Synthesis, enantiomeric resolution, F-18 labeling and biodistribution of reboxetine analogs: promising radioligands for imaging the norepinephrine transporter with positron emission tomography

Racemic and enantiomerically pure ((S,S) and (R,R)) 2-[α-(2-(2-[18F]fluoroethoxy)phenoxy)benzyl]morpholine ([18F]FRB) and its tetradeuterated form [18F]FRB-D4, analogs of the highly selective norepinephrine reuptake inhibitor reboxetine (2-[α-(2-ethoxyphenoxy)benzyl]morpholine, RB), have been synthesized for studies of norepinephrine transporter (NET) system with positron emission tomography (PET). The [18F]fluorinated precursor, (S,S)/(R,R)-N-tert-butyloxycarbonyl-2-[α-(2-hydroxyphenoxy)benzyl]morpholine ((S,S)/(R,R)-N-Boc-desethylRB), was prepared by the N-protection of (S,S)/(R,R)-2-[α-(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 [18F]FRB and [18F]FRB-D4 via the following three-step procedure: (1) formation of 1-bromo-2-[18F]fluoroethane ([18F]BFE or [18F]BFE-D4) by nucleophilic displacement of 2-bromoethyl triflate (or D4 analog) with no-carrier added [18F]F− in THF; (2) reaction of [18F]BFE (or [18F]BFE-D4) 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 [18F]FRB and [18F]FRB-D4 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/μmol (EOB). The results of the whole-body biodistribution studies with (S,S)-[18F]FRB-D4 were similar to those with (S,S)-[18F]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)-[18F]FRB-D4 may be a potentially useful ligand for imaging NET with PET.