In Vivo 3-D Multi-Isotope Autoradiography of Radiopharmaceutical Therapy - Abstract: Radiopharmaceutical therapy (RPT) is a highly effective cancer treatment, especially for metastatic cancers. There is significant interest in developing novel radiopharmaceuticals labeled with β-emitters (βRPT) or α-emitters (αRPT) for various cancer types. Due to the limited range of α-particles and the low energy of β-particles, it is crucial to measure the distribution of these radiopharmaceuticals at a microscale level within the organs and tumor anatomy of small animals, commonly used for studying RPT toxicity and efficacy. For example, while the full liver and kidneys may serve as sources and targets in the regular dosimetry schema for intermediate-to-high energy βRPT, more relevant sources for αRPT and low-energy βRPT might be the blood sinuses in the liver lobules or individual glomeruli in the kidney nephrons. Associated targets could include the central Kupffer cells or the convoluted proximal tubules, respectively. Conversely, tumor morphology is intricate, involving cells at different stages of the cell cycle, each potentially associated with distinct target densities and distributions for radiopharmaceuticals. Current imaging technology lacks the capability to convey high-resolution information on in vivo radioactivity distribution, necessitating the acquisition of data through ex vivo methods. Importantly, these methods also lack the ability to provide real-time mapping of the distribution of RPTs and their kinetics in living animals. In this project, we propose to develop a hyperspectral single-photon emission microscope system, named Alpha-Scope, for in vivo 3D autoradiography of radiopharmaceuticals and the radioactive daughter radionuclide in small animals. The Alpha-Scope system utilizes a novel CZT imaging spectrometer, offering excellent intrinsic detector resolution and unprecedented energy resolution over a wide energy range of 30-600 keV. This allows for effective separation of the γ-ray and x-ray peaks from therapeutic radionuclides and most of their radioactive daughters. The advanced detector hardware will be combined with a novel synthetic compound eye gamma camera design to provide ultrahigh sensitivity while allowing simultaneous imaging of multiple radionuclides at an excellent imaging resolution of 100 μm. Furthermore, we will develop a novel approach that leverages predicted posterior estimates and incorporates data fidelity corrections to handle high-noise data. The new imaging system will be validated through phantom experiments and small animal studies using αRPT currently under investigation at JHU. The outcome of this project will yield an unprecedented imaging tool crucial for the development and comprehension of novel RPTs. As specified in the STRIPE FOA, this tool will be particularly valuable for examining target efficacy, studying microdosimetry, and understanding radiobiological effects on both normal tissues and tumors, facilitating treatment optimization.
