Synthesis and comparative biological evaluation of l- and d-isomers of 18F-labeled fluoroalkyl phenylalanine derivatives as tumor imaging agents

Introductionl-Amino acid-based tracers have established their important role as tumor metabolic imaging agents. Recently, a number of studies demonstrated that d-amino acids may have improved imaging properties than their corresponding l-isomers. We synthesized and evaluated the d-isomer of a new phenylalanine derivative, p-(2-[18F]fluoroethyl)-phenylalanine ([18F]FEP), in comparison to its l-isomer and previously reported the l- and d-isomers of O-(2-[18F]fluoroethyl)-tyrosine ([18F]FET).Methodsl- and d-Isomers of [18F]FET and [18F]FEP were successfully synthesized via a rapid and efficient two-step nucleophilic fluorination and deprotection reaction. In vitro studies were carried out in 9L glioma cells. In in vivo studies, Fisher 344 rats bearing the 9L tumor model were used.Resultsl- and d-Isomers of 18F-fluoroalkyl tyrosine and phenylalanine derivatives were efficiently labeled with high enantiomeric purity (>95%), good yield (11–45%) and high specific activity (21–75 GBq/μmol). d-[18F]FEP showed a similar linear time-dependent uptake as d-[18F]FET, while their corresponding l-isomers had much faster and higher uptake (4.3- to 16.0-fold at maximum uptake). The maximum uptake of the new compounds, l- and d-[18F]FEP, was 1.4- and 5.2-fold of that reported for l- and d-[18F]FET, respectively. Transport characterization studies indicated that both l- and d-[18F]FEP were selective substrates for system L. While l-[18F]FEP exhibited preference towards one subtype of system L, LAT1, d-[18F]FEP did not exhibit the same preference. Small animal PET imaging studies showed that both l- and d-[18F]FEP had higher uptake in 9L tumor compared to surrounding tissues, but d-isomer had lower tumor-to-muscle ratio in comparison with its l-isomer.ConclusionBoth l- and d-[18F]FEP are substrates for system L amino acid transporter with different preference toward its subtypes. Small animal imaging studies of 9L tumor showed that d-[18F]FEP did not show better imaging properties than their corresponding l-isomer.