Synthesis and preliminary biological evaluation of O-2((2-[(18)F]fluoroethyl)methylamino)ethyltyrosine ([(18)F]FEMAET) as a potential cationic amino acid PET tracer for tumor imaging

Amino Acids. 2014 Aug;46(8):1947-59. doi: 10.1007/s00726-014-1754-7. Epub 2014 May 7.

Abstract

Amino acid transport is an attractive target for oncologic imaging. Despite a high demand of cancer cells for cationic amino acids, their potential as PET probes remains unexplored. Arginine, in particular, is involved in a number of biosynthetic pathways that significantly influence carcinogenesis and tumor biology. Cationic amino acids are transported by several cationic transport systems including, ATB(0,+) (SLC6A14), which is upregulated in certain human cancers including cervical, colorectal and estrogen receptor-positive breast cancer. In this work, we report the synthesis and preliminary biological evaluation of a new cationic analog of the clinically used PET tumor imaging agent O-(2-[(18)F]fluroethyl)-L-tyrosine ([(18)F]FET), namely O-2((2-[(18)F]fluoroethyl)methylamino)ethyltyrosine ([(18)F]FEMAET). Reference compound and precursor were prepared by multi-step approaches. Radiosynthesis was achieved by no-carrier-added nucleophilic [(18)F]fluorination in 16-20% decay-corrected yields with radiochemical purity >99%. The new tracer showed good stability in vitro and in vivo. Cell uptake assays demonstrated that FEMAET and [(18)F]FEMAET accumulate in prostate cancer (PC-3) and small cell lung cancer cells (NCI-H69), with an energy-dependent mechanism. Small animal PET imaging with NCI-H69 xenograft-bearing mice revealed good tumor visualization comparable to [(18)F]FET and low brain uptake, indicating negligible transport across the blood-brain barrier. In conclusion, the non-natural cationic amino acid PET probe [(18)F]FEMAET accumulates in cancer cells in vitro and in vivo with possible involvement of ATB(0,+).

MeSH terms

  • Amino Acid Transport Systems* / analysis
  • Amino Acids / analysis
  • Amino Acids / metabolism
  • Animals
  • Blood-Brain Barrier
  • Cell Line, Tumor
  • Diagnostic Imaging / methods
  • Female
  • Fluorine Radioisotopes / chemistry
  • Humans
  • Lung Neoplasms / diagnosis
  • Lung Neoplasms / diagnostic imaging*
  • Male
  • Mice
  • Mice, Nude
  • Neoplasm Transplantation
  • Positron-Emission Tomography / methods
  • Prostatic Neoplasms / diagnosis
  • Prostatic Neoplasms / diagnostic imaging*
  • Protein Transport
  • Radiopharmaceuticals
  • Small Cell Lung Carcinoma / diagnosis
  • Small Cell Lung Carcinoma / diagnostic imaging*
  • Transplantation, Heterologous
  • Tyrosine / analogs & derivatives*
  • Tyrosine / chemical synthesis

Substances

  • Amino Acid Transport Systems
  • Amino Acids
  • Fluorine Radioisotopes
  • O-2((2-fluoroethyl)methylamino)ethyltyrosine
  • Radiopharmaceuticals
  • Tyrosine