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.