[18F]F-ET-OTSSP167 Targets Maternal Embryo Leucine Zipper Kinase for PET Imaging of Triple-Negative Breast Cancer,Molecular Pharmaceutics

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[18F]F-ET-OTSSP167 Targets Maternal Embryo Leucine Zipper Kinase for PET Imaging of Triple-Negative Breast Cancer
Molecular Pharmaceutics ( IF 4.5 ) Pub Date : 2021-08-17 , DOI: 10.1021/acs.molpharmaceut.1c00454
Fan Hu _{1,

2} , Chengpeng Gong _{1,

2} , Yongkang Gai _{1,

2} , Dawei Jiang _{1,

2} , Qingyao Liu _{1,

2} , Sheng Wang ₃ , Mengmeng Hu _{1,

2} , Rundong Pi _{1,

2} , Hua Shu _{1,

2} , Jia Hu _{1,

2} , Xiaoli Lan _{1,

2}

Affiliation

Maternal embryo leucine zipper kinase (MELK) is a serine/threonine kinase and is highly expressed in triple-negative breast cancer (TNBC). This study aimed to develop a ¹⁸F-radiolabeled tracer based on the structure of a small-molecule MELK inhibitor OTSSP167 and evaluate its application for PET imaging of MELK expression in TNBC. OTSSP167 was modified with ethylene glycol to adjust its pharmacokinetics and was then radiolabeled with ¹⁸F to obtain [¹⁸F]F-ET-OTSSP167 at a labeling yield of 7.14 ± 2.19% and a molar activity of 16.23 ± 1.13 MBq/nmol. In vitro binding assays showed differentiated binding affinities of [¹⁸F]F-ET-OTSSP167 in different breast cancer cell lines, with high uptake in MDA-MB-231 (mild MELK expression) and low uptake in MCF-7 (negative MELK expression). PET imaging revealed that MDA-MB-231 tumors could be clearly delineated in vivo, while low tracer uptake was observed in MCF-7 tumors. These findings were confirmed by ex vivo biodistribution studies and were consistent with the immunohistochemistry and tissue staining results. Tracer accumulation in MDA-MB-231 tumors was significantly inhibited by excess amounts of OTSSP167, indicating high specificity of the tracer. In summary, [¹⁸F]F-ET-OTSSP167, an easily-prepared probe, can be used to visualize MELK positive tumors, demonstrating its promising clinical potential in selecting patients for MELK inhibitor therapy.

中文翻译：

[18F]F-ET-OTSSP167靶向母体胚胎亮氨酸拉链激酶用于三阴性乳腺癌的PET成像

母体胚胎亮氨酸拉链激酶 (MELK) 是一种丝氨酸/苏氨酸激酶，在三阴性乳腺癌 (TNBC) 中高度表达。本研究旨在开发一种基于小分子 MELK 抑制剂 OTSSP167 结构的^{18 F放射性示踪剂，并评估其在 TNBC 中 MELK 表达的 PET 成像中的应用。}OTSSP167 用乙二醇修饰以调节其药代动力学，然后用¹⁸ F 进行放射性标记，得到 [ ¹⁸ F]F-ET-OTSSP167，标记产率为 7.14 ± 2.19%，摩尔活性为 16.23 ± 1.13 MBq/nmol。体外结合试验显示 [ ^{18 ] 的不同结合亲和力}F]F-ET-OTSSP167 在不同的乳腺癌细胞系中，MDA-MB-231 摄取量高（MELK 表达温和），MCF-7 摄取量低（MELK 表达阴性）。PET 成像显示 MDA-MB-231 肿瘤可以在体内清楚地描绘出来，而在 MCF-7 肿瘤中观察到低示踪剂摄取。这些发现通过离体生物分布研究得到证实，并且与免疫组织化学和组织染色结果一致。过量的 OTSSP167 显着抑制了 MDA-MB-231 肿瘤中的示踪剂积累，表明示踪剂具有高特异性。总之，[ ¹⁸F]F-ET-OTSSP167 是一种易于制备的探针，可用于可视化 MELK 阳性肿瘤，证明其在选择患者接受 MELK 抑制剂治疗方面具有广阔的临床潜力。

更新日期：2021-09-06

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