Protected homocysteine peptides as precursors of labelled methionine peptides. Application in preparation of methionine-enkephalin.

Abstract

A synthetic scheme from N-benzyloxycarbonyl S-benzyl homocysteine peptide benzyl ester, assembled using well-established procedures in solution and purified, to the corresponding free methionine peptide, has been explored preparatively. Deprotection by sodium in liquid ammonia followed by alkylation on sulfur with methyl iodide gave, after purification by semipreparative HPLC, in the case of methionine-enkephalin a pure product in high yield. No evidence from side-reactions on tyrosine could be detected by HPLC. The scheme was primarily designed to be adaptable to the preparation of 11C-labelled methionine-enkephalin and, in particular, to exploit 11C-methyl iodide, now in routine production in our laboratory, in peptide synthesis, thus providing access to 11C-labelled enkephalins with high specific radioactivity for in vivo experiments. Applying 2H-, 3H-, 13C- or 14C-methyl iodide instead, however, this approach should be equally useful for the preparation of the corresponding peptides. Provided overalkylation by methyl iodide and fatal splitting of peptide bonds by the sodium/ammonia reagent can be avoided, the scheme should be applicable also to the synthesis of other methionine-containing peptides.