Synthesis and evaluation of (18)F labeled alanine derivatives as potential tumor imaging agents

IntroductionThis paper reports the synthesis and labeling of ¹⁸F alanine derivatives. We also investigate their biological characteristics as potential tumor imaging agents mediated by alanine–serine–cysteine preferring (ASC) transporter system.MethodsThree new ¹⁸F alanine derivatives were prepared from corresponding tosylate-precursors through a two-step labeling reaction. In vitro uptake studies to evaluate and to compare these three analogs were carried out in 9L glioma and PC-3 prostate cancer cell lines. Potential transport mechanisms, protein incorporation and stability of 3-(1-[¹⁸F]fluoromethyl)-L-alanine (L-[¹⁸F]FMA) were investigated in 9L glioma cells. Its biodistribution was determined in a rat-bearing 9L tumor model. PET imaging studies were performed on rat bearing 9L glioma tumors and transgenic mouse carrying spontaneous generated M/tomND tumor (mammary gland adenocarcinoma).ResultsNew ¹⁸F alanine derivatives were prepared with 7%–34% uncorrected radiochemical yields, excellent enantiomeric purity (> 99%) and good radiochemical purity (> 99%). In vitro uptake of the L-[¹⁸F]FMA in 9L glioma and PC-3 prostate cancer cells was higher than that observed for the other two alanine derivatives and [¹⁸F]FDG in the first 1 h. Inhibition of cell uptake studies suggested that L-[¹⁸F]FMA uptake in 9L glioma was predominantly via transport system ASC. After entering into cells, L-[¹⁸F]FMA remained stable and was not incorporated into protein within 2 h. In vivo biodistribution studies demonstrated that L-[¹⁸F]FMA had relatively high uptake in liver and kidney. Tumor uptake was fast, reaching a maximum within 30 min. The tumor-to-muscle, tumor-to-blood and tumor-to-brain ratios at 60 min post injection were 2.2, 1.9 and 3.0, respectively. In PET imaging studies, tumors were visualized with L-[¹⁸F]FMA in both 9L rat and transgenic mouse.ConclusionL-[¹⁸F]FMA showed promising properties as a PET imaging agent for up-regulated ASC transporter associated with tumor proliferation.