Preparation and 11C-labelling of a Substance P analogue containing D-tryptophan in positions 7 and 9

Abstract

An efficient synthesis of ¹¹C-labelled [D-Trp^7,9]-Substance P, a putative Substance P antagonist, is presented. The preparation of the precursor peptide, Z-[D-Trp,^7,9 Hcy(Bzl)¹¹]-Substance P was achieved in solution according to a [(3 + 4)+ 4] strategy. The yields in the various steps were generally high. A novel feature of the synthesis was the use of tryptophan intermediates protected on the indole nitrogen with Boc together with phenylisopropyloxycarbonyl (Ppoc) as a general N^α-protecting group to suppress acid-mediated side reactions during deprotection. After conventional removal of the acid-labile side-chain protective groups, the remaining benzyloxycarbonyl and S-benzyl groups were smoothly cleaved off with sodium in liquid ammonia and the generated homocysteine sulphide anion methylated with [¹¹C]methyl iodide. The resulting labelled undecapeptide [S-methyl-¹¹C][D-Trp^7,9]-Substance P was obtained in 25–50% yield after h.p.l.c. The radiochemical purity of the purified peptide exceeded 98%.