Synthesis and comparative biological evaluation of L- and D-isomers of 18F-labeled fluoroalkyl phenylalanine derivatives as tumor imaging agents.

INTRODUCTION

L-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-[(18)F]fluoroethyl)-phenylalanine ([(18)F]FEP), in comparison to its L-isomer and previously reported the L- and D-isomers of O-(2-[(18)F]fluoroethyl)-tyrosine ([(18)F]FET).

METHODS

L- and D-Isomers of [(18)F]FET and [(18)F]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.

RESULTS

L- and D-Isomers of (18)F-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-[(18)F]FEP showed a similar linear time-dependent uptake as D-[(18)F]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-[(18)F]FEP, was 1.4- and 5.2-fold of that reported for L- and D-[(18)F]FET, respectively. Transport characterization studies indicated that both L- and D-[(18)F]FEP were selective substrates for system L. While L-[(18)F]FEP exhibited preference towards one subtype of system L, LAT1, D-[(18)F]FEP did not exhibit the same preference. Small animal PET imaging studies showed that both L- and D-[(18)F]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.

CONCLUSION

Both L- and D-[(18)F]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-[(18)F]FEP did not show better imaging properties than their corresponding L-isomer.