Synthesis and biological evaluation of ¹⁸F-labeled fluoropropyl tryptophan analogs as potential PET probes for tumor imaging

Abstract

In the search for an efficient, fluorine-18 labeled amino acid based radiotracer for tumor imaging with positron emission tomography (PET), two new tryptophan analogs were synthesized and characterized in vitro and in vivo. Both are tryptophan alkyl-derivatives, namely 2-(3-[(18)F]fluoropropyl)-DL-tryptophan ([(18)F]2-FPTRP) and 5-(3-[(18)F]fluoro-propyl)-DL-tryptophan ([(18)F]5-FPTRP). Standard reference compounds and precursors were prepared by multi step approaches. Radiosynthesis was achieved by no-carrier-added nucleophilic [(18)F]fluorination in 29-34% decay corrected yields with radiochemical purity over 99%. In vitro cell uptake assays showed that both compounds are substrates for amino acid transport and enter small cell lung cancer cells (NCI-H69) most probably almost exclusively via large neutral amino acids transporter(s) (LAT). Small animal PET imaging with xenograft bearing mice revealed high tumor/background ratios for [(18)F]2-FPTRP comparable to the well established tyrosine analog O-(2-[(18)F]fluroethyl)-L-tyrosine ([(18)F]FET). Radiometabolite studies showed no evidence of involvement of a biotransformation step in tumor accumulation.

Keywords: 2-(3-[(18)F]fluoropropyl)-dl-tryptophan); 2-amino-2-norbornanecarboxylic acid; 2-deoxy-2-((18)F)fluoro-d-glucose; 3-[(123)I]iodo-alpha-methyl-l-tyrosine); 5-(2-[(18)F]fluoroethoxy)-l-tryptophan; 5-(3-[(18)F]fluoropropyl)-dl-tryptophan; 5-hydroxy-l-[β-(11)C]tryptophan; APUD; Amino acids; BCH; BF(3)·Et(2)O; EBSS; Earle balanced salt solution; L-3,4-dihydroxy-6-[(18)F]fluorophenylalanine; LAT; O-(2-[(18)F]fluroethyl)-l-tyrosine; PET; SUV; TBAHCO(3); TBAOH; TEBAC; Tryptophan; Tumor imaging; [(11)C]5HTP; [(11)C]MET; [(123)I]IMT; [(18)F]2-FPTRP; [(18)F]5-FPTRP; [(18)F]FACBC; [(18)F]FDG; [(18)F]FDOPA; [(18)F]FET; [(18)F]L-FEHTP; aadc; amine precursor uptake and decarboxylation; anti-1-amino-3-[(18)F]-fluoro-cyclobutane-1-carboxylic acid; aromatic amino acid decarboxylase; boron trifluoride etherate; l-[(11)C-methyl]methionine); large amino acid transporter; positron emission tomography; standardized uptake values; tetrabutylammonium bicarbonate; tetrabutylammonium hydroxide; triethylbenzylammonium chloride.