18
F]fluorobenzyl halide derivatives are key intermediates for the synthesis of various radiopharmaceuticals such as 4-[ 18 F]fluoro-L-phenylalanine, 6-[ 18 F]fluoro-L-dopa or 2-[ 18 F]fluoro-Ltyrosine. These compounds are produced in our laboratory through a nca nucleophilic, multistep radiosynthesis approach [1]. So far gaseous HBr was used for the nucleophilic substitution of the [ 18 F]fluorobenzyl alcohol derivatives. Due to the fact that this reagent is quite cumbersome to handle and leads to poor yields for 4-[ 18 F]fluorobenzyl bromide, new strategies were investigated. In the present study, two new approaches for the preparation of this key substrate are reported.
(i) Bromination of 4-[ 18 F]fluorobenzyl alcohol with polymer-supported reagent.
The first method implies the preparation of a polymer-supported reagent which acts as an anhydrous HBr source [2]. This type of approach seems a good alternative to solve gaseous HBr automatisation's problem because HBr trapped on the resin is less toxic, more convenient to handle and can be easily removed after halogenation by filtration. N-piperidinoaminomethylpolystyrene hydrobromide resin is generated by bubbling gaseous HBr into a suspension of N-piperidinoaminomethylpolystyrene in diethylether at 0ยฐC and proved to be stable for several weeks at 4ยฐC.
Halogenation of 4-[ 18 F]fluorobenzyl alcohol in dichloromethane affords the 4-[ 18 F]fluorobenzyl bromide with a radiochemical yield of 90 % (HPLC based on alcohol, corrected, n = 14) (90ยฐC, 10 min.). The purity of the product obtained after filtration allows the following alkylation reaction leading after hydrolysis to 4-[ 18 F]fluoro-L-phenylalanine.
Experiments were also realized with a "homemade" cartridge of the resin, but lower yields were obtained.
2-[ 18 F]fluoro-4-methoxybenzyl alcohol, 6-[ 18 F]fluoro-3,4-dimethoxybenzyl alcohol and benzhydrol were also successfully transformed with this resin with the same yields.
(ii) Reductive bromination with alkylboron dibromides.
The second approach implies the reaction of an isopinocampheylboron-dibromide dimethylsulfide complex with 4-[ 18 F]fluorobenzaldehyde [3].
The isopinocampheyl group is one of the most effective for reducing carbonyl compounds via betahydrogen transfer reactions. The complex is generated by refluxing HBBr 2 (SMe 2 ) with ฮฑ-pinene in dichloromethane for 3 h. The reductive halogenation proceeds in dichloromethane with 1 eq of complex (90ยฐC, 10 min.) and leads to a radiochemical yield of 90 % (HPLC based on aldehyde, corrected, n = 9). In order to insure a smooth subsequent alkylation reaction, the crude 4-[ 18 F]fluorobenzyl bromide needed to be roughly purified with a simple "homemade" K 2 CO 3 cartridge (โผ 1 g).
Further optimizations for the two methods reported here are underway, so far the first one seems to be more interesting because it doesn't remain smelling by-products after purification.