Appl. Radiat.Isot. Vol. 42, No. 7, pp. 629-635, 1991 ht. J. Radiat.Appl. Instrum. Part A Printed in Great Britain. All rights reserved 0883-2889/91 $3.00 + 0.00 Copyright Q 1991 Pergamon Press plc An approach to the Asymmetric Synthesis of L-6[ ‘*F]Fluorodopa via NCA Nucleophilic Fluorination* CHRISTIAN LEMAIRE, MARCEL GUILLAUMET, ROBERT CANTINEAU, ALAIN PLENEVAUX and LEON CHRISTIAENS Cyclotron Research Center, Litge University, 4000 Litge, Belgium (Received 24 July 1990; in revised form 23 November 1990) The NCA asymmetric synthesis of zyxwvutsrqponmlkjihgfedcbaZYXWVUTSRQPONMLKJIHGFEDCBA L-6-[ ‘*F]fluorodopa starting from (lR,2R,5R)-[( +)-2_hydroxypinanyl- 3-idenelglycine t-butyl ester as chiral agent has been developed. After ‘8F-fluorination of the two commercially available aldehydes either 6-nitroveratraldehyde or 6-nitropiperonal, the required alkylating [ ‘SF]fluorobenzyl bromide derivative can be easily prepared by treatment with NaBH, followed by SOBr,. Alkylation of the Schiff base was carried out with the lithium salt of 2,2,6,6_tetramethylpiperidine as base in anhydrous THF at -78°C. Following hydrolysis of the protecting groups with hydroxylamine and Hl, the L-amino acid was obtained in 75% L form (ee 50%) with a 10% decay corrected (120min) radiochemical yield. Introduction A large number of neuropsychiatric diseases are related to alterations occurring in the dopaminergic system. In uiuo characterization of intracerebral dis- tribution and metabolism of dopamine in the human brain by means of positron emission tomography (PET) using a specific radiopharmaceutical, L-6- [‘EF]fluorodopa, was first reported by Garnett zyxwvutsrqponmlkjihgfedcbaZYXWVUTSRQPONMLKJIHGFED et al. (1983). In spite of the numerous production pathways for L-6-[ ‘*F]fluorodopa reported in the literature over the last ten years, the development of a method starting from easily prepared [“Flfluoride is still a desirable objective. Most of the described syntheses are based on the electrophilic fluorination of an optically active protected derivative of L-dopa, or fluorination of L-dopa itself (Adam et al., 1986a,b; Chaly and Diksic, 1986; Chirakal et al., 1984, 1986; Coenen er al., 1988; Firnau et al., 1980, 1984, 1986). These preparations generally lead without loss of chirality during the synthesis to a mixture of fluoro isomers of variable specific activity (<2 Ci/mmol). The methods have been extended to desylylation and demercuration reactions which are stereospecific for the 6-fluoro isomer (Diksic and Farrokhzad, 1985; Adam and Jivan, 1988; Luxen et al., 1986, 1990). *Part of this work was presented at the 36th Annual M eeting of the Society of Nuclear Medicine, St Louis, MO, 13-16 June, 1989, Abstract 99. tAuthor for correspondence. Nearly all currently used ‘*F-labelled radio- pharmaceuticals are synthesized with [ ‘8F]fluoride produced by proton bombardment of enriched [ ‘80]water. A synthesis of L-6-[ ‘*F]fluorodopa start- ing from [ ‘8F]fluoride would greatly simplify labora- tory procedures as well as making available higher activities of this radiopharmaceutical in the no- carrier-added (NCA) form. Recently, a nucleophilic route using 18F produced from enriched [ ‘80]water was successfully developed for the regioselective preparation of L-6- [‘8F]fluorodopa by the NCA fluorination method (replacement of nitro groups by “F) starting from two commercially available precursors: 6-nitrovera- traldehyde and 6-nitropiperonal (Lemaire et al., 1990). Condensation of the fluoro-aldehydes with phenyloxazolone and subsequent hydrolysis lead, after HPLC purification, to the D and L forms of L-6-[ “Flfluorodopa in equal quantities. A chiral HPLC separation with a 50% loss of activity is necessary to obtain the pure L-form. An asymmetric synthesis with a chiral agent induc- ing chirality in the final molecule therefore appears as a promising pathway for the preparation of the enantiometrically pure D- or L-forms of the 6- [“Flfluorodopa in high activities. This paper reports an asymmetric synthesis of L-6-[“Flfluorodopa using the same two precursors as in the recently described oxazolone method (Lemaire et al., 1990) but followed by a chiral alkylation under basic conditions as shown in Schemes 1 and 2. 629