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-[α-(2-(2-[ 18F]fluoroethoxy)phenoxy)benzyl]morpholine ([ 18F]FRB) and its tetradeuterated form [ 18F]FRB-D 4, 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-D 4 via the following three-step procedure: (1) formation of 1-bromo-2-[ 18F]fluoroethane ([ 18F]BFE or [ 18F]BFE-D 4) by nucleophilic displacement of 2-bromoethyl triflate (or D 4 analog) with no-carrier added [ 18F]F − in THF; (2) reaction of [ 18F]BFE (or [ 18F]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 [ 18F]FRB and [ 18F]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/μmol (EOB). The results of the whole-body biodistribution studies with ( S, S)-[ 18F]FRB-D 4 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-D 4 may be a potentially useful ligand for imaging NET with PET.