[²²⁵Ac]Ac-PSMA I&T: A Preclinical Investigation on the Fate of Decay Nuclides and Their Influence on Dosimetry of Salivary Glands and Kidneys

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 [²²⁵Ac]Ac-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 [²²⁵Ac]Ac-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: [²²⁵Ac]Ac-PSMA I&T demonstrated cell-binding characteristics and cellular retention similar to those of [¹⁷⁷Lu]Lu-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 [²²⁵Ac]Ac-PSMA I&T are similar to those of [¹⁷⁷Lu]Lu-PSMA I&T. The progeny of [²²⁵Ac]Ac-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.