Framework for subcellular localization of alpha emitting radionuclides

OBJECTIVE: Accurate assessment of radionuclide distributions at the cellular and subcellular scales is essential for targeted alpha therapy, as cell-scale dosimetry is needed due to the short range of alpha particles. Although radioluminescence microscopy (RLM) enables optical visualization of alpha particle tracks, single-focal plane imaging cannot reliably localize decay origins due to oblique particle trajectories and the lack of depth information. This study aims to establish a multifocal RLM-based framework for quantitative localization of alpha emitting radionuclides. Approach: A multifocal RLM system was modeled using Monte Carlo simulations (OpenTOPAS), incorporating alpha particle transport, scintillation photon generation, and ray tracing-based image formation. Simultaneously acquired RLM images at two focal planes within a GAGG:Ce scintillator were generated. A reconstruction pipeline was developed to localize decay origins by extracting track centroids in each focal plane, matching corresponding tracks between planes based on spatial and intensity criteria, and extrapolating inferred trajectories to estimate emission positions. The framework was evaluated for monoenergetic alpha particles (4-8 MeV) and for 225Ac decay chains under secular equilibrium, including uniformly distributed and cell-confined source configurations. Main results: For monoenergetic sources, the proposed approach achieved detection rates exceeding 85% for alpha energies representative of 225Ac daughters, with spatial resolution near 2 µm. Under 225Ac decay chain conditions, median lateral localization errors of approximately 1-2 µm were obtained at activity levels up to 0.2-0.4 kBq per cell, which are relevant to targeted alpha therapy studies. The results further revealed trade-offs between detection efficiency, source density, and particle energy, providing quantitative guidance for experimental design. Significance: This study demonstrates the feasibility of multifocal RLM as a quantitative framework for micrometer-scale localization of alpha-emitting radionuclides. By extending conventional RLM from qualitative track visualization to decay origin estimation, the proposed approach provides a physical foundation for experimental validation of subcellular radionuclide distributions.