AbstractThe use of O-(2-[¹⁸F]fluoroethyl)-l-tyrosine ([¹⁸F]FET) as a positron emission tomography (PET) tracer for brain tumor imaging might have some limitations because of the relatively low affinity for the L-type amino acid transporter 1 (LAT1). To assess the stereospecificity and evaluate the influence of aromatic ring modification of phenylalanine LAT1 targeting tracers, six different fluoroalkylated phenylalanine analogues were synthesized. After in vitro K_i determination, the most promising compound, 2-[¹⁸F]-2-fluoroethyl-l-phenylalanine (2-[¹⁸F]FELP), was selected for further evaluation and in vitro comparison with [¹⁸F]FET. Subsequently, 2-[¹⁸F]FELP was assessed in vivo and compared with [¹⁸F]FET and [¹⁸F]FDG in a F98 glioblastoma rat model. 2-[¹⁸F]FELP showed improved in vitro characteristics over [¹⁸F]FET, especially when the affinity and specificity for system L is concerned. Based on our results, 2-[¹⁸F]FELP is a promising new PET tracer for brain tumor imaging.