Aziridines in the synthesis of 11C- and 18F-labelled compounds

Racemic [4-11C]aspartic acid, [4-11C]asparagine and 2,4-diamino[4-11C]butyric acid were synthesised by the ring-opening of an N-activated aziridine-2-carboxylate with 11C]cyanide, followed by preparative HPLC and hydrolysis/reduction. These labelled amino acids arise from nucleophilic attack at the β-carbon of the aziridine ring. A radioactive by-product of ca. 25% was attributed to the product of α-attack. Several N-activated 2-aryl aziridines were synthesised for the attempted synthesis of β-[18F] fluorophenylalanine and β-[18F]fluorodopa. Ring-opening with [18F]fluoride showed no evidence of β-fluorinated products and it is proposed that attack occurs exclusively at the α-carbon, giving the corresponding α-[18F]fluoro-β-amino acids. Further evidence for this was the reaction of the β-unsubstituted N-activated aziridine-2-carboxylate with [18F]fluoride. This reaction was totally regiospecific and afforded exclusively the α-substituted product, α-[18F]fluoro-β-alanine. Aziridine precursors were resolved by chiral HPLC. On labelling the chiral aziridines, however, racemic 11C- and 18F-labelled amino acids were obtained. This was attributed to racemisation of the initially formed ring-opened products. The use of [11C]methyl lithium as a nucleophile for aziridine ring-opening was investigated. Reaction was expected to occur at low temperature, thus potentially avoiding racemisation. No products corresponding to aziridine ring-opening with [11C]methyl lithium were, however, observed. A difluorinated analogue of amphetamine was synthesised by fluorination of an azirine (via an aziridine). This racemic compound was resolved as its chiral tartarate salts and subsequently labelled by methylation with [11C]methyl iodide, giving the novel compound β, β-difluoro[N-methyl-11C]methamphetamine in high specific activity for in vivo binding studies using positron emission tomography. The non-radioactive reference compound was also synthesised to confirm the identity of the labelled product. (author)