Elsevier

Applied Radiation and Isotopes

Volume 67, Issue 9, September 2009, Pages 1650-1653
Applied Radiation and Isotopes

Automated synthesis of n.c.a. [18F]FDOPA via nucleophilic aromatic substitution with [18F]fluoride

https://doi.org/10.1016/j.apradiso.2009.03.003Get rights and content

Abstract

An improved, automated synthesis of [18F]FDOPA including four synthetic steps (fluorination, reductive iodination, alkylation and hydrolysis) is reported with each step optimized individually. In a home-made automatic synthesizer, 9064±3076 MBq of [18F]FDOPA were produced within 120 min from EOB (n=5). Radiochemical purity and enantiomeric excess were both ⩾95%. Specific activity was ca. 50 GBq/μmol at EOS. This automatically operable synthesis is well suited for the multi-patient-dose routine production of n.c.a. [18F]FDOPA.

Introduction

[18F]FDOPA is a well accepted and applied radiotracer especially for the evaluation of the presynaptic dopaminergic function by means of PET (Seibyl et al., 2007). The labeling of [18F]FDOPA can be accomplished either by electrophilic or nucleophilic substitution. In most cases, the routine production of [18F]FDOPA is still realized by electrophilic methods (Fuechtner et al., 2002; Dollé et al., 1998). However, low yields of [18F]F2 produced at the cyclotron using the 20Ne(d,α)18F nuclear reaction or at least the need of a dedicated gas target using the 18O(p,n)18F reaction make a synthetic route via a nucleophilic mechanism with [18F]fluoride highly attractive. In addition, only in the latter case high specific activities can be achieved. Since 1990s, several approaches employing the nucleophilic method have been reported (Reddy et al., 1993; Kaneko et al., 1999; Tierling, 2002; Krasikova et al., 2004). The strategy of Lemaire et al. (2004) seems the most promising for routine production of [18F]FDOPA, as disadvantages for a remote operation, i.e. low temperature and chiral preparative HPLC separation, can be avoided. Moreover, the product is provided in high specific activities and enantiomeric excess. Therefore, the synthesis described in this paper was developed based on this method. In order to realize a reliable large-scale production of [18F]FDOPA, the automated synthesis was improved regarding two aspects: chemical improvements (increased radiochemical yields (RCYs) for every single synthetic step) and technical optimization (e.g. to prevent marked radioactivity losses during the entire process).

Section snippets

General

Acetonitrile (for DNA synthesis) for azeotropic distillation as well as Kryptofix 2.2.2 were obtained from Merck (Darmstadt, Germany). For radiolabeling DMF (dried over molecular sieve) was used as solvent (Fluka, Germany). The compound 2-nitro-4,5-dimethoxybenzaldehyde as labeling precursor was from ABCR (Germany). O-allyl-N-(9-anthracenylmethyl)cinchonidinium as chiral phase transfer catalyst (PTC) in the alkylation reaction was prepared according to a published procedure (Zhang et al., 2002

Fluorination

The first synthetic step was 18F-fluorination of the precursor 4,5-dimethoxy-2-nitrobenzaldehyde via nucleophilic aromatic substitution. In literature, usually DMSO was used as solvent in this labeling reaction (Lemaire et al., 1992, Rengan et al., 1993). However, we previously observed the potential of DMSO to oxidize the benzaldehyde precursor to benzoic acid (Shen et al., 2007). Therefore, DMF was used instead of DMSO for the fluorination resulting in a RCY of 71±4% (n=40). In addition, it

Conclusion

N.c.a. [18F]FDOPA was synthesized in an automated system via a four-step procedure including nucleophilic aromatic substitution with [18F]fluoride. Although it has to be taken into account that maintenance of the synthesizer after each synthesis is laborious and time consuming due to the nature of chemistry involved in the process, the synthesis is reliable and the produced activities are suitable for multi-dose utilization.

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