Comparable daughter radionuclide redistribution with superior tumor absorbed dose of the SSTR2 antagonist Ac-DOTA-TATE

It has been hypothesized that effective cellular internalization is required for the retention of 225Ac daughter radionuclides. The complex decay chain of 225Ac and recoil-mediated release of daughters, particularly 213Bi (half-life (t1/2) = 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 [225Ac]Ac-SSO110 and [225Ac]Ac-DOTA-TATE. MethodsBiodistribution and 213Bi 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 225Ac and 213Bi 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 213Bi redistribution. Real-time in vitro binding assays were conducted to characterize cellular retention of [225Ac]Ac-SSO110. Results[225Ac]Ac-SSO110 demonstrated higher tumor uptake and prolonged retention compared with [225Ac]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 213Bi from tumor was minimal and comparable between agonist and antagonist, with maximum tumor loss of 3.5% for [225Ac]Ac-SSO110 and 2% for [225Ac]Ac-DOTA-TATE. Accounting for daughter redistribution reduced TAD by less than 5% for both radioconjugates. No sustained 213Bi 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 {beta}- signal following incubation with [225Ac]Ac-SSO110. ConclusionReceptor-mediated internalization is not required for effective retention of 225Ac daughter radionuclides. Despite negligible internalization, [225Ac]Ac-SSO110 achieved superior TAD and higher tumor-to-kidney ratio without increased daughter redistribution compared with the internalizing agonist [225Ac]Ac-DOTA-TATE. These findings question the necessity of internalization for daughter retention and support further evaluation of antagonist-based 225Ac radioligand therapy.