Synthesis of high specific activity (+)- and (-)-6-18Ffluoronorepinephrine via the nucleophilic aromatic substitution reaction

The first example of a no-carrier-added 18F-labeled catecholamine, 6-18Ffluoronorepinephrine (6-18FFNE), has been synthesized via nucleophilic aromatic substitution. The racemic mixture was resolved on a chiral HPLC column to obtain pure samples of (-)-6-18FFNE and (+)6-18FFNE. 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/mumol 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 beta-hydroxylase. Positron emission tomography (PET) studies with racemic 6-18FFNE show high uptake and retention in the baboon heart. This work demonstrates that nucleophilic aromatic substitution by 18Ffluoride 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.