Department of Nuclear Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China; Hubei Key Laboratory of Molecular Imaging, Wuhan 430022, China.
School of Pharmacy, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, Hubei, China.
Bioorg Chem. 2021 Feb;107:104609. doi: 10.1016/j.bioorg.2020.104609. Epub 2021 Jan 5.
Maternal embryonic leucine zipper kinase (MELK) plays an important role in the regulation of tumor cell growth. It is abundant in triple-negative breast cancers (TNBC), making it a promising target for molecular imaging and therapy. Based on the structure of a potent MELK inhibitor (OTSSP167) with high affinity, we developed a novel carbon-11 radiolabeled molecular probe C-methoxy-OTSSP167, and evaluated its application in positron emission tomography (PET) imaging of TNBC. C-methoxy-OTSSP167 was successfully synthesized and was identical to its non-radiolabeled compound methoxy-OTSSP167 in high-pressure liquid chromatography (HPLC) chromatogram. The obtained tracer had 10 ± 2% radiolabeling yield with a total synthesis time of 40 min. The radiochemical purity of the tracer was more than 95%. The maximum uptake (9.97 ± 0.70%) of C-methoxy-OTSSP167 in MELK-overexpressing MDA-MB-231 cells was at 60 min in vitro. On PET, MDA-MB-231 tumors were clearly visible at 30, 60, and 90 min after injection of C-methoxy-OTSSP167, while no obvious radioactivity accumulation was found in the low-MELK MCF-7 tumors. In vivo biodistribution data were consistent with the findings of the PET images. However, the radioactive tracer showed high uptake in normal organs such as liver and intestine, which may limit the application of the tracer. In addition, a markedly different MELK expression level in MDA-MBA-231 and MCF-7 tumors was verified via IHC staining. In conclusion, C-methoxy-OTSSP167 was successfully developed and exhibited elevated uptake in MELK overexpressed tumor, indicating its potential for noninvasively imaging of MELK overexpressed TNBC.
母体胚胎亮氨酸拉链激酶（MELK）在调节肿瘤细胞生长中发挥着重要作用。它在三阴性乳腺癌（TNBC）中含量丰富，使其成为分子成像和治疗的有前途的靶点。基于具有高亲和力的强效 MELK 抑制剂（OTSSP167）的结构，我们开发了一种新型的碳-11 放射性标记分子探针 C-甲氧基-OTSSP167，并评估了其在 TNBC 的正电子发射断层扫描（PET）成像中的应用。C-甲氧基-OTSSP167 成功合成，其高效液相色谱（HPLC）图谱与非放射性标记化合物甲氧基-OTSSP167 完全相同。该示踪剂的放射性标记产率为 10±2%，总合成时间为 40 分钟。示踪剂的放射化学纯度大于 95%。在体外，MELK 过表达的 MDA-MB-231 细胞中 C-甲氧基-OTSSP167 的最大摄取率（9.97±0.70%）为 60 分钟。在 PET 上，注射 C-甲氧基-OTSSP167 后 30、60 和 90 分钟，MDA-MB-231 肿瘤清晰可见，而 MCF-7 低 MELK 肿瘤未见明显放射性积聚。体内生物分布数据与 PET 图像的结果一致。然而，放射性示踪剂在肝脏和肠道等正常器官中显示出高摄取，这可能限制了示踪剂的应用。此外，通过 IHC 染色验证了 MDA-MBA-231 和 MCF-7 肿瘤中 MELK 表达水平的明显差异。总之，成功开发了 C-甲氧基-OTSSP167，并且在过表达 MELK 的肿瘤中显示出了更高的摄取率，表明其在非侵入性成像过表达 MELK 的 TNBC 方面具有潜力。
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