以其高灵敏度而闻名的异二聚体示踪剂的进步标志着用于癌症诊断的放射性示踪剂发展的重要趋势。我们之前对 [68Ga]Ga-HX01（一种针对 CD13 和整合素 αvβ3 的异二聚体示踪剂）的研究工作使其获得了中国国家药品监督管理局 (NMPA) 的 I 期临床试验批准。然而，其快速清除和有限的肿瘤保留对更广泛的癌症治疗临床应用提出了挑战。本研究旨在开发一种具有增加肿瘤摄取和延长保留时间的新型放射性药物，使其成为潜在的治疗候选药物。基于HX01的结构合成了新的白蛋白结合剂缀合化合物。用 68Ga 标记后，对这些新化合物进行了体外和体内评估。使用 BxPC-3 异种移植小鼠模型在注射后 0.5-6 小时 (p.i.) 的不同时间点进行小动物 PET/CT 成像。具有最佳成像性能的化合物进一步用 177Lu 进行放射性标记，用于小动物 SPECT/CT 和离体生物分布研究。我们以 HX01 的结构为基础，合成了新型白蛋白结合剂缀合化合物。当用 68Ga 放射性标记时，所有化合物均表现出改善的药代动力学 (PK)。小动物PET/CT研究表明，与没有白蛋白结合剂的[68Ga]Ga-L0相比，这些新的白蛋白结合剂缀合化合物，特别是[68Ga]Ga-L6，表现出显着增强的肿瘤积累和保留。 [68Ga]Ga-L6 的性能优于[68Ga]Ga-L7，后者是一种使用先前报道的白蛋白结合剂开发的化合物。此外，[177Lu]Lu-L6 在小动物 SPECT/CT 和生物分布研究中表现出从正常组织的快速清除、高肿瘤摄取和长时间保留，使其成为放射治疗应用的理想候选者。一种新的整合素 αvβ3 和 CD13 靶向筛选出化合物。该化合物具有新型白蛋白结合剂，在 BxPC-3 肿瘤中表现出增加的肿瘤摄取和延长的肿瘤保留，以及正常器官中的低背景，使其成为用 177Lu 放射性标记时放射治疗的完美候选者。© 2024。作者，下获得 Springer-Verlag GmbH 德国（Springer Nature 旗下公司）的独家许可。

The advancement of heterodimeric tracers, renowned for their high sensitivity, marks a significant trend in the development of radiotracers for cancer diagnosis. Our prior work on [68Ga]Ga-HX01, a heterodimeric tracer targeting CD13 and integrin αvβ3, led to its approval for phase I clinical trials by the China National Medical Production Administration (NMPA). However, its fast clearance and limited tumor retention pose challenges for broader clinical application in cancer treatment. This study aims to develop a new radiopharmaceutical with increased tumor uptake and prolonged retention, rendering it a potential therapeutic candidate.New albumin binder-conjugated compounds were synthesized based on the structure of HX01. In vitro and in vivo evaluation of these new compounds were performed after labelling with 68Ga. Small-animal PET/CT imaging were conducted at different time points at 0.5-6 h post injection (p.i.) using BxPC-3 xenograft mice models. The one with the best imaging performance was further radiolabeled with 177Lu for small-animal SPECT/CT and ex vivo biodistribution investigation.We have synthesized novel albumin binder-conjugated compounds, building upon the structure of HX01. When radiolabeled with 68Ga, all compounds demonstrated improved pharmacokinetics (PK). Small-animal PET/CT studies revealed that these new albumin binder-conjugated compounds, particularly [68Ga]Ga-L6, exhibited significantly enhanced tumor accumulation and retention compared with [68Ga]Ga-L0 without an albumin binder. [68Ga]Ga-L6 outperformed [68Ga]Ga-L7, a compound developed using a previously reported albumin binder. Furthermore, [177Lu]Lu-L6 demonstrated rapid clearance from normal tissues, high tumor uptake, and prolonged retention in small-animal SPECT/CT and biodistribution studies, positioning it as an ideal candidate for radiotherapeutic applications.A new integrin αvβ3 and CD13 targeting compound was screened out. This compound bears a novel albumin binder and exhibits increased tumor uptake and prolonged tumor retention in BxPC-3 tumors and low background in normal organs, making it a perfect candidate for radiotherapy when radiolabeled with 177Lu.© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.