Synthesis and evaluation of 2-amino-5-(4-[(18)F]fluorophenyl)pent-4-ynoic acid ([(18)F]FPhPA): a novel (18)F-labeled amino acid for oncologic PET imaging

Nucl Med Biol. 2014 Sep;41(8):660-9. doi: 10.1016/j.nucmedbio.2014.05.140. Epub 2014 Jun 2.

Abstract

Introduction: (18)F-labeled amino acids are important PET radiotracers for molecular imaging of cancer. This study describes synthesis and radiopharmacological evaluation of 2-amino-5-(4-[(18)F]fluorophenyl)pent-4-ynoic acid ([(18)F]FPhPA) as a novel amino acid radiotracer for oncologic imaging.

Methods: (18)F]FPhPA was prepared using Pd-mediated Sonogashira cross-coupling reaction between 4-[(18)F]fluoroiodobenzene ([(18)F]FIB) and propargylglycine. The radiopharmacological profile of [(18)F]FPhPA was evaluated in comparison with O-(2-[(18)F]fluoroethyl)-L-tyrosine ([(18)F]FET) using the murine breast cancer cell line EMT6 involving cellular uptake studies, radiotracer uptake competitive inhibition experiments and small animal PET imaging.

Results: (18)F]FPhPA was prepared in 42±10% decay-corrected radiochemical yield with high radiochemical purity >95% after semi-preparative HPLC purification. Cellular uptake of L-[(18)F]FPhPA reached a maximum of 58±14 % radioactivity/mg protein at 90 min. Lower uptake was observed for racemic and D-[(18)F]FPhPA. Radiotracer uptake inhibition studies by synthetic and naturally occurring amino acids suggested that Na(+)-dependent system ASC, especially ASCT2, and Na(+)-independent system L are important amino acid transporters for [(18)F]FPhPA uptake into EMT6 cells. Small animal PET studies demonstrated similar high tumor uptake of [(18)F]FPhPA in EMT6 tumor-bearing mice compared to [(18)F]FET reaching a maximum standardized uptake value (SUV) of 1.35 after 60 min p.i.. Muscle uptake of [(18)F]FPhPA was higher (SUV30min=0.65) compared to [(18)F]FET (SUV30min=0.40), whereas [(18)F]FPhPA showed a more rapid uptake and clearance from the brain compared to [(18)F]FET.

Conclusion: L-[(18)F]FPhPA is the first (18)F-labeled amino acid prepared through Pd-mediated cross-coupling reaction.

Advances in knowledge and implications for patient care: L-[(18)F]FPhPA displayed promising properties as a novel amino acid radiotracer for molecular imaging of system ASC and system L amino acid transporters in cancer.

Keywords: (18)F; Amino acid transporters; Amino acids; Positron emission tomography (PET); Sonogashira reaction; Tumor imaging.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Transport System ASC / metabolism
  • Amino Acids / chemical synthesis*
  • Amino Acids / chemistry
  • Amino Acids / metabolism
  • Amino Acids, Aromatic / chemical synthesis*
  • Amino Acids, Aromatic / chemistry
  • Amino Acids, Aromatic / metabolism
  • Animals
  • Binding, Competitive
  • Biological Transport
  • Cell Line, Tumor
  • Chemistry Techniques, Synthetic
  • Gene Expression Regulation, Neoplastic
  • Kinetics
  • Large Neutral Amino Acid-Transporter 1 / metabolism
  • Mammary Neoplasms, Experimental / diagnostic imaging*
  • Mammary Neoplasms, Experimental / metabolism
  • Mammary Neoplasms, Experimental / pathology
  • Mice
  • Minor Histocompatibility Antigens
  • Positron-Emission Tomography / methods*
  • Radiochemistry
  • Temperature

Substances

  • 2-amino-5-(4-fluorophenyl)pent-4-ynoic acid
  • Amino Acid Transport System ASC
  • Amino Acids
  • Amino Acids, Aromatic
  • Large Neutral Amino Acid-Transporter 1
  • Minor Histocompatibility Antigens
  • Slc1a4 protein, mouse
  • Slc1a5 protein, mouse