BEST IN PHYSICS (RADIOPHARMACEUTICALS): Quantitative Decay-Chain-Resolved Autoradiography Enables Microscale Assessment of ²²⁵Ac Daughter Redistribution In Tissue
Abstract
Purpose
Redistribution of radioactive daughters following ²²⁵Ac decay is a major dose-limiting uncertainty in α-emitter radiopharmaceutical therapy (αRPT). Free daughter species may diffuse from their site of origin, yet their microscale fate within tissue remains poorly understood and may influence normal-organ toxicity and intratumoral dose redistribution. We present a quantitative, decay-chain-resolved autoradiography (AR) framework for spatially resolving ²²⁵Ac parent and daughter contributions.
Methods
Ex vivo tissue sections from mice treated with ²²⁵Ac-based αRPT were imaged using an iQID AR device operated in list mode, recording spatial coordinates and detection times of individual α events. Event timestamps were analyzed using an unbinned Poisson mixture model to achieve pixel-wise separation of ²²⁵Ac equilibrium chain activity and free ²¹³Bi contributions without temporal binning. Performance was benchmarked against a conventional least-squares (LS) fit applied to time-binned activity histograms using simulated datasets with known ground truth.
Results
In simulation studies, time-binned LS fitting exhibited systematic bias and inflated variance under low-count conditions, whereas list-mode decomposition provided low-bias, low-variance estimates of both free ²¹³Bi and total decay-chain activity. Applied to in vivo mouse tissue, decay-chain-resolved AR revealed microscale spatial divergence between parent (²²⁵Ac) and daughter (²¹³Bi) activity that is not apparent in time-integrated imaging. In representative kidney sections, parent and daughter maps exhibited clearly distinct spatial distributions, providing direct experimental evidence of microscale daughter redistribution. Similar spatial divergence was observed in tumor tissue.
Conclusion
Decay-chain-resolved AR imaging using list-mode iQID detection provides a direct experimental method to assess ²²⁵Ac daughter redistribution at the microscale, addressing a central uncertainty in αRPT dosimetry and toxicity modeling. This framework enables robust separation of parent and daughter contributions under realistic low-count conditions and establishes a new experimental basis for understanding dose redistribution in α-emitter therapies.