Development of dual SST₂/SST₅ targeting radioligands through rational structural design

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.