Synthesis, uptake mechanism characterization and biological evaluation of (18)F labeled fluoroalkyl phenylalanine analogs as potential PET imaging agents.

INTRODUCTION: Amino acids based tracers represent a promising class of tumor metabolic imaging agents with successful clinical applications. Two new phenylalanine derivatives, p-(2-[(18)F]fluoroethyl)-L-phenylalanine (FEP, [(18)F]2) and p-(3-[(18)F]fluoropropyl)-L-phenylalanine (FPP, [(18)F]3) were synthesized and evaluated in comparison to clinically utilized O-(2-[(18)F]fluoroethyl)-L-tyrosine (FET, [(18)F]1).

METHODS: FEP ([(18)F]2) and FPP ([(18)F]3) were successfully synthesized by a rapid and efficient two-step nucleophilic fluorination of tosylate precursors and deprotection reaction. In vitro cell uptake studies were carried out in 9L glioma cells. In vivo studies, 9L tumor xenografts were implanted in Fisher 344 rats.

RESULTS: FEP ([(18)F]2) and FPP ([(18)F]3) could be efficiently labeled within 90 min with good enantiomeric purity (>95%), good yield (11-37%) and high specific activity (21-69 GBq/μmol). Cell uptake studies showed FEP had higher uptake than FPP as well as reference ligand FET ([(18)F]1). Uptake mechanism studies suggested that FEP is a selective substrate for system L and prefers its subtype LAT1. In vivo biodistribution studies demonstrated FEP had specific accumulation in tumor cells and tumor to background ratio reached 1.45 at 60 min. Small animal positron emission tomography (PET) imaging studies showed FEP was comparable to FET for imaging rats bearing 9L tumor model. FEP had high uptake in 9L tumor compared to surrounding tissue and was quickly excreted through urinary tract.

CONCLUSION: Biological evaluations indicate that FEP ([(18)F]2) is a potential useful tracer for tumor imaging with PET.