[212Pb]Pb-AG1002的临床前评估：一种新一代SSTR2靶向、非激动剂放射性药物

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 [ 212 Pb]Pb-AG1002, a next generation SSTR2 non-agonist theragnostic agent,with the alpha-emitter 212 Pb 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 [ 212 Pb]Pb-AG1002 was analyzed by harvesting the organs of interest and measuring the radioactivity with gamma counter. In efficacy studies, [ 212 Pb]Pb-AG1002 was administrated comparing to [ 212 Pb]Pb-DOTAM-TATE. The tumor growth inhibition and median survival time were measured and analyzed at time intervals post dosing. Results: [ 212 Pb]Pb-AG1002 achieved high radiochemical purities following radiolabeling. In biodistribution studies, it demonstrated a superior pharmacokinetic profile compared to [ 212 Pb]Pb-DOTAM-TATE and [ 212 Pb]Pb-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 [ 212 Pb]Pb-AG1002 had robust tumor growth inhibition and a more durable response than those treated with [ 212 Pb]Pb-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: [ 212 Pb]Pb-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 alpha-therapeutic agent for SSTR2-positive tumors.