Single photon emission computed tomography (SPECT) is the most versatile nuclear medicine imaging modality. In principle, it can image any radionuclide whose decay leads to photon emissions. There are more than 200 photon emitters with physics properties (half-life, photon energy and yield) appropriate for medical imaging using SPECT. In large part due to instrumentation constraints, only 12 or so are used in medicine. We propose to develop a SPECT system that will vastly expand the number of radionuclides that could be candidates for medical imaging. Our CZT-based system will double the range of imageable photon energies; improve the photon energy resolution and also the spatial resolution more than two-fold (1.5% vs 10% at 140 keV and 4 to 7 vs 10 to 15 mm respectively). The sensitivity will be increased more than 10-fold. Current SPECT imaging technology does not meet the clinical demands of recent and potentially transformative advances in radiopharmaceutical therapy, theranostics and precision medicine. These clinical advances require imaging that is rigorously quantitative, has a high spatial resolution and can simultaneously image more than one radionuclide. These capabilities must be offered at a fraction of current imaging times. We have chosen design specifications for the device to meet the highly demanding imaging needs of radiopharmaceutical therapy with alpha-particle emitters (αRPT). Alpha-emitters decay via a complex scheme that includes multiple daughters; the agents are incredibly potent such that treatment is effective at sub GBq administered activity levels. Dosimetry and, therefore quantitative accuracy at high spatial resolution is essential. We will build and characterize the “alpha- SPECT” camera via the following specific aims: 1. Develop a large area 3-D CZT imaging-spectrometer that is capable of providing an unprecedented energy resolution; this detector platform will be the basic building block for alpha-SPECT. 2. Combine the CZT-based detection system with a synthetic compound-eye gamma camera design to achieve a compact detection system with ultrahigh resolution over a wide field of view in a 45 cm diameter ring. 3. Develop quantitative multi-isotope reconstruction methods that are tailored to the high performance capability of Alpha-SPECT. 4. Evaluate system performance in phantoms and in large animal preclinical studies. 5. Use the system for lesion and normal tissue dosimetry in metastatic prostate cancer patients treated with Radium-223 (Xofigo). The proposal is founded on a partnership of unparalleled instrumentation development capability (Dr. Meng), coupled with cutting-edge capability in implementing advanced algorithms for multi-dimensional image generation (Drs. Frey and Du) that will be applied to the dosimetry demands (Dr. Sgouros) of a new and promising treatment that delivers highly potent radiation to disseminated cancer cells. Beyond the specific clinical scenario that is driving the proposed applica...