Development of Lipid-Engineered PSMA-Targeted Radioligands with Quinoline Scaffold.

Prostate-specific membrane antigen (PSMA) is highly overexpressed in prostate cancer, making it an effective diagnostic biomarker and therapeutic target for PCa. However, many PSMA-targeted small-molecule probes suffer from suboptimal tumor uptake and retention. In this study, a series of PSMA ligands were rationally designed and synthesized using classical lipidation and fatty acid modification strategies, and subsequently labeled with 68Ga/177Lu to address these limitations. Cellular studies and molecular docking simulations confirmed their PSMA specificity and protein-binding properties. In a PC-3 PIP xenograft mouse model, nine 68Ga-labeled PSMA-targeted radioligands were evaluated using PET imaging. Among them, [68Ga]Ga-PDA2-C6 and [68Ga]Ga-PDA1-1 demonstrated remarkable tumor accumulation and retention, with improved tumor-to-nontarget (T/NT) ratios. Biodistribution studies further revealed pronounced tumor retention of [177Lu]Lu-PDA2-C6 and [177Lu]Lu-PDA1-1. Overall, this proof-of-concept study validated that conjugating PSMA ligands with tailor-made lipid chain and fatty acids can markedly enhance tumor uptake and retention while maintaining a low level of kidney retention.