Comparable daughter radionuclide redistribution with superior tumor absorbed dose of the SSTR2 antagonist [ 225 Ac]Ac-SSO110 versus [ 225 Ac]Ac- DOTA-TATE

Abstract It has been hypothesized that effective cellular internalization is required for the retention of 225 Ac daughter radionuclides. The complex decay chain of 225 Ac and recoil-mediated release of daughters, particularly 213 Bi (half-life (t 1/2 ) = 46 min), raise concerns about redistribution that may reduce tumor absorbed dose (TAD) and increase off-target radiation exposure. Because somatostatin receptor subtype 2 (SSTR2) antagonists such as SSO110 are not internalized, it has been proposed that the daughter radionuclides are less effectively retained compared to internalizing agonists such as DOTA-TATE. We therefore performed a direct and quantitative comparison of daughter radionuclide redistribution following administration of [ 225 Ac]Ac-SSO110 and [ 225 Ac]Ac-DOTA-TATE. Methods Biodistribution and 213 Bi redistribution were evaluated in Balb/c nude mice bearing NCI-H69 small cell lung cancer xenografts. Repeated gamma counting combined with bi-exponential modeling was used to quantify 225 Ac and 213 Bi activity in tumor, blood, bone marrow, kidneys, liver, and intestines up to 96 h post-injection. TAD was calculated with and without accounting for experimentally-derived 213 Bi redistribution. Real-time in vitro binding assays were conducted to characterize cellular retention of [ 225 Ac]Ac-SSO110. Results [ 225 Ac]Ac-SSO110 demonstrated higher tumor uptake and prolonged retention compared with [ 225 Ac]Ac-DOTA-TATE, resulting in a 1.9-fold higher tumor-to-kidney ratio at 96 h and a 2.8-fold higher TAD. Redistribution of 213 Bi from tumor was minimal and comparable between agonist and antagonist, with maximum tumor loss of 3.5% for [ 225 Ac]Ac-SSO110 and 2% for [ 225 Ac]Ac-DOTA-TATE. Accounting for daughter redistribution reduced TAD by less than 5% for both radioconjugates. No sustained 213 Bi accumulation was observed in blood, kidneys, or liver, and only minimal activity was detected in bone marrow and intestines. Real-time binding studies demonstrated sustained cell-associated β - signal following incubation with [ 225 Ac]Ac-SSO110. Conclusion Receptor-mediated internalization is not required for effective retention of 225 Ac daughter radionuclides. Despite negligible internalization, [ 225 Ac]Ac-SSO110 achieved superior TAD and higher tumor-to-kidney ratio without increased daughter redistribution compared with the internalizing agonist [ 225 Ac]Ac-DOTA-TATE. These findings question the necessity of internalization for daughter retention and support further evaluation of antagonist-based 225 Ac radioligand therapy.