Abstract Somatostatin receptor 2 (SSTR2), overexpressed in neuroendocrine tumors and other solid malignancies, is a validated target for radioligand therapies (RLTs). Here, we present the preclinical evaluation of 212PbPb-AG1002, a next generation SSTR2 non-agonist theragnostic agent,with the alpha-emitter 212Pb for therapeutic purposes. Methods: In-vivo PET/CT imaging, biodistribution and efficacy studies were conducted in athymic nude mice bearing AR42J (SSTR2+) xenografts. The biodistribution of 212PbPb-AG1002 was analyzed by harvesting the organs of interest and measuring the radioactivity with gamma counter. In efficacy studies, 212PbPb-AG1002 was administrated comparing to 212PbPb-DOTAM-TATE. The tumor growth inhibition and median survival time were measured and analyzed at time intervals post dosing. Results: 212PbPb-AG1002 achieved high radiochemical purities following radiolabeling. In biodistribution studies, it demonstrated a superior pharmacokinetic profile compared to 212PbPb-DOTAM-TATE and 212PbPb-TCMC-JR11, exhibiting higher tumor uptake and prolonged retention, and reduced kidney accumulation, giving rise to excellent tumor-to-kidney ratios. Efficacy studies in SSTR2-expressing models showed that mice treated with 212PbPb-AG1002 had robust tumor growth inhibition and a more durable response than those treated with 212PbPb-DOTAM-TATE. Preclinical dosimetry studies further revealed low radiation absorption in normal organs, indicating a favorable safety profile with strong translational potential to humans. Conclusion: 212PbPb-AG1002 exhibits excellent radiolabeling efficiency, desirable pharmacokinetics, anti-tumor efficacy and favorable safety profile. Its robust preclinical pharmacological profiles support clinical development as a next generation α-therapeutic agent for SSTR2-positive tumors. Citation Format: Xuexiang Zhang, Xuefei Li, Shaohua Xu, Xiao Tang, Xiang Gu, Vivi Yang, Guiyu Liu, Maijing Liao, Tao Robert Wu, Xin Gan, . Preclinical evaluation of 212PbPb-AG1002, a next generation SSTR2-targeting, non-agonist radiopharmaceutical abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 5811.
Zhang et al. (Fri,) studied this question.