Combination of the amide‐to‐triazole substitution strategy with alternative structural modifications for the metabolic stabilization of tumor‐targeting, radiolabeled peptides

Radiolabeled peptides play a key role in nuclear medicine to selectively deliver radionuclides to malignancies for diagnosis (imaging) and therapy. Yet, their efficiency is often compromised by low metabolic stability. The use of 1,4‐disubstituted 1,2,3‐triazoles (1,4‐Tzs) as stable amide bond bioisosteres can increase the half‐life of peptides in vivo while maintaining their biological properties. Previously, the amide‐to‐triazole substitution strategy was used for the stabilization of the pansomatostatin radioligand [ 111 In]In‐AT2S, resulting in the mono‐triazolo‐peptidomimetic [ 111 In]In‐XG1, a radiotracer with moderately enhanced stability in vivo and retained ability to bind multiple somatostatin receptor (SSTR) subtypes. However, inclusion of additional 1,4‐Tz led to a loss of affinity towards SST 2 R, the receptor overexpressed by most SSTR‐positive cancers. To enhance further the stability of [ 111 In]In‐XG1, alternative modifications at the enzymatically labile position Thr 10 ‐Phe 11 were employed. Three novel 1,4,7,10‐tetraazacyclododecane‐1,4,7,10‐tetraacetic acid (DOTA)‐peptide conjugates were synthesized with a 1,4‐Tz (Asn 5 ‐ Ψ [Tz]‐Phe 6 ) and either a β‐amino acid (β‐Phe 11 ), reduced amide bond (Thr 10 ‐ Ψ [NH]‐Phe 11 ), or N‐methylated amino acid ( N ‐Me‐Phe 11 ). Two of the new peptidomimetics were more stable in blood plasma in vitro than [ 111 In]In‐XG1. Yet none of them retained high affinity towards SST 2 R. We demonstrate for the first time the combination of the amide‐to‐triazole substitution strategy with alternative stabilization methods to improve the metabolic stability of tumor‐targeting peptides.