title: 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.
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,+).
authors.affiliation: Center for Radiopharmaceutical Sciences ETH-PSI-USZ, Institute of Pharmaceutical Sciences ETH, Zurich, Switzerland.
authors.forename: Aristeidis
authors.initials: A
authors.lastname: Chiotellis
authors.forename: Adrienne
authors.initials: A
authors.lastname: Müller
authors.forename: Karin
authors.initials: K
authors.lastname: Weyermann
authors.forename: Dominique S
authors.initials: DS
authors.lastname: Leutwiler
authors.forename: Roger
authors.initials: R
authors.lastname: Schibli
authors.forename: Simon M
authors.initials: SM
authors.lastname: Ametamey
authors.forename: Stefanie D
authors.initials: SD
authors.lastname: Krämer
authors.forename: Linjing
authors.initials: L
authors.lastname: Mu
mesh_terms: D026905:Amino Acid Transport Systems / Q000032:analysis; D000596:Amino Acids / Q000032:analysis / Q000378:metabolism; D000818:Animals; D001812:Blood-Brain Barrier; D045744:Cell Line, Tumor; D003952:Diagnostic Imaging / Q000379:methods; D005260:Female; D005462:Fluorine Radioisotopes / Q000737:chemistry; D006801:Humans; D008175:Lung Neoplasms / Q000175:diagnosis / Q000000981:diagnostic imaging*; D008297:Male; D051379:Mice; D008819:Mice, Nude; D009368:Neoplasm Transplantation; D049268:Positron-Emission Tomography / Q000379:methods; D011471:Prostatic Neoplasms / Q000175:diagnosis / Q000000981:diagnostic imaging*; D021381:Protein Transport; D019275:Radiopharmaceuticals; D055752:Small Cell Lung Carcinoma / Q000175:diagnosis / Q000000981:diagnostic imaging*; D014183:Transplantation, Heterologous; D014443:Tyrosine / Q000031:analogs & derivatives* / Q000138:chemical synthesis
chemical_list: D026905:Amino Acid Transport Systems; D000596:Amino Acids; D005462:Fluorine Radioisotopes; C000597007:O-2((2-fluoroethyl)methylamino)ethyltyrosine; D019275:Radiopharmaceuticals; D014443:Tyrosine