Prostate cancer (PCa) is one of the most important health issues facing the male population. In both the United States and Europe, it is the most common form of cancer in men and is currently the second most common cause of cancer death in men. Prostate-specific antigen (PSA) testing and trans-rectal ultrasound (TRUS) examination allow early detection of PCA; however, neither exam is very specific and most patients require trans-rectal biopsy for confirmation and staging of the disease. However, biopsy is invasive and is susceptible to sampling errors. Further if after initial biopsy, the diagnosis is considered low risk, the patient is put on active surveillance that may require biopsy follow-up on a fairly regular basis. Thus, the long term goal of this project is to develop imaging technology that will replace biopsy as the gold standard for PCa diagnosis and staging. The optimism for an imaging based PCa biomarker is being driven by the recent development of a number of highly targeted positron emission tomography (PET) tracers for PCa cells. The goal of this project is to develop advanced PET detector imaging technology that will enable the development of moderate cost, high image resolution, prostate specific PET imaging systems. A two curved panel detector geometry will be utilized. To support artifact-free prostate imaging, the panel detectors will support time-of-flight (TOF) PET imaging with a goal of <150 psec coincidence timing resolution. In addition, the imaging system will support <1.5 mm full width at half maximum (FWHM) image resolution. To accomplish this goal, a hybrid PET (HyPET) detector will be developed with sub-units that will meet or exceed the overall design goals. Each HyPET detector will consist of two independent detector layers. The front layer will be optimized for coincidence timing resolution (i.e., <150 psec). The rear detector will be optimized for intrinsic spatial resolution, depth of interaction (DOI) positioning resolution and detection efficiency. It will utilize a monolithic crystal detector design. Using numerical and anthropomorphic digital phantoms realistic uptake distributions will be simulated to optimize the design of HyPET detectors and system geometry. Prototype HyPET detectors based upon the optimum design configurations derived from the simulation studies will be fabricated and tested for coincidence timing resolution, intrinsic and coincidence spatial resolution, energy resolution and detection efficiency. In addition, a tailored Penalized Weighted Least Squares image reconstruction approach using the <150 psec TOF data to create an image prior and optimized weighting of all the different types of hybrid coincidence data will be developed and optimized to provide high resolution, artifact-free images. At the end of this project, a novel hybrid PET detector will have been designed and tested to support the development of a high performance, panel-based, prostate specific, PET imaging system. While the detector and system geometry will be optimized for prostate cancer imaging, the tools and basic HyPET detector concept will be in place to design similar systems for other organs and/or pathologies (e.g., PET imager for rheumatoid arthritis or breast imaging).