Studies on the impact of modifications at the Gln-Trp site in RM2-based GRPR ligands.

Background: One of the most studied, and preclinically as well as clinically applied gastrin-releasing peptide receptor (GRPR) ligands represents the antagonist RM2 (DOTA-Pip-D-Phe-Gln-Trp-Ala-Val-Gly-His-Sta-Leu-NH). As an improved in vivo stability was observed for a RM2 analog comprising the unnatural amino acid α-methyl-L-tryptophan instead of L-Trp, we aimed to elucidate the impact of other unnatural amino acids (homoserine [Hse], β-(3-benzothienyl)alanine [Bta]) at the metabolically less stable Gln-Trp site. Furthermore, we conjugated either DOTA, NOTA or NODAGA to the RM2 peptide and its modified derivatives, and evaluated each analog preclinically using Ga and Cu, as well as Lu (only DOTA-comprising compounds).