Feasibility study of ²²⁵Ac-PSMA-CY313 dosimetry in mCRPC patients using SPECT

Actinium-225 (²²⁵Ac)-labeled prostate-specific membrane antigen (PSMA) radiopharmaceuticals represent a promising therapeutic approach for metastatic castration-resistant prostate cancer (mCRPC), yet clinical implementation remains limited by the absence of accurate dosimetric assessment methods. The complex decay chain and non-imaging alpha emissions of ²²⁵Ac pose substantial challenges for quantitative imaging. We aimed to evaluate the feasibility of quantitative single photon emission computed tomography (SPECT)-based dosimetry for ²²⁵Ac-PSMA-CY313 therapy by exploiting gamma emissions from daughter radionuclides francium-221 (²²¹Fr) and bismuth-213 (²¹³Bi).

Four mCRPC patients received 185.8 ± 11.7 µCi ²²⁵Ac-PSMA-CY313 and underwent multi-timepoint SPECT/CT and whole-body planar imaging at 6, 24, 48, and 96 h post-injection. Quantitative SPECT reconstruction used ordered-subsets expectation-maximization with comprehensive corrections for attenuation, scatter, resolution blur, and crosstalk. Volume of interest were defined using co-registered ¹⁸F-PSMA-CY313 positron emission tomography /computed tomography (PET/CT). Time-activity curves were fitted with mono- or bi-exponential models, and absorbed doses were calculated using validated Monte Carlo-based software and International Commission on Radiological Protection reference phantoms.

High-quality quantitative imaging was successfully achieved across all timepoints. Among normal organs, kidneys and liver exhibited the highest absorbed doses (1.55 ± 0.38 Gy and 1.07 ± 0.19 Gy, respectively), corresponding to dose coefficients of 0.23 ± 0.07 Gy/MBq and 0.16 ± 0.03 Gy/MBq. Soft-tissue lesions exhibited higher absorbed doses than bone metastases (5.03 ± 5.51 Gy versus 1.61 ± 2.28 Gy), with corresponding dose coefficients of 0.73 ± 0.80 Gy/MBq and 0.25 ± 0.33 Gy/MBq. Tumor-to-critical organ dose ratios indicated favorable therapeutic windows, with red marrow showing the highest ratio (14.84), followed by adrenal glands (6.35) and salivary glands (4.96), while the dose-limiting kidneys demonstrated a ratio of 1.55.

Quantitative SPECT-based dosimetry for ²²⁵Ac-PSMA-CY313 therapy is clinically feasible using standard imaging systems. This methodology demonstrates preferential tumor targeting with acceptable organ-at-risk dose distributions, supporting the therapeutic potential of ²²⁵Ac-PSMA-CY313 for mCRPC and providing a practical framework for personalized dosimetry in targeted alpha therapy.