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Synthesis, enantiomeric resolution, and selective C‐11 methylation of a highly selective radioligand for imaging the norepinephrine transporter with positron emission tomography
Author(s) -
Lin KuoShyan,
Ding YuShin
Publication year - 2004
Publication title -
chirality
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.43
H-Index - 77
eISSN - 1520-636X
pISSN - 0899-0042
DOI - 10.1002/chir.20055
Subject(s) - chemistry , morpholine , enantiomer , radioligand , radiosynthesis , high performance liquid chromatography , norepinephrine transporter , chiral column chromatography , enantiomeric excess , stereochemistry , positron emission tomography , medicinal chemistry , chromatography , organic chemistry , enantioselective synthesis , transporter , receptor , medicine , biochemistry , radiology , catalysis , gene
Reboxetine, 2‐[α‐(2‐ethoxyphenoxy)benzyl]morpholine, is a highly selective norepinephrine transporter (NET) blocker that has been used for the treatment of depression. Its methyl analogue, 2‐[α‐(2‐methoxyphenoxy)benzyl]morpholine (MRB), has been radiolabeled with C‐11 for studies of the NET system with positron emission tomography (PET). The normethyl precursor, 2‐[α‐(2‐hydroxyphenoxy)benzyl]morpholine (desethylreboxetine), was synthesized in 6% overall yield via a multi‐step regio‐ and stereo‐specific synthesis, starting from a mono‐O‐protected catechol. The resulting racemic mixture of desethylreboxetine was resolved by chiral HPLC to provide the (2 S ,3 S ) and (2 R ,3 R ) enantiomers in >98% enantiomeric excess. These enantiomers were then used as precursors for radiosynthesis to prepare enantiomerically pure individual 11 C‐labeled MRB enantiomers for comparative PET studies in baboons. Selective C‐11 methylation at the phenolic oxygen with [ 11 C]CH 3 I was achieved in the presence of excess base. After HPLC purification, racemic ((2 S ,3 S )/(2 R ,3 R )) or enantiomerically pure ((2 S ,3 S ) or (2 R ,3 R )) [ 11 C]MRB was obtained in 61–74% decay‐corrected radiochemical yields from [ 11 C]CH 3 I in a synthesis time of 40 min with a radiochemical purity of >96% and a specific activity of 1.7–2.3 Ci/μmol (63–85 GBq/μmol) corrected from the end of bombardment (EOB). Chirality 16:475–481, 2004 . © 2004 Wiley‐Liss, Inc.