Development of dual SST₂/SST₅ targeting radioligands through rational structural design.
- 1Division of Radiopharmaceutical Chemistry, Department Theragnostics, University Hospital Basel, University of Basel Basel 4031 Switzerland [email protected] [email protected] +41(0)61 556 58 91.
- 2Institute of Pharmacology and Toxicology, University Hospital Jena, Friedrich Schiller University Jena 07747 Germany.
Abstract
Radioligand therapy targeting somatostatin receptors has emerged as a highly effective treatment strategy for neuroendocrine tumors, with growing evidence indicating that SST₂ antagonists and dual SST₂/SST₅ targeting approaches may further enhance tumor coverage and therapeutic efficacy. In this study, DOTA-NOC, a somatostatin analog with high affinity for SST₂ and SST₅, served as the scaffold for the design of novel ligands incorporating structural features associated with receptor antagonism. The resulting ligands were conjugated to DOTA for ¹⁷⁷Lu radiolabeling and evaluated for receptor affinity, antagonistic potency, and in vivo properties. Among the series, ¹⁷⁷Lu-10 displayed high affinity for both receptor subtypes while acting selectively as an SST₅ antagonist. Compared to [¹⁷⁷Lu]Lu-DOTA-NOC, it showed similar SST₂ tumor uptake but nearly 5-fold higher accumulation in SST₅-expressing tumors. This work provides new insights into the structural determinants underlying SST₂ and SST₅ affinity, selectivity, and antagonistic behavior, demonstrating that receptor recognition and functional activity arise from the combined contribution of multiple structural elements and supporting the development of dual SST₂/SST₅-targeted radioligands.
Related
- Tolerability of [161Tb]Tb-SibuDAB in comparison to other PSMA-targeting radioligands in the preclinical setting
- Toward selective amyloid clearance through rational nanomedicine design
- Targeting conserved interaction surfaces of alphavirus nsP4 supports the rational design of live-attenuated vaccine candidates
- Structural engineering of dual-targeting antisense oligonucleotides enhances exon 44 skipping for treating Duchenne muscular dystrophy
- Structural basis for cross-alphaherpesvirus neutralization by an antibody targeting a conserved hotspot on glycoprotein B
BibTeX
@article{spinnler2026development,
title = {{Development of dual SST₂/SST₅ targeting radioligands through rational structural design.}},
author = {Fabienne Spinnler and Luigi Del Pozzo and Lennart Bohrmann and Sandra Zanger and Nina Kathleen Blum and Monique Brendel and Stefan Schulz and Rosalba Mansi and Melpomeni Fani},
journal = {RSC medicinal chemistry},
year = {2026},
month = oct,
doi = {10.1039/d6md00646a},
url = {https://europepmc.org/article/MED/42836142},
note = {CC BY},
}
RIS
TY - JOUR
TI - Development of dual SST₂/SST₅ targeting radioligands through rational structural design.
AU - Fabienne Spinnler
AU - Luigi Del Pozzo
AU - Lennart Bohrmann
AU - Sandra Zanger
AU - Nina Kathleen Blum
AU - Monique Brendel
AU - Stefan Schulz
AU - Rosalba Mansi
AU - Melpomeni Fani
PY - 2026
DA - 2026/10/05
JO - RSC medicinal chemistry
DO - 10.1039/d6md00646a
UR - https://europepmc.org/article/MED/42836142
AB - Radioligand therapy targeting somatostatin receptors has emerged as a highly effective treatment strategy for neuroendocrine tumors, with growing evidence indicating that SST₂ antagonists and dual SST₂/SST₅ targeting approaches may further enhance tumor coverage and therapeutic efficacy. In this study, DOTA-NOC, a somatostatin analog with high affinity for SST₂ and SST₅, served as the scaffold for the design of novel ligands incorporating structural features associated with receptor antagonism. The resulting ligands were conjugated to DOTA for ¹⁷⁷Lu radiolabeling and evaluated for receptor affinity, antagonistic potency, and in vivo properties. Among the series, ¹⁷⁷Lu-10 displayed high affinity for both receptor subtypes while acting selectively as an SST₅ antagonist. Compared to [¹⁷⁷Lu]Lu-DOTA-NOC, it showed similar SST₂ tumor uptake but nearly 5-fold higher accumulation in SST₅-expressing tumors. This work provides new insights into the structural determinants underlying SST₂ and SST₅ affinity, selectivity, and antagonistic behavior, demonstrating that receptor recognition and functional activity arise from the combined contribution of multiple structural elements and supporting the development of dual SST₂/SST₅-targeted radioligands.
SN - 2632-8682
ER -