Synthesis, enantiomeric resolution, and selective C‐11 methylation of a highly selective radioligand for imaging the norepinephrine transporter with positron emission tomography

Abstract

Reboxetine, 2-[alpha-(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-[alpha-(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-[alpha-(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 (2S,3S) and (2R,3R) enantiomers in >98% enantiomeric excess. These enantiomers were then used as precursors for radiosynthesis to prepare enantiomerically pure individual 11C-labeled MRB enantiomers for comparative PET studies in baboons. Selective C-11 methylation at the phenolic oxygen with [11C]CH3I was achieved in the presence of excess base. After HPLC purification, racemic ((2S,3S)/(2R,3R)) or enantiomerically pure ((2S,3S) or (2R,3R)) [11C]MRB was obtained in 61-74% decay-corrected radiochemical yields from [11C]CH3I in a synthesis time of 40 min with a radiochemical purity of >96% and a specific activity of 1.7-2.3 Ci/micromol (63-85 GBq/micromol) corrected from the end of bombardment (EOB).

A novel nicotinic acetylcholine receptor antagonist radioligand for PET studies

“…[ 11 C]NMI-EPB was obtained using a procedure similar to that described in our previous papers for the radiosynthesis of norepinephrine ligands 18,19 by alkylating 1.0 mg of the corresponding demethylated precursor 16 of NMI-EPB in DMF (0.25 mL) with [ 11 C]methyl iodide. After 5 min at 110°C, the product was purified by HPLC using a Phenomenex Luna C-18 semi-preparative column (250 mm · 10 mm, 5 lm) eluting with 20:80 CH 3 CN/0.2 M NH 4 OAc at a flow rate of 3.0 mL/min.…”

Rearrangement of β‐amino alcohols and application to the synthesis of biologically active compounds

“…(S,S)-Reboxetine is a selective norepinephrine reuptake inhibitor (NRI) which has been widely studied for its pharmacological properties. 48,49 We have to point out that the (S,S)-reboxetine has a greater affinity and selectivity for the norepinephrine transporter than its (R,R)-enantiomer 50 and different methods have been developed to access the (S,S)-enantiomer such as chemical resolution, 51,52 capillary electrophoresis, 53 chiral HPLC, [54][55][56] and asymmetric syntheses. 51,[57][58][59][60][61] As the rearrangement of linear b-amino alcohols was very selective under catalytic conditions, the synthesis of (S,S)-reboxetine was envisaged to pass through b-amino alcohol K. Rearrangement of compound K should lead to L, a known precursor of (S,S)-reboxetine (Scheme 7).…”

Labeled 3-aryl-4-indolylmaleimide derivatives and their potential as angiogenic PET biomarkers

“…The radiolabeling approach was based on the general C-11 methylation reaction of the free hydroxy group 23 and was adapted for use in a commercial module (GE, Münster, Germany). Carbon-11 methyl iodide was prepared according to well documented procedures.…”