ASYMMETRIC RADIOSYNTHESIS OF ALPHA-[C-11]METHYL-L-TRYPTOPHAN FOR PET STUDIES

Asymmetric radiosynthesis of alpha-[C-11]methyl-L-tryptophan has been achieved using the enantioselective [C-11]methylation of the enolate of either 8-(phenylsulfonyl) or 8-acetyl substituted derivatives of dimethyl (2S.3aR, 8aS)-(+)-hexahydropyrrolo[2,3-b]indole-1,2-dicarboxylate. Reaction of the enolates generated by treatment with LDA at -78 degrees C, with [C-11]methyl iodide at -78 degrees C gave in 5 min incorporation of the radiolabel of 86% for 8-phenylsulfonyl derivative and 63% for 8-acetyl derivative. The hexahydropyrrolo[2,3-b]indoles were then decyclized to the fully protected alpha-[(11)]methyl-L-tryptophan by treatment with trifluoroacetic acid. Removal of all the protecting groups, including the phenylsulfonyl, was achieved by reaction with 10 N NaOH at 210 degrees C in a sealed vial. Neutralization of the alkali with 10 N H2SO4 followed by purification by HPLC gave alpha-[C-11]methyl-L-tryptophan with an overall radiochemical yield of 20% (uncorrected for decay) relative to the amounts of[C-11]CH3I from 8-phenylsulfonyl derivative, and 9% (relative to [C-11]CH3I; uncorrected for decay) from 8-acetyl derivative in a preparation time of 40 min after [C-11]methyl iodide was introduced into the reaction mixture.