Synthesis of High Specific Activity (+)- and (-)-6-[¹⁸F]Fluoronorepinephrine via the Nucleophilic Aromatic Substitution Reaction

The first example of a no-carrier-added ¹⁸F-labeled catecholamine, 6-[¹⁸F]fluoronorepinephrine (6-[¹⁸F]FNE), has been synthesized via nucleophilic aromatic substitution. The racemic mixture was resolved on a chiral HPLC column to obtain pure samples of (-)-6-[¹⁸F]FNE and (+)6-[¹⁸F]FNE. Radiochemical yields of 20% at the end of bombardment (EOB) for the racemic mixture (synthesis time 93 min), 6% for each enantiomer (synthesis time 128 min) with a specific activity of 2-5 Ci/μmol at EOB were obtained. Chiral HPLC peak assignment for the resolved enantiomers was achieved by using two independent methods: polarimetric determination and reaction with dopamine β-hydroxylase. Positron emission tomography (PET) studies with racemic 6-[¹⁸F]FNE show high uptake and retention in the baboon heart. This work demonstrates that nucleophilic aromatic substitution by [¹⁸F] fluoride ion is applicable to systems having electron-rich aromatic rings, leading to high specific activity radiopharmaceuticals. Furthermore, the suitably protected dihydroxynitrobenzaldehyde 1 may serve as a useful synthetic precursor for the radiosynthesis of other complex ¹⁸F-labeled radiotracers.