title: Synthesis and biological evaluation of (18)F-labeled Fluoroethoxy tryptophan analogues as potential PET tumor imaging agents.
abstract: As a continuation of our research efforts toward the development of tryptophan-based radiotracers for tumor imaging with positron emission tomography (PET), three new fluoroethoxy tryptophan analogues were synthesized and evaluated in vivo. These new tracers (namely, 4-(2-[(18)F]fluoroethoxy)-dl-tryptophan ([(18)F]4-FEHTP), 6-(2-[(18)F]fluoroethoxy)-dl-tryptophan ([(18)F]6-FEHTP), and 7-(2-[(18)F]fluoroethoxy)-dl-tryptophan ([(18)F]7-FEHTP) carry the fluoroethoxy side chain either at positions 4-, 6-, or 7- of the indole core. Reference compounds and precursors were synthesized by multistep approaches. Radiosynthesis was accomplished by no-carrier-added nucleophilic (18)F-fluorination following either an indirect approach (O-alkylation of the corresponding hydroxytryptophan with [(18)F]fluoroethyltosylate) or a direct approach (nucleophilic [(18)F] fluorination using a protected mesyl precursor). Radiochemical yields (decay corrected) for both methods were in the range of 10-18%. Small animal PET imaging with xenograft-bearing mice revealed the highest tumor/background ratio for [(18)F]6-FEHTP which, in a direct comparison, outperformed the other two tryptophan tracers and also the well-established tyrosine analogue O-(2-[(18)F]fluoroethyl)-l-tyrosine ([(18)F]l-FET). Investigation of the transport mechanism of [(18)F]6-FEHTP in small cell lung cancer cells (NCI-H69) revealed that it is most probably taken up exclusively via the large neutral amino acid transporter(s) (LAT).
authors.affiliation: Center for Radiopharmaceutical Sciences ETH-PSI-USZ, Institute of Pharmaceutical Sciences ETH , Vladimir-Prelog-Weg 4, 8093 Zurich, Switzerland.
authors.forename: Aristeidis
authors.initials: A
authors.lastname: Chiotellis
authors.forename: Adrienne
authors.initials: A
authors.lastname: Muller
authors.forename: Linjing
authors.initials: L
authors.lastname: Mu
authors.forename: Claudia
authors.initials: C
authors.lastname: Keller
authors.forename: Roger
authors.initials: R
authors.lastname: Schibli
authors.forename: Stefanie D
authors.initials: SD
authors.lastname: Krämer
authors.forename: Simon M
authors.initials: SM
authors.lastname: Ametamey
mesh_terms: D006916:5-Hydroxytryptophan / Q000737:chemistry; D027182:Amino Acid Transport System y+ / Q000378:metabolism; D027241:Amino Acid Transport System y+L; D000818:Animals; D045744:Cell Line, Tumor; D015195:Drug Design; D005260:Female; D005462:Fluorine Radioisotopes / Q000737:chemistry*; D006801:Humans; D008175:Lung Neoplasms / Q000000981:diagnostic imaging; D051379:Mice; D008819:Mice, Nude; D009368:Neoplasm Transplantation; D049268:Positron-Emission Tomography; D019275:Radiopharmaceuticals / Q000138:chemical synthesis; D014364:Tryptophan / Q000031:analogs & derivatives / Q000138:chemical synthesis*
chemical_list: C000599876:4-(2-fluoroethoxy)tryptophan; C000599877:6-(2-fluoroethoxy)tryptophan; C000599878:7-(2-fluoroethoxy)tryptophan; D027182:Amino Acid Transport System y+; D027241:Amino Acid Transport System y+L; D005462:Fluorine Radioisotopes; D019275:Radiopharmaceuticals; C518287:Slc7a7 protein, mouse; D014364:Tryptophan; D006916:5-Hydroxytryptophan
keywords: LAT1; PET; tryptophan; tumor imaging