The synthesis of α-([11C]methyl)phenylalanine and α-([11C]methyl)tyrosine from 11C-labelled malonic esters

Abstract

The synthesis of α-([¹¹C]methyl)tyrosine 4a and α-([¹¹C]methyl)phenylalanine 4b from dimethyl 2-(4-methoxybenzyl)-2-([¹¹C] methyl)malonate 1a and dimethyl 2-benzyl-2-([¹¹C] methyl)malonate 1b, respectively is reported. After the alkylation of dimethyl 2-(4-methoxybenzyl)malonate or dimethyl 2-benzylmalonate with [¹¹C]methyl iodide, a selective enzymatic hydrolysis to monomethyl 2-(4-methoxybenzyl)-2-([¹¹C]methyl) malonic acid 2a or monomethyl 2-benzy-2-([¹¹C]methyl)malonic acid 2b was carried out using pig liver esterase (EC 3.1.1.1). Conversion of the carboxylic acid moiety of 2a, b into the corresponding isocyanate 3a, b was achieved by a modified Curtius rearrangement using diphenylphosphoryl azide (DPPA). The simultaneous hydrolysis of the isocyanate and ester moieties of 3a, b using conc. hydrochloric acid produced the desired amino acids 4a, b. In the case of α-([¹¹C]methyl)tyrosine, the methyl ether protecting group was removed using trimethylsilyl chloride-sodium iodide prior to acidic hydrolysis. The amino acids were obtained in 12–20% decay corrected radiochemical yields in a synthesis time of 45–50 min, counted from the start of [¹¹C] methyl iodide synthesis, and with a radiochemical purity greater than 98% after preparative HPLC purification. Enantiomeric purities of 4a, b were determined by the HPLC separation of the respective. 1-fluoro-5-(2,4-dinitrophenyl)-L-alanine amide (FDAA) diastereoisomers, which showed an enantiomeric excess of 62% for 4a but no observable enantiomeric induction for 4b. To confirm the position of labelling, a ¹³C synthesis was carried out using (¹³C)methyl iodide in the same reaction sequence, and the product analysed by ¹³C NMR spectroscopy.