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

Introduction: This paper reports the synthesis and labeling of F-18 alanine derivatives. We also investigate their biological characteristics as potential tumor imaging agents mediated by alanine-serine-cysteine preferring (ASC) transporter system. Methods: Three new F-18 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-[F-18]fluoromethyl)-L-alanine (L-[F-18]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). Results: New F-18 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-[F-18] FMA in 9L glioma and PC-3 prostate cancer cells was higher than that observed for the other two alanine derivatives and [F-18]FDG in the first 1 h. Inhibition of cell uptake studies suggested that L-[F-18]FMA uptake in 9L glioma was predominantly via transport system ASC. After entering into cells, L[F-18]FMA remained stable and was not incorporated into protein within 2 h. In vivo biodistribution studies demonstrated that L-[F-18]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-[F-18]FMA in both 9L rat and transgenic mouse. Conclusion: L-[F-18]FMA showed promising properties as a PET imaging agent for up-regulated ASC transporter associated with tumor proliferation. (c) 2012 Elsevier Inc. All rights reserved.