A novel carbon-11 radiolabeled maternal embryonic leucine zipper kinase inhibitor for PET imaging of triple-negative breast cancer

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-11-methoxy-OTSSP167, and evaluated its application in positron emission tomography (PET) imaging of TNBC. C-11-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-11-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-11-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-11-methoxy-OTSSP167 was successfully developed and exhibited elevated uptake in MELK overexpressed tumor, indicating its potential for noninvasively imaging of MELK overexpressed TNBC.

Automated summary

A novel carbon-11 radiolabeled molecular probe C-11-methoxy-OTSSP167 was successfully synthesized and exhibited elevated uptake in MELK overexpressed tumors, showing potential for noninvasive imaging of TNBC. This tracer had high radiochemical purity and specifically targeted triple-negative breast cancers.