TY - JOUR
T1 - Combination of the amide-to-triazole substitution strategy with alternative structural modifications for the metabolic stabilization of tumor-targeting, radiolabeled peptides
AU - Guarrochena, Xabier
AU - Anderla, Maximilian
AU - Salomon, Philipp
AU - Feiner, Irene V.J.
AU - Nock, Berthold A.
AU - Maina, Theodosia
AU - Mindt, Thomas L.
N1 - Publisher Copyright:
© 2024 The Author(s). Journal of Peptide Science published by European Peptide Society and John Wiley & Sons Ltd.
Accession Number
WOS:001309869900001
PubMed ID
39262129
PY - 2025/1
Y1 - 2025/1
N2 - 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 [111In]In-AT2S, resulting in the mono-triazolo-peptidomimetic [111In]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 SST2R, the receptor overexpressed by most SSTR-positive cancers. To enhance further the stability of [111In]In-XG1, alternative modifications at the enzymatically labile position Thr10-Phe11 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 (Asn5-Ψ[Tz]-Phe6) and either a β-amino acid (β-Phe11), reduced amide bond (Thr10-Ψ[NH]-Phe11), or N-methylated amino acid (N-Me-Phe11). Two of the new peptidomimetics were more stable in blood plasma in vitro than [111In]In-XG1. Yet none of them retained high affinity towards SST2R. 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.
AB - 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 [111In]In-AT2S, resulting in the mono-triazolo-peptidomimetic [111In]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 SST2R, the receptor overexpressed by most SSTR-positive cancers. To enhance further the stability of [111In]In-XG1, alternative modifications at the enzymatically labile position Thr10-Phe11 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 (Asn5-Ψ[Tz]-Phe6) and either a β-amino acid (β-Phe11), reduced amide bond (Thr10-Ψ[NH]-Phe11), or N-methylated amino acid (N-Me-Phe11). Two of the new peptidomimetics were more stable in blood plasma in vitro than [111In]In-XG1. Yet none of them retained high affinity towards SST2R. 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.
KW - bioisosteres
KW - CuAAC
KW - peptide-based radiotracer
KW - proteolytic stability
KW - somatostatin
KW - triazolo-peptidomimetic
UR - http://www.scopus.com/inward/record.url?scp=85203525135&partnerID=8YFLogxK
U2 - 10.1002/psc.3654
DO - 10.1002/psc.3654
M3 - Article
AN - SCOPUS:85203525135
SN - 1075-2617
VL - 31
JO - Journal of Peptide Science
JF - Journal of Peptide Science
IS - 1
M1 - e3654
ER -