Abstract：
Legumain, a lysosomal cysteine protease overexpressed in a variety of tumors, has been considered a promising biomarker for various cancers. Precise detection of legumain activity in the lysosome represents an important strategy for early diagnosis and prognosis of tumors. Small-molecule probes with the property of target-enabled self-assembly hold great potential for molecular imaging. In this study, we reported two dual-targeting radiotracers ([18F]SF-AAN-M and [18F]SF-AAN-HEM) with a property of legumain-mediated self-assembly for positron emission tomography (PET) imaging. Both the radiotracers were synthesized with high labeling yield (>50%) and the radiochemical purity was over 99% via one-step straightforward 18F-labeling. Both tracers were efficiently activated by the reducing agent and legumain to self-assemble into aggregates and showed enhanced retention in legumain-overexpressed MDA-MB-468 cells and tumors, indicating that the introduction of lysosome-targeting morpholine increased the tumor uptake and extended the retention of radiotracers in legumain-overexpressed tumors. In addition, [18F]SF-AAN-HEM with a hydrophilic (histidine-glutamate)3 tag displayed significantly reduced liver uptake with no conspicuous reduction in tumor uptake, affording high signal-to-noise ratios (tumor/liver and tumor/muscle). All of these results suggest that dual-targeting tracer [18F]SF-AAN-HEM could provide a promising tool for in vivo monitoring legumain activity in tumors.
摘要：
莱古曼,溶酶体半胱氨酸蛋白酶在多种肿瘤中过度表达，已被认为是各种癌症的有希望的生物标志物。精确检测溶酶体中的豆蔻素活性代表了肿瘤早期诊断和预后的重要策略。具有靶向自组装特性的小分子探针在分子成像中具有巨大的潜力。在这项研究中,我们报道了两种双靶向放射性示踪剂([18F]SF-AAN-M和[18F]SF-AAN-HEM),其具有用于正电子发射断层扫描(PET)成像的legumain介导的自组装特性.两种放射性示踪剂均以高标记产率(>50%)合成,并且通过一步直接的18F-标记,放射化学纯度超过99%。两种示踪剂均被还原剂和legumain有效激活，以自组装成聚集体，并在legumain过表达的MDA-MB-468细胞和肿瘤中显示出增强的保留，这表明溶酶体靶向吗啉的引入增加了肿瘤的摄取，并延长了在过表达的肿瘤中放射性示踪剂的保留。此外,[18F]SF-AAN-HEM与亲水（组氨酸-谷氨酸）3标签显示肝脏摄取显著降低，肿瘤摄取没有明显减少，提供高信噪比（肿瘤/肝脏和肿瘤/肌肉）。所有这些结果表明，双靶向示踪剂[18F]SF-AAN-HEM可以为体内监测肿瘤中的豆球蛋白活性提供有希望的工具。
