title: Synthesis, enantiomeric resolution, F-18 labeling and biodistribution of reboxetine analogs: promising radioligands for imaging the norepinephrine transporter with positron emission tomography.
abstract: Racemic and enantiomerically pure ((S,S) and (R,R)) 2-[alpha-(2-(2-[(18)F]fluoroethoxy)phenoxy)benzyl]morpholine ([(18)F]FRB) and its tetradeuterated form [(18)F]FRB-D(4), analogs of the highly selective norepinephrine reuptake inhibitor reboxetine (2-[alpha-(2-ethoxyphenoxy)benzyl]morpholine, RB), have been synthesized for studies of norepinephrine transporter (NET) system with positron emission tomography (PET). The [(18)F]fluorinated precursor, (S,S)/(R,R)-N-tert-butyloxycarbonyl-2-[alpha-(2-hydroxyphenoxy)benzyl]morpholine ((S,S)/(R,R)-N-Boc-desethylRB), was prepared by the N-protection of (S,S)/(R,R)-2-[alpha-(2-hydroxyphenoxy)benzyl]morpholine ((S,S)/(R,R)-desethylRB) with a tert-butyloxycarbonyl (Boc) group followed by enantiomeric resolution with chiral HPLC to provide both (S,S) and (R,R) enantiomers with >99% enantiomeric purity. These compounds were then used for radiosynthesis to prepare enantiomerically pure [(18)F]FRB and [(18)F]FRB-D(4) via the following three-step procedure: (1) formation of 1-bromo-2-[(18)F]fluoroethane ([(18)F]BFE or [(18)F]BFE-D(4)) by nucleophilic displacement of 2-bromoethyl triflate (or D(4) analog) with no-carrier added [(18)F]F(-) in THF; (2) reaction of [(18)F]BFE (or [(18)F]BFE-D(4)) with N-Boc-desethylRB in DMF in the presence of excess base; and (3) deprotection with trifluoroacetic acid. The racemates, (S,S) and (R,R) enantiomers of [(18)F]FRB and [(18)F]FRB-D(4) were obtained in 11-27% (decay corrected to the end of bombardment, EOB) in 120-min synthesis time with a radiochemical purity of >98% and specific activities of 21-48 GBq/micromol (EOB). The results of the whole-body biodistribution studies with (S,S)-[(18)F]FRB-D(4) were similar to those with (S,S)-[(18)F]FRB but showed relatively faster blood clearance and no significant in vivo defluorination. Positron emission tomography studies in baboon brain also showed that (S,S)-[(18)F]FRB-D(4) may be a potentially useful ligand for imaging NET with PET.
authors.affiliation: Chemistry Department, Brookhaven National Laboratory, Upton, New York 11973, USA.
authors.forename: Kuo-Shyan
authors.initials: KS
authors.lastname: Lin
authors.forename: Yu-Shin
authors.initials: YS
authors.lastname: Ding
authors.forename: Sung-Won
authors.initials: SW
authors.lastname: Kim
authors.forename: Kun-Eek
authors.initials: KE
authors.lastname: Kil
mesh_terms: D000818:Animals; D005240:Feasibility Studies; D005462:Fluorine Radioisotopes / Q000737:chemistry / Q000493:pharmacokinetics*; D008297:Male; D008657:Metabolic Clearance Rate; D051379:Mice; D009025:Morpholines / Q000493:pharmacokinetics*; D050484:Norepinephrine Plasma Membrane Transport Proteins; D009928:Organ Specificity; D019275:Radiopharmaceuticals / Q000138:chemical synthesis / Q000493:pharmacokinetics; D000077593:Reboxetine; D027981:Symporters / Q000378:metabolism*; D014018:Tissue Distribution
chemical_list: D005462:Fluorine Radioisotopes; D009025:Morpholines; D050484:Norepinephrine Plasma Membrane Transport Proteins; D019275:Radiopharmaceuticals; C493228:Slc6a2 protein, mouse; D027981:Symporters; D000077593:Reboxetine