Comparable Daughter Radionuclide Redistribution with Superior Tumor Absorbed Dose of the SSTR2 Antagonist [225Ac]Ac-SSO110 Versus [225Ac]Ac-DOTATATE.

Abstract

It has been hypothesized that effective cellular internalization is required for the retention of 225Ac daughter radionuclides. Both the complex decay chain of 225Ac and the recoil-mediated release of daughters, particularly 213Bi (half-life, 46 min), raise concerns about redistribution that may reduce tumor absorbed dose (TAD) and increase off-target radiation exposure. Because somatostatin receptor subtype 2 antagonists, such as satoreotide tetraxetan (SSO110, also known as DOTA-JR11), are not internalized, it has been proposed that the daughter radionuclides are less effectively retained compared with internalizing agonists, such as DOTATATE. In this study, we performed a direct and quantitative comparison of daughter radionuclide redistribution after administration of [225Ac]Ac-SSO110 and [225Ac]Ac-DOTATATE. Methods: Biodistribution and 213Bi redistribution were evaluated in BALB/c nude mice bearing NCI-H69 small cell lung cancer xenografts. Repeated γ-counting combined with biexponential modeling was used to quantify 225Ac and 213Bi activity in tumors, blood, bone marrow, kidneys, the liver, and the intestines up to 96 h postinjection. 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-DOTATATE. Redistribution of 213Bi from tumors was minimal and comparable between the agonist and antagonist and reduced the TAD by 4.5% for [225Ac]Ac-SSO110 and 3.9% for [225Ac]Ac-DOTATATE. After accounting for this redistribution, [225Ac]Ac-SSO110 delivered a 2.8-fold higher TAD and a 1.8-fold higher tumor-to-kidney absorbed dose (AD) ratio compared with [225Ac]Ac-DOTATATE. Moreover, 213Bi redistribution had no relevant impact on AD estimates in evaluated healthy organs, including the kidneys, the intestines, blood, and bone marrow. Real-time binding studies demonstrated a sustained cell-associated β--signal after incubation with [225Ac]Ac-SSO110. Conclusion: Despite negligible internalization, [225Ac]Ac-SSO110 did not show increased macroscopic 213Bi redistribution compared with the internalizing agonist [225Ac]Ac-DOTATATE. Redistribution was limited for both radiopeptides and had only a minor effect on AD estimates for tumors and the evaluated healthy tissues. [225Ac]Ac-SSO110 achieved a higher TAD and more favorable tumor-to-kidney ratio compared with [225Ac]Ac-DOTATATE. Overall, these findings support further evaluation of antagonist-based 225Ac radiopharmaceutical therapy.

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