用于[⁶⁸Ga]Ga-和[¹⁷⁷Lu]Lu-基PSMA放射诊疗的双螯合剂偶联物
{"_":"Dual-Chelator conjugates for [Ga]Ga- and [Lu]Lu-based PSMA Radiotheranostics.","sup":["68","177"]}
摘要(中文译文)
前列腺特异性膜抗原（PSMA）在前列腺癌（PCa）中高表达，是放射诊疗应用中有吸引力的靶点。传统方法通常通过螯合剂替换将PSMA靶向显像剂转化为治疗对应物，而我们通过将HBED-CC和DOTA整合到PSMA-093支架中，探索了一种双螯合剂策略。该设计生成了三种双螯合剂偶联物（1-3），能够在单一分子平台上同时螯合诊断性和治疗性放射性核素。这些化合物成功用[Ga]Ga和[Lu]Lu进行了放射性标记，质谱分析证实了HBED-CC对Ga和DOTA对Lu的位点选择性配位。所有偶联物在体外均保持高PSMA结合亲和力，其中[Ga]Ga/[Lu]Lu-2和[Ga]Ga/[Lu]Lu-3在22Rv1-FOLH-oe（PSMA过表达）细胞中表现出增强的细胞摄取。体内PET/CT显像和生物分布研究显示，[Ga]Ga-2具有良好的药代动力学特征，包括快速背景清除和改善的肿瘤滞留。重要的是，[Lu]Lu-2实现了高肿瘤摄取，注射后24小时达到8.35%ID/g，表明有效的肿瘤靶向和延长滞留。这些发现支持双螯合剂策略作为开发下一代PSMA靶向放射诊疗剂的有前景平台。通过在单一分子内实现诊断显像和放射性核素治疗的高效整合，该方法在保持良好生物学性能的同时，为放射性药物设计提供了增强的灵活性。双螯合剂概念可能促进更有效的伴随诊断-治疗配对的发展，并有助于推动精准肿瘤学的进步。
Abstract
Prostate-specific membrane antigen (PSMA) is highly overexpressed in prostate cancer (PCa) and represents an attractive target for radiotheranostic applications. While conventional approaches often convert PSMA-targeted imaging agents into therapeutic counterparts through chelator substitution, we explored a dual-chelator strategy by integrating HBED-CC and DOTA into the PSMA-093 scaffold. This design generated three dual-chelator conjugates (1-3) capable of supporting the chelation of both diagnostic and therapeutic radionuclides within a single molecular platform. The compounds were successfully radiolabeled with [Ga]Ga and [Lu]Lu, and mass spectrometric analysis confirmed site-selective coordination of Ga by HBED-CC and Lu by DOTA. All conjugates retained high PSMA-binding affinity in vitro, with [Ga]Ga/[Lu]Lu-2 and [Ga]Ga/[Lu]Lu-3 demonstrating enhanced cellular uptake in 22Rv1-FOLH-oe (PSMA overexpression) cells. In vivo PET/CT imaging and biodistribution studies revealed that [Ga]Ga-2 exhibited favorable pharmacokinetics, including rapid background clearance and improved tumor retention. Importantly, [Lu]Lu-2 achieved high tumor uptake, reaching 8.35%ID/g at 24 h post-injection, indicating effective tumor targeting and prolonged retention. These findings support the dual-chelator strategy as a promising platform for the development of next-generation PSMA-targeted radiotheranostic agents. By enabling efficient integration of diagnostic imaging and radionuclide therapy within a single molecule, this approach offers enhanced flexibility for radiopharmaceutical design while preserving favorable biological performance. The dual-chelator concept may facilitate the development of more effective companion diagnostic-therapeutic pairs and contribute to the advancement of precision oncology.
如何引用
AMA
Wenbin Jin, Yang Luo, Zhaohui Zhu, Lin Zhu, Hank F Kung. {"_":"Dual-Chelator conjugates for [Ga]Ga- and [Lu]Lu-based PSMA Radiotheranostics.","sup":["68","177"]}. Bioorganic chemistry. 2026; doi:10.1016/j.bioorg.2026.110236.
APA
Wenbin Jin, Yang Luo, Zhaohui Zhu, Lin Zhu, Hank F Kung (2026). {"_":"Dual-Chelator conjugates for [Ga]Ga- and [Lu]Lu-based PSMA Radiotheranostics.","sup":["68","177"]}. Bioorganic chemistry. https://doi.org/10.1016/j.bioorg.2026.110236
GB/T 7714
Wenbin Jin, Yang Luo, Zhaohui Zhu, Lin Zhu, Hank F Kung. {"_":"Dual-Chelator conjugates for [Ga]Ga- and [Lu]Lu-based PSMA Radiotheranostics.","sup":["68","177"]}[J]. Bioorganic chemistry, 2026 doi:10.1016/j.bioorg.2026.110236.
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