Fully automated synthesis module for the high yield one-pot preparation of 6-[${}^{18}\text{F}$]fluoro-l-DOPA

Abstract

A fully automated one-pot synthesis of 6-[${}^{18}\text{F}$]fluoro-l-DOPA, an important radiopharmaceutical for studies on the presynaptic dopamine metabolism with positron emission tomography, is described. 6-[${}^{18}\text{F}$]Fluoro-l-DOPA was prepared in high radiochemical yield (33±4%, c.f.d.) and radiochemical purity (>99%) in 45 min synthesis time by a fluorodestannylation reaction, followed by acidic removal of the protecting groups. CFCl₃ was found to be a better solvent for the fluorodestannylation reaction than CHCl₃ or acetonitrile. In CFCl₃, [${}^{18}\text{F}$]F₂ was a superior fluorinating agent over [${}^{18}\text{F}$]acetyl hypofluorite.

Introduction

Nowadays, 6-[${}^{18}\text{F}$]fluoro-l-3,4-dihydroxyphenylalanine (6-[${}^{18}\text{F}$]fluoro-l-DOPA, 3) has become a well-established tracer to study the presynaptic dopamine metabolism in vivo with positron emission tomography (PET) Garnett et al., 1983, Vingerhoets et al., 1994. The increased demand for 6-[${}^{18}\text{F}$]fluoro-l-DOPA in our institution has created the need for a simple, reliable and fully automated procedure for its routine production for clinical studies. In the past two decades, several approaches for the synthesis of 6-[${}^{18}\text{F}$]fluoro-l-DOPA have been described and reviewed (Luxen et al., 1992), e.g. nucleophilic substitution (radiochemical yield up to 23%, c.f.d.; Lemaire et al., 1989, Lemaire et al., 1994), non-regioselective direct electrophilic substitution (radiochemical yield up to 18%, c.f.d.; Firnau et al., 1984, Chirakal et al., 1986, Ishiwata et al., 1993) and electrophilic fluorodemetalation (radiochemical yield up to 26%. c.f.d.; Luxen et al., 1990, Namavari et al., 1992, Dolle et al., 1998, Szajek et al., 1998). Although the production of [${}^{18}\text{F}$]F₂ gas for the electrophilic substitution is more difficult than the production of [${}^{18}\text{F}$]fluoride, the preparation of 6-[${}^{18}\text{F}$]fluoro-l-DOPA via nucleophilic substitution does not appear to be very attractive for automation of routine production, since it consists of a multistep procedure using sensitive reagents. A disadvantage of the synthesis of 6-[${}^{18}\text{F}$]fluoro-l-DOPA by direct electrophilic fluorination of a protected DOPA derivative is the formation of isomers that have to be separated.

On the other hand, the preparation of 6-[${}^{18}\text{F}$]fluoro-l-DOPA via electrophilic fluorodemetalation, especially via fluorodestannylation, is facile, stereoselective and gives good yields. For these reasons, we adapted the fluorodestannylation method described by Namavari and coworkers (Namavari et al., 1992) and developed a simple, fully automated synthesis module for the routine clinical production of 6-[${}^{18}\text{F}$]fluoro-l-DOPA by modification of a commercially available PET Tracer Synthesizer (Nuclear Interface).