title: Synthesis and evaluation of 18F labeled alanine derivatives as potential tumor imaging agents.
abstract: BACKGROUND
  This paper reports the synthesis and labeling of (18)F 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 (18)F 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-[(18)F]fluoromethyl)-L-alanine (L-[(18)F]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 (18)F 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-[(18)F]FMA in 9L glioma and PC-3 prostate cancer cells was higher than that observed for the other two alanine derivatives and [(18)F]FDG in the first 1h. Inhibition of cell uptake studies suggested that L-[(18)F]FMA uptake in 9L glioma was predominantly via transport system ASC. After entering into cells, L-[(18)F]FMA remained stable and was not incorporated into protein within 2h. In vivo biodistribution studies demonstrated that L-[(18)F]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-[(18)F]FMA in both 9L rat and transgenic mouse.
  
  
  CONCLUSIONS
  L-[(18)F]FMA showed promising properties as a PET imaging agent for up-regulated ASC transporter associated with tumor proliferation.
authors.affiliation: Department of Radiology, University of Pennsylvania, Philadelphia, PA 19104, USA.
authors.forename: Limin
authors.initials: L
authors.lastname: Wang
authors.forename: Zhihao
authors.initials: Z
authors.lastname: Zha
authors.forename: Wenchao
authors.initials: W
authors.lastname: Qu
authors.forename: Hongwen
authors.initials: H
authors.lastname: Qiao
authors.forename: Brian P
authors.initials: BP
authors.lastname: Lieberman
authors.forename: Karl
authors.initials: K
authors.lastname: Plössl
authors.forename: Hank F
authors.initials: HF
authors.lastname: Kung
mesh_terms: D000409:Alanine / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000493:pharmacokinetics; D000818:Animals; D001692:Biological Transport; D045744:Cell Line, Tumor; D060326:Chemistry Techniques, Synthetic; D005260:Female; D005462:Fluorine Radioisotopes; D006801:Humans; D007553:Isotope Labeling; D008297:Male; D008325:Mammary Neoplasms, Experimental / Q000000981:diagnostic imaging*; D051379:Mice; D049268:Positron-Emission Tomography / Q000379:methods*; D051381:Rats; D013237:Stereoisomerism
chemical_list: D005462:Fluorine Radioisotopes; D000409:Alanine