Ascorbic acid analogue 6-Deoxy-6-[¹⁸F] fluoro-L-ascorbic acid as a tracer for identifying human colorectal cancer with SVCT2 overexpression

L-ascorbic acid (AA) was reported to have an anti-cancer effect over 40 years. In recent years, several ongoing clinical trials are exploring the safety and efficacy of intravenous high-dose AA for cancer treatment. The lack of appropriate imaging modality limits the identification of potentially suitable patients for AA treatment. This study focuses on identifying AA-sensitive tumor cells using molecular imaging. 6-Deoxy-6-[¹⁸F] fluoro-L-ascorbic Acid (¹⁸F-DFA), a structural analog of AA, was synthesized and labeled to visualize the metabolism of AA in vivo. Colorectal cancer (CRC) cell lines with high and low expression of sodium-dependent vitamin C transporters 2 (SVCT2) were used for a series of cellular uptake tests. PET imaging was performed on xenograft tumor-bearing mice. More AA uptake was observed in CRC cells with high SVCT2 expression than in cells with low SVCT2 expression. The substrate (unlabeled AA) can competitively inhibit the ¹⁸F-DFA tracer uptake by CRC cells. The biodistribution of ¹⁸F-DFA in mice showed high radioactivity was seen in organs such as adrenal glands, kidneys, and liver that were known to have high concentrations of AA. Both PET imaging and tissue distribution showed that cancer cells with high SVCT2 expression enhanced the accumulation of ¹⁸F-DFA in mice after tumor formation. Immunohistochemistry was used to verify the corresponding results. As a radiotracer, ¹⁸F-DFA can provide powerful imaging information to identify tumor with high affinity of AA, and SVCT2 can be a potential biomarker in this process.