铅 203 (203Pb)/铅 212 (212Pb) 元素相同的放射性核素对在图像引导的癌症靶向 α 粒子治疗领域引起了极大的兴趣。新出现的证据表明，与基于 β 粒子的神经内分泌肿瘤 (NET) 疗法相比，针对生长抑素受体亚型 2 (SSTR2) 的 212Pb 标记肽放射性药物可能会提供更好的疗效。本研究旨在通过对基于 Tyr3-奥曲肽 (TOC) 的放射性药物进行结构修饰来提高 SSTR2 靶向放射性核素成像和治疗的性能。设计和合成了新的 SSTR2 靶向肽，目的是通过使用改进的环化技术；引入 Pb 特异性螯合剂 (PSC)；以及聚乙二醇 (PEG) 连接体的插入。使用胰腺 AR42J (SSTR2) 肿瘤细胞评估肽的结合亲和力和 203Pb 标记肽的细胞摄取，并在 AR42J 肿瘤异种移植小鼠模型中评估 203Pb 标记肽的生物分布和成像。鉴定出一种先导肽（即 PSC-PEG2-TOC），然后进一步评估其在 212Pb 治疗研究中的功效。先导放射性肽药物缀合物 (RPDC) - [203Pb]Pb-PSC-PEG2-TOC - 显着改善了与 [203Pb]Pb-DOTA0-Tyr3-奥曲肽 (DOTATOC) 相比，肿瘤靶向特性，包括受体结合以及肿瘤积累和保留。此外，改良的 RPDC 比 DOTATOC 对应物表现出更快的肾脏清除率。 [212Pb]Pb-PSC-PEG2-TOC 的这些有利特性在 AR42J 异种移植模型中产生剂量依赖性治疗效果，且毒性迹象最小。分三剂分次施用 3.7 MBq [212Pb]Pb-PSC-PEG2-TOC 可进一步提高抗肿瘤效果，使小鼠模型在 120 天内存活率达到 80%（70% 完全缓解）。螯合剂和连接体的结构修饰组合物改善了用于 NET 治疗学的 203/212Pb 肽基放射性药物的肿瘤靶向性和药代动力学 (PK)。这些发现表明，PSC-PEG2-TOC 是用于 NET 和表达 SSTR2 的其他类型癌症的基于 Pb 的靶向放射性核素治疗的有前途的候选者。© 2023。作者。

The lead-203 (203Pb)/lead-212 (212Pb) elementally identical radionuclide pair has gained significant interest in the field of image-guided targeted alpha-particle therapy for cancer. Emerging evidence suggests that 212Pb-labeled peptide-based radiopharmaceuticals targeting somatostatin receptor subtype 2 (SSTR2) may provide improved effectiveness compared to beta-particle-based therapies for neuroendocrine tumors (NETs). This study aims to improve the performance of SSTR2-targeted radionuclide imaging and therapy through structural modifications to Tyr3-octreotide (TOC)-based radiopharmaceuticals.New SSTR2-targeted peptides were designed and synthesized with the goal of optimizing the incorporation of Pb isotopes through the use of a modified cyclization technique; the introduction of a Pb-specific chelator (PSC); and the insertion of polyethylene glycol (PEG) linkers. The binding affinity of the peptides and the cellular uptake of 203Pb-labeled peptides were evaluated using pancreatic AR42J (SSTR2+) tumor cells and the biodistribution and imaging of the 203Pb-labeled peptides were assessed in an AR42J tumor xenograft mouse model. A lead peptide was identified (i.e., PSC-PEG2-TOC), which was then further evaluated for efficacy in 212Pb therapy studies.The lead radiopeptide drug conjugate (RPDC) - [203Pb]Pb-PSC-PEG2-TOC - significantly improved the tumor-targeting properties, including receptor binding and tumor accumulation and retention as compared to [203Pb]Pb-DOTA0-Tyr3-octreotide (DOTATOC). Additionally, the modified RPDC exhibited faster renal clearance than the DOTATOC counterpart. These advantageous characteristics of [212Pb]Pb-PSC-PEG2-TOC resulted in a dose-dependent therapeutic effect with minimal signs of toxicity in the AR42J xenograft model. Fractionated administrations of 3.7 MBq [212Pb]Pb-PSC-PEG2-TOC over three doses further improved anti-tumor effectiveness, resulting in 80% survival (70% complete response) over 120 days in the mouse model.Structural modifications to chelator and linker compositions improved tumor targeting and pharmacokinetics (PK) of 203/212Pb peptide-based radiopharmaceuticals for NET theranostics. These findings suggest that PSC-PEG2-TOC is a promising candidate for Pb-based targeted radionuclide therapy for NETs and other types of cancers that express SSTR2.© 2023. The Author(s).