Peng Tukang, Wen Jun, Huang Gang, Zhao Haitao, Liu Jianjun
Department of Nuclear Medicine, Institute of Clinical Nuclear Medicine, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 210000, China.
Department of Nuclear Medicine, Institute of Clinical Nuclear Medicine, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 210000, China; Shanghai Key Laboratory of Molecular Imaging, Shanghai University of Medicine and Health Sciences, Shanghai 210000, China.
Bioorg Chem. 2025 Jan;154:108085. doi: 10.1016/j.bioorg.2024.108085. Epub 2024 Dec 21.
The non-specificity of F-FDG, coupled with high false-positive rates in pancreatitis, underscores an unmet clinical need for using specific positron emission tomography (PET) radiopharmaceuticals in noninvasive pancreatic cancer detection. ST14, a trypsin-like protease and a member of the type II transmembrane serine protease family, is overexpressed in various solid malignancies, including pancreatic cancer. This study aimed to develop a Ga-labeled PET radiopharmaceutical targeting ST14 for pancreatic cancer detection. A precursor ST14-06 was designed, and molecular docking was employed to preliminarily predict the binding mode. ST14-06 emerged as the preferred precursor with experimental inhibition assays confirming its high affinity for ST14 (IC = 1.06 ± 0.08 nM). Ga-ST14-06 was successfully synthesized with high radiochemical purity (RCP, >95 %) and molar activity (25-30 GBq/μmol) and was stable in saline and serum. In vitro studies demonstrated specific binding of the tracer to ST14-positive AsPC-1 cells compared to the blocking group (11.45 ± 0.12 % vs. 2.48 ± 0.34 %, P < 0.01). PET/CT imaging in AsPC-1 tumor-bearing mice confirmed ST14-specific uptake, which was reduced by co-administration of an excess blocking agent. Biodistribution studies revealed higher distribution in AsPC-1 tumors (0.99 ± 0.08 %ID/g) than in PANC-1 tumors (0.32 ± 0.02 %ID/g) and the blocking group (0.32 ± 0.04 %ID/g) at 1 h post-injection. Immunohistochemistry results showed that ST14 was highly positive in AsPC-1 tumors, but was negative in PANC-1 tumors. These preliminary findings suggest that Ga-ST14-06 has potential as a first-generation PET radiopharmaceutical for ST14-specific imaging, offering a promising tool for pancreatic cancer detection.
F-FDG的非特异性，再加上胰腺炎中较高的假阳性率，凸显了在无创性胰腺癌检测中使用特异性正电子发射断层扫描（PET）放射性药物尚未满足的临床需求。ST14是一种类胰蛋白酶，属于II型跨膜丝氨酸蛋白酶家族成员，在包括胰腺癌在内的多种实体恶性肿瘤中过表达。本研究旨在开发一种靶向ST14的镓标记PET放射性药物用于胰腺癌检测。设计了前体ST14-06，并采用分子对接初步预测其结合模式。ST14-06成为首选前体，实验性抑制试验证实其对ST14具有高亲和力（IC = 1.06±0.08 nM）。成功合成了放射性化学纯度高（RCP，>95%）且摩尔活度高（25 - 30 GBq/μmol）的Ga-ST14-06，并且在盐水和血清中稳定。体外研究表明，与阻断组相比，该示踪剂与ST14阳性的AsPC-1细胞有特异性结合（11.45±0.12%对2.48±0.34%，P<0.01）。对荷AsPC-1肿瘤小鼠进行的PET/CT成像证实了ST14特异性摄取，过量阻断剂共同给药可使其降低。生物分布研究显示，注射后1小时，AsPC-1肿瘤中的分布（0.99±0.08%ID/g）高于PANC-1肿瘤（0.32±0.02%ID/g）和阻断组（0.32±0.04%ID/g）。免疫组织化学结果显示，ST14在AsPC-1肿瘤中呈高度阳性，但在PANC-1肿瘤中呈阴性。这些初步研究结果表明，Ga-ST14-06有潜力作为第一代用于ST14特异性成像的PET放射性药物，为胰腺癌检测提供了一种有前景的工具。
