Head-to-head preclinical comparison of a triazine-based SSTR2 homodimer and SSTR2/FAP heterodimer in neuroendocrine tumors

Abstract Objective To compare the tumor targeting and pharmacokinetic properties of a SSTR2 (somatostatin receptor type 2) homodimer 8 and a SSTR2/FAP (fibroblast activation protein) heterodimer 14 for neuroendocrine tumors. Methods Both dimers were synthesized on a modular triazine platform with PEG 2 linkers and labeled with lutetium-177. Radiochemical purity, lipophilicity, receptor affinity, and cellular uptake were evaluated. Ex vivo biodistribution studies were conducted in H69 tumor-bearing mice at 1, 4, and 24 h post-injection (p.i.). Autoradiography and immunohistochemistry were performed on tumor sections. Results Both dimers showed high radiochemical purity (> 95%), good stability, and SSTR2 affinity similar to DOTA-TATE. The heterodimer 14 showed approximately 2-fold higher uptake in FAP-positive cells than [ 177 Lu]Lu-FAPI-46. In H69 xenografts, both dimers demonstrated comparable tumor exposure (AUC 0−24 h = 98.21 ± 5.45 vs. 97.89 ± 3.50) and retention kinetics (t 1/2 = 12.6 h vs. 12.9 h). Compared with homodimer 8 , heterodimer 14 exhibited favorable pharmacokinetics, including reduced renal uptake and prolonged blood circulation. Under SSTR2 blockade, heterodimer 14 retained partial tumor uptake, suggesting additional non-SSTR2-mediated interactions. Autoradiography demonstrated the blockade-resistant uptake of [¹⁷⁷Lu]Lu- 14 , and immunohistochemistry confirmed FAP expression in H69 tumors. Conclusion Both dimers achieved effective SSTR2-mediated tumor targeting. Compared with homodimer 8 , heterodimer 14 exhibited distinct pharmacokinetic characteristics while maintaining comparable tumor targeting, supporting the feasibility of SSTR2/FAP dual-targeting.