α-therapy with 225Ac-labeled radioligands targeting prostate-specific membrane antigen (PSMA) has emerged as a promising treatment option for advanced metastatic castration-resistant prostate cancer. Because of α-recoil, the progeny is released from the PSMA-targeted molecule and can undergo redistribution, contributing to off-target toxicity. Here, we report on biodistribution and dosimetry studies of 225AcAc-PSMA I&T performed in mice to investigate the pharmacokinetics of the radioligand compared with unbound progeny. Moreover, the cellular uptake and externalization kinetics of 225AcAc-PSMA I&T were compared with those of its 177Lu-labeled analog. Methods: In vitro studies were performed on LNCaP and PC3 PIP cells. Biodistribution studies (performed 10 min to 7 d after injection) were conducted in LNCaP tumor–bearing and healthy mice. Equilibrium uptake was determined 24 h after dissection by quantification of 221Fr (218 keV) and 213Bi (440 keV). Tissues of interest (kidneys, salivary glands, and tumor tissue) were measured immediately after dissection until reaching equilibrium to determine the time-dependent activity distribution of 221Fr and 213Bi. Absorbed doses were calculated using MIRDcalc, assuming decay of the progeny at the site of the first decay versus taking into account redistribution of unbound progeny. Results: 225AcAc-PSMA I&T demonstrated cell-binding characteristics and cellular retention similar to those of 177LuLu-PSMA I&T. In biodistribution studies, no redistribution of 221Fr and 213Bi was measured from tumor tissue. Higher uptake of 213Bi was found in the kidneys (2-fold higher at 10 min and at 1 h after injection) and salivary glands (1.7-fold and 8.5-fold higher at 10 min and 1 h after injection, respectively) at the time of death compared with equilibrium. This contribution increased the absorbed dose in the kidneys and salivary glands by a factor of 1.3 and 2.5, respectively, assuming uptake of 221Fr and in situ formation of 213Bi. Conclusion: The PSMA-targeting characteristics and pharmacokinetics of 225AcAc-PSMA I&T are similar to those of 177LuLu-PSMA I&T. The progeny of 225AcAc-PSMA I&T is trapped in tumor tissue. Uptake of liberated decay products into the salivary glands and kidneys was identified as an additional factor explaining the increased side effects of 225Ac therapy compared with 177Lu-based radioligands.
Wurzer et al. (2025) studied this question.