Abstract
252094
Introduction: The clinical translation of radiopharmaceutical therapy (RPT) necessitates a preclinical evaluation of the radioactive agent's safety and efficacy, incorporating imaging and dosimetry techniques. However, for certain isotopes, such as pure beta emitters and many alpha emitters (e.g., 90Y and 225Ac), accurate preclinical imaging and dosimetry are challenging due to their minimal gamma emissions, which reduces their suitability for precise activity quantification using μSPECT/PET imaging. Cherenkov radiation, generated by high-energy beta emitters or alpha daughter decay products, can be visualized with standard small animal bioluminescence imagers, providing a widely accessible method for imaging difficult isotopes. This study aims to develop and validate a quantitative in vivo activity measurement framework based on Cherenkov radiation, utilizing 86Y as a model isotope to compare activity quantification between PET and Cherenkov imaging across two murine models.
Methods: A well plate phantom with varying 86YCl₃ activities (0–50 μCi) was imaged through different depths (0-10mm) of an intralipid/blood mixture to create a calibration curve correlating radiance, activity, and tissue depth. In the first murine model, athymic nude mice (n=4) intravenously received 100 μCi of 86Y in ammonium acetate buffer. Serial PET/CT and Cherenkov luminescence (CL) images were obtained at 1-, 24-, and 48-hours post-injection. In the second murine model, tumor-bearing mice (n=4) with MC38 colorectal right-flank tumors intravenously received 250 μCi of 86Y-NM600, an alkylphosphocholine analog targeting MC38 cells, with imaging at 3-, 24-, 48-, and 96-hours post-injection. Relevant organs were contoured on the CTs at each timepoint, and the average depth of each organ was calculated. CL images were registered to each CT. Deconvolution using Geant4-generated Cherenkov point spread functions minimized signal diffusion, and organ-specific signals were isolated and quantified using the CT contours and depth dependent calibration coefficients.
Results: The phantom study showed a linear calibration response with depth (slope: –615.3 p/sec·cm²·sr·μCi·mm; bias: 9763.8 p/sec·cm²·sr·μCi). In the first mouse cohort, free 86Y localized to the kidneys and skeleton, with PET-CL activity estimation differences of 16.4% (kidneys) and 14.7% (femurs) at the earliest timepoint, increasing to 113.5% and 38.1% by the third timepoint due to reduced absolute activity. In the tumor-bearing mice, 86Y-NM600 localized to tumors and liver, with CL and PET liver activity differing by 7.7% on average across the first three timepoints but rising to 182% at the last due to low liver activity and Cherenkov background. Cherenkov-measured tumor activity was on average 32% greater than the PET value but maintained proportionality throughout all mice and timepoints. Although Cherenkov-based activity quantification diverges from PET measurements at later timepoints, the small absolute differences in activity are unlikely to significantly impact dose calculation.
Conclusions: Quantitative Cherenkov luminescence imaging presents a promising alternative for tumor and normal tissue dosimetry of hard-to-image isotopes in preclinical research. Despite challenges posed by irregular tumor geometries, CLI shows strong agreement with PET and holds significant potential as a dosimetry tool to advance the preclinical development of novel pure beta and alpha emitting radiopharmaceuticals.
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