imaging/therapy towards PSMA based imaging/therapy. In another word, NTSR1 targeted therapy could be used when PSMA targeted therapy fails. In this project, AccuNovo Biotech Inc. will partner with Profs. Zibo Li and Rihe Liu at UNC Chapel Hill to develop new theranostic agents targeting NTSR1 based on the recent progress on ligand discovery. Recently, we found that the introduction of crosslinked polyamines into SR142948A (leading to new agent SR-CP-05) could increase the tumor uptake by 10 times compared with peptide-based agent. This discovery offered us an unprecedented opportunity to develop NTSR1 targeted theranostic agents. We will focus on imaging agent development in Phase I. The specific aims of this proposal are: Aim 1: Develop 64Cu labeled NTSR1-targeting PET agents with high and persistent tumor uptake; Aim 2: Perform side-by-side comparison of lead agents in prostate cancer mouse models and select the best agent for Phase II efficacy study. The success of this project will not only lead to an accurate imaging-based method to efficiently detect NTSR1 expression in prostate cancer (for patient screening and treatment monitoring), but also be further developed into a radionuclide-based agent for prostate cancer therapy.