背景:目前,金属核素标记放射性药物的合成途径主要分为两个步骤:把螯合剂和靶分子连接起来,第二,将金属核素标记到螯合剂上。然而,标记金属核素的反应的第二步需要高温(90-100°C),它倾向于使目标分子变性和失活,导致生物活动的丧失,尤其是瞄准能力。一个可行的解决方案可能是点击化学标记法,其包括使金属核素与螯合剂反应以产生中间体,然后经由点击化学中间体和目标分子-炔烃化合物合成放射性药剂。在这项研究中,通过177Lu-DOTA-N3与前列腺特异性膜抗原(PSMA)-炔化合物的点击化学,合成了177Lu标记的PSMA靶向分子探针,并评估了其从血液中清除并迅速分布到组织和器官的潜力,实现高目标/非目标比率。177Lu-PSMA-617用作在合成效率和PSMA靶向能力方面进行比较的类似物。
结果:通过177Lu-DOTA-N3与PSMA-炔化合物的点击化学成功合成了一种新型的177Lu标记的PSMA放射性配体,缩写为177Lu-DOTA-CC-PSMA,通过SepPakC18柱纯化时,放射化学收率为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,177Lu-DOTA-CC-PSMA被表征为在室温下表现出稳定性和良好的药代动力学性质的亲水性化合物,例如22Rv1荷瘤小鼠的异种移植物内的优异摄取(0.5h时的19.75±3.02%ID/g)和保留(24h时的9.14±3.16%ID/g)。SPECT/CT显像显示肾脏和膀胱的放射性在24小时后基本消除,而177Lu-DOTA-CC-PSMA进一步富集并保留在表达PSMA的肿瘤中,导致较高的目标/非目标比率。
结论:这项研究证明了点击化学可以统一金属放射性药物的合成,发现177Lu-DOTA-CC-PSMA作为PSMA靶向的放射性配体具有快速清除和适当的化学稳定性。
BACKGROUND: 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 177Lu-DOTA-N3 with prostate-specific membrane antigen (PSMA)-alkyne compound, 177Lu-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. 177Lu-PSMA-617 was utilized as an analogue for comparison in terms of synthesizing efficiency and PSMA-targeting ability.
RESULTS: A novel 177Lu-labeled PSMA radioligand was successfully synthesized through the click chemistry of 177Lu-DOTA-N3 with PSMA-alkyne compound, and abbreviated as 177Lu-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, 177Lu-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 177Lu-DOTA-CC-PSMA was further enriched and retained in PSMA-expressing tumors, resulting in the high target/non-target ratio.
CONCLUSIONS: This study demonstrated the potential of click chemistry to unify the synthesis of metal radiopharmaceuticals, and 177Lu-DOTA-CC-PSMA was found for rapid clearance and appropriate chemical stability as a PSMA-targeted radioligand.