Theranostic Study of PSMA-Targeted Radioligands Modified with Enhancer SNAC

PSMA is an attractive theranostic target for prostate cancer (PCa). Inspired by the oral absorption enhancer SNAC, we report a novel strategy for optimizing PSMA-targeted radioligands via covalent SNAC conjugation distinct from conventional albumin-binding designs. Three SNAC-modified ligands (PSA3-1, PDA3-1, PDB3-1) bearing quinoline/naphthalene linkers were radiolabeled with ⁶⁸Ga and ¹⁷⁷Lu, affording high radiochemical purity (>98%) and hydrophilicity. PDB3-1 displayed the highest PSMA binding affinity (IC₅₀ = 19.1 nM; docking score: -12.3 kcal/mol). In PC-3 PIP tumor-bearing mice, [⁶⁸Ga]Ga-PDB3-1 PET revealed high tumor uptake with minimal background. Corresponding [¹⁷⁷Lu]Lu-PDB3-1 biodistribution studies confirmed low systemic retention and rapid renal clearance. Therapy [¹⁷⁷Lu]Lu-PDB3-1 achieved tumor inhibition and survival benefits comparable to [¹⁷⁷Lu]Lu-PSMA-617, even at a reduced dose (9.25 MBq). High-tolerated dose studies (111 MBq) confirmed safety with unremarkable histopathology. These findings suggest that SNAC conjugation may represent a promising approach for the development of PSMA-targeted radiotheranostics for PCa.