Zheng Xiaobei, Xue Shuai, Zhao Zhongqi, Jin Shuxin, He Shuhua, Jia Lina, Li Zheng, Vanhove Christian, De Vos Filip, Kuang Zijun, Wang Tiantian, Neyt Sara, Zhang Lan, Li Xiao
Shanghai Institute of Applied Physics, Chinese Academy of Sciences, Shanghai, 201800, China.
University of Chinese Academy of Sciences, Beijing, 100049, China.
EJNMMI Radiopharm Chem. 2024 Jul 31;9(1):56. doi: 10.1186/s41181-024-00287-7.
Currently, the synthesis pathway of metal nuclide-labeled radiopharmaceuticals is mainly divided into two steps: first, connecting the chelator with the target molecule, and second, labeling the metal nuclide to the chelator. However, the second step of the reaction to label the metal nuclide requires high temperature (90-100 °C), which tends to denature and inactivate the target molecule, leading to loss of biological activities, especially the targeting ability. A feasible solution may be the click chemistry labeling method, which consists of reacting a metal nuclide with a chelating agent to generate an intermediate and then synthesizing a radiopharmaceutical agent via the click chemistry intermediate and the target molecule-alkyne compound. In this study, through the click chemistry of Lu-DOTA-N with prostate-specific membrane antigen (PSMA)-alkyne compound, Lu-labeled PSMA-targeted molecular probe was synthesized and evaluated for its potential to be cleared from the bloodstream and rapidly distributed to tissues and organs, achieving a high target/non-target ratio. Lu-PSMA-617 was utilized as an analogue for comparison in terms of synthesizing efficiency and PSMA-targeting ability.
A novel Lu-labeled PSMA radioligand was successfully synthesized through the click chemistry of Lu-DOTA-N with PSMA-alkyne compound, and abbreviated as Lu-DOTA-CC-PSMA, achieving a radiochemical yield of 77.07% ± 0.03% (n = 6) and a radiochemical purity of 97.62% ± 1.49% (n = 6) when purified by SepPak C18 column. Notably, Lu-DOTA-CC-PSMA was characterized as a hydrophilic compound that exhibited stability at room temperature and commendable pharmacokinetic properties, such as the superior uptake (19.75 ± 3.02%ID/g at 0.5 h) and retention (9.14 ± 3.16%ID/g at 24 h) within xenografts of 22Rv1 tumor-bearing mice. SPECT/CT imaging indicated that radioactivity in both kidneys and bladder was essentially eliminated after 24 h, while Lu-DOTA-CC-PSMA was further enriched and retained in PSMA-expressing tumors, resulting in the high target/non-target ratio.
This study demonstrated the potential of click chemistry to unify the synthesis of metal radiopharmaceuticals, and Lu-DOTA-CC-PSMA was found for rapid clearance and appropriate chemical stability as a PSMA-targeted radioligand.
目前，金属核素标记放射性药物的合成途径主要分为两步：第一步，将螯合剂与靶分子连接；第二步，将金属核素标记到螯合剂上。然而，标记金属核素的第二步反应需要高温（90-100°C），这往往会使靶分子变性和失活，导致生物活性丧失，尤其是靶向能力。一种可行的解决方案可能是点击化学标记方法，该方法包括使金属核素与螯合剂反应生成中间体，然后通过点击化学中间体与靶分子-炔化合物合成放射性药物制剂。在本研究中，通过Lu-DOTA-N与前列腺特异性膜抗原（PSMA）-炔化合物的点击化学，合成了Lu标记的PSMA靶向分子探针，并评估了其从血液中清除并快速分布到组织和器官的潜力，实现了高靶/非靶比。使用Lu-PSMA-617作为类似物，在合成效率和PSMA靶向能力方面进行比较。
通过Lu-DOTA-N与PSMA-炔化合物的点击化学成功合成了一种新型的Lu标记PSMA放射性配体，简称为Lu-DOTA-CC-PSMA，经SepPak C18柱纯化后，放射化学产率为77.07%±0.03%（n = 6），放射化学纯度为97.62%±1.49%（n = 6）。值得注意的是，Lu-DOTA-CC-PSMA被表征为一种亲水性化合物，在室温下表现出稳定性，并具有良好的药代动力学性质，例如在22Rv1荷瘤小鼠异种移植瘤中的摄取率较高（0.5小时时为19.75±3.
