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Combination of the amide-to-triazole substitution strategy with alternative structural modifications for the metabolic stabilization of tumor-targeting, radiolabeled peptides.
Guarrochena, Xabier; Anderla, Maximilian; Salomon, Philipp; Feiner, Irene V J; Nock, Berthold A; Maina, Theodosia; Mindt, Thomas L.
Afiliación
  • Guarrochena X; Institute of Inorganic Chemistry, Faculty of Chemistry, University of Vienna, Vienna, Austria.
  • Anderla M; Vienna Doctoral School in Chemistry, University of Vienna, Vienna, Austria.
  • Salomon P; Department of Biomedical Imaging and Image Guided Therapy, Division of Nuclear Medicine, Medical University of Vienna, Vienna, Austria.
  • Feiner IVJ; Institute of Inorganic Chemistry, Faculty of Chemistry, University of Vienna, Vienna, Austria.
  • Nock BA; Vienna Doctoral School in Chemistry, University of Vienna, Vienna, Austria.
  • Maina T; Department of Biomedical Imaging and Image Guided Therapy, Division of Nuclear Medicine, Medical University of Vienna, Vienna, Austria.
  • Mindt TL; Joint Applied Medicinal Radiochemistry Facility, University of Vienna and Medical University of Vienna, Vienna, Austria.
J Pept Sci ; : e3654, 2024 Sep 11.
Article en En | MEDLINE | ID: mdl-39262129
ABSTRACT
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 ß-amino acid (ß-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.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Idioma: En Revista: J Pept Sci Asunto de la revista: BIOQUIMICA Año: 2024 Tipo del documento: Article País de afiliación: Austria Pais de publicación: Reino Unido
Texto completo
Añadir a Mi BVS
Imprimir
XML
PubMed Links
Buscar en Google

Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Idioma: En Revista: J Pept Sci Asunto de la revista: BIOQUIMICA Año: 2024 Tipo del documento: Article País de afiliación: Austria Pais de publicación: Reino Unido