Chen Xiang-Yi, Zhang Yan, Duan Xiaojiang, Zhang Jingming, Zhang Zhuochen, Yang Xing, Wei Zhi-Xiao, He Zuo-Xiang
Department of Nuclear Medicine, The First Affiliated Hospital of Guangxi Medical University, Nanning, 530021, People's Republic of China.
Department of Nuclear Medicine, Beijing Tsinghua Changgung Hospital, School of Clinical Medicine, Tsinghua Medicine, Tsinghua University, Beijing, 102218, People's Republic of China.
Mol Imaging Biol. 2025 Aug 7. doi: 10.1007/s11307-025-02035-y.
Prostate-specific membrane antigen-targeted radioligand therapy (PSMA-RLT) is a promising approach to treating metastatic castration-resistant prostate cancer (mCRPC). With the emergence of oxalyldiaminopropionic acid urea (ODAP-Urea) based radioligands targeting PSMA, novel paradigms focused on PSMA-RLT are garnering attention. This study aims to assess potentially novel ODAP-Urea-based radioligands prepared for PSMA-RLT.
Albumin binding moieties (ABMs) were selected for optimization. Candidates were evaluated in vitro and subsequently investigated through biodistribution and imaging studies in 22Rv1 tumor-bearing mice.
We synthesized five novel ODAP-Urea-based derivatives (CXY-18, CXY-19, CXY-20, CXY-21, CXY-23) with specific ABM. All compounds demonstrated high affinities for PSMA (K values ranging from 0.21 nM to 3.6 nM) and strong human albumin protein binding abilities (83.4 ± 1.6% to 94.6 ± 0.4%). [Ga]Ga-CXY-18 (CXY-18) PET/CT exhibited the highest tumor uptake and blood retention properties. Moreover, the internalization of [Ga]Ga-CXY-18 in the 22Rv1 cell line (23.81 ± 1.67%) exceeded that of [Ga]Ga-PSMA-617 (9.99 ± 0.98%). Biodistribution studies confirmed prolonged blood retention and enhanced tumor uptake with [Lu]Lu-CXY-18, peaking at 48 h post-injection (4 h: 27.22 ± 3.61%ID/g; 24 h: 30.61 ± 4.96%ID/g; 48 h: 33.92 ± 2.98%ID/g; 96 h: 30.97 ± 1.87%ID/g; 192 h: 9.03 ± 3.49%ID/g).
Our study indicates that CXY-18 possesses high PSMA specificity and tumor uptake, underscoring its promising potential for PSMA-RLT using 4-IBA.
前列腺特异性膜抗原靶向放射性配体疗法（PSMA-RLT）是治疗转移性去势抵抗性前列腺癌（mCRPC）的一种有前景的方法。随着基于草酰二氨基丙酸尿素（ODAP-Urea）的PSMA靶向放射性配体的出现，聚焦于PSMA-RLT的新范例正受到关注。本研究旨在评估为PSMA-RLT制备的潜在新型基于ODAP-Urea的放射性配体。
选择白蛋白结合部分（ABMs）进行优化。对候选物进行体外评估，随后通过在荷22Rv1肿瘤小鼠中的生物分布和成像研究进行考察。
我们合成了五种具有特定ABM的新型基于ODAP-Urea的衍生物（CXY-18、CXY-19、CXY-20、CXY-21、CXY-23）。所有化合物对PSMA均表现出高亲和力（K值范围为0.21 nM至3.6 nM）以及强大的人白蛋白蛋白结合能力（83.4±1.6%至94.6±0.4%）。[镓]镓-CXY-18（CXY-18）PET/CT显示出最高的肿瘤摄取和血液滞留特性。此外，[镓]镓-CXY-18在22Rv1细胞系中的内化（23.81±1.67%）超过了[镓]镓-PSMA-617（9.99±0.98%）。生物分布研究证实，[镥]镥-CXY-18具有延长的血液滞留和增强的肿瘤摄取，在注射后48小时达到峰值（4小时：27.22±3.61%ID/g；24小时：30.61±4.96%ID/g；48小时：33.92±2.98%ID/g；96小时：30.97±1.87%ID/g；192小时：9.03±3.49%ID/g）。
我们的研究表明，CXY-18具有高PSMA特异性和肿瘤摄取，突出了其使用4-IBA进行PSMA-RLT的有前景的潜力。
