Prostate cancer is the most commonly diagnosed cancer in males and the second leading cause of cancer- related death among men in the United States. Unfortunately, no curative treatment exists for metastatic prostate cancer. Early diagnosis of prostate cancer followed by prompt surgical removal provides patients the best opportunities for cures or prolonged survivals. Current ProstaScint(R) SPECT (single photon emission computed tomography) and [18F] FDG (2-[18F] fluoro-2-deoxy-D-glucose) PET (positron emission tomography) imaging have limited use by lack of specificity. Novel receptor-targeting diagnostic and therapeutic agents are urgently needed to improve the detection accuracy and enhance the therapeutic efficacy of prostate cancer. Our strategy to improve the detection accuracy and enhance the therapeutic efficacy of prostate cancer focuses on developing novel theranostic (diagnostic & therapeutic) 177Lu-labeled gonadotropin-releasing hormone (GnRH) peptides to target the GnRH receptors (GnRHRs). GnRHR is a distinct target in this project for developing effective prostate cancer-specific imaging probes due to its over-expression on human prostate cancer cells and specimens, and dramatic low expression on healthy prostate cells and no expression on most normal tissue cells. Recently, we have firstly identified a novel GnRH peptide {111In-DOTA-Ahx-(D-Lys6-GnRH)} as an imaging probe for human prostate cancer detection. Very recently, we found that the introduction of D- Phe dramatically improved the GnRHR binding affinity of DOTA-D-Phe-Ahx-(D-Lys6-GnRH) (7.6 nM) by 4.8- fold as compared to DOTA-Ahx-(D-Lys6-GnRH) (36.1 nM). In this project, we will perform structure-activity relationship (SAR) studies to identify more potent 177Lu-labeled GnRH peptides for prostate cancer imaging and therapy based on the unique DOTA-D-Phe-Ahx-(D-Lys6-GnRH) construct. Specifically, we will synthesize and evaluate 8 novel GnRH peptides with neutral hydrocarbon and amino acid linkers in vitro and in vivo. We hypothesize that the GnRH peptides can specifically bind the GnRH receptors and target theranostic radionuclide (177Lu) to human prostate cancer cells for prostate cancer imaging and therapy. Our positive preliminary results strongly support our hypothesis and research design. Importantly, we have assembled a strong multidisciplinary research team with established expertise that is uniquely suited to carry out this exciting translational project. The success of this project will provide a new insight into the design of novel theranostic agents for prostate cancer detection and treatment, as well as open the avenue of treating human prostate cancer with low-energy beta-radiation (177Lu), high-energy beta-radiation (90Y) and alpha- radiation {212Pb/212Bi and 213Bi} in the future (future directions), providing patients with personalized therapeutic agents to meet individual need (i.e. tumor size or metastases). Identification of novel theranostic peptides promoted by this project will pave the way for evaluation of this novel class of peptides in US FDA-approved clinical trials in the future, enhancing the opportunities of cures to patients with metastatic prostate cancer.