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

• Published in: Nuclear medicine and biology Vol. 39; no. 7; pp. 933 - 943
• Main Authors: Wang, Limin, Zha, Zhihao, Qu, Wenchao, Qiao, Hongwen, Lieberman, Brian P., Plössl, Karl, Kung, Hank F.
• Format: Journal Article
• Language: English
• Published: New York, NY Elsevier Inc 01-10-2012; Elsevier
• Subjects: 18F; Alanine - analogs & derivatives; Alanine - chemical synthesis; Alanine - pharmacokinetics; Alanine derivatives; Alanine–serine–cysteine preferring amino acid transporter; Amino acids; Animals; ASC; Biological and medical sciences; Biological Transport; Cell Line, Tumor; Chemistry Techniques, Synthetic; Contrast media. Radiopharmaceuticals; Female; Fluorine Radioisotopes; Humans; Isotope Labeling; Male; Mammary Neoplasms, Experimental - diagnostic imaging; Medical sciences; Mice; PET; Pharmacology. Drug treatments; Positron-Emission Tomography - methods; Rats; Stereoisomerism; Tumor imaging; FDG; MeAIB; Amino acids; TFA; ASC; FACBC; HRMS; Alanine–serine–cysteine preferring amino acid transporter; ASCT2; GA; L-FMA; HPLC; PBS; L-FEA; BCH; Solid-phase extraction; IMT; TCA; Alanine derivatives; FET; FDOPA; Tumor imaging; FC; GPNA; PET; 18F; Radionuclide study; Nuclear medicine; Thiol; Alanine; Cysteine; Radiolabelling; Serine; Biological transport; F; amino acid transporter; Sulfur containing aminoacid; Synthesis; Aminoacid; Alanine-serine-cysteine preferring; Tumor; Radioisotopic product; Derived product; Positron emission tomography; Emission tomography
• ISSN: 0969-8051; 1872-9614
• DOI: 10.1016/j.nucmedbio.2012.03.007

This 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.
Three 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).
New 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 1h. 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 2h. 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 30min. The tumor-to-muscle, tumor-to-blood and tumor-to-brain ratios at 60min 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.
L-[18F]FMA showed promising properties as a PET imaging agent for up-regulated ASC transporter associated with tumor proliferation.