Project Summary Breast cancer is the most diagnosed cancer among American women and is projected to become the most common cancer globally in 2021. To minimize the morbidity and mortality of this disease, it is imperative to develop improved testing methods to enable more effective treatment. The proposed work is to develop a new Single Photon Emission Breast Tomography (SPEBT) scanner to carry out radionuclide tracer based molecular breast imaging which has demonstrated clear advantages in the early detection of cancer malignancy in clinical trials, because of its 1) capability to detect pathological functional changes which take place before morphological anatomical developments and 2) up-to pico-mole sensitivity, which stems from collecting signals directly at the molecular level. The SPEBT system will have a system detection efficiency of 3.5×10-2 and spatial resolution of 2-mm, which are 50 and 2 times better than that of state-of-the-art dedicated single photon emission molecular breast imaging cameras, respectively. The significant imaging performance improvement will ease existing concerns on radiation dose and the inability to detect tumors of less than 5-mm in size — issues that have prevented molecular breast imaging from playing a much more prominent role in clinical breast cancer diagnosis and screening. The enabling concept behind the high-performance of the SPEBT is a novel detector architecture, a three-dimensional sparse position-sensitive detector, that achieves collimation largely by and for itself, which is termed self-collimation. This architecture allows the SPEBT to achieve both high-resolution and high detection efficiency. This is a critical conceptual breakaway from the mechanical-collimator-based detector structure that single-photon emission imaging technology relies on for years — mechanical collimator mandates an inverse interdependency between the resolution and detection efficiency, therefore, sets a hard ceiling for overall imaging performance. The proposed approach opens up a broad path to better imaging performance for breast and other imaging applications. The proposed project is to design and evaluate a SPEBT system with optimized configurations and develop and test a proof-of-concept SPEBT prototype.