A Novel Type of PSMA-Targeting Ligands via β-Branched Aromatic α-Amino Acid Modification, Bearing Enhanced Tumor Targeting and Reduced Renal Toxicity
Z.‐R. LIU, Xueyao Chen, Xin Gao, Siqi Zhang, Chunxiao Xing, Rui Wang, Kuan Hu, Li‐Cheng Yang
Abstract
We designed and synthesized a novel type of PSMA radioligand incorporating (2 S, 3 R ) β-branched aromatic α-amino acids within the linker segment of its structure. In vivo PET/CT imaging and biodistribution analysis revealed that β-branched aromatic α-amino acids modified PSMA radioligands could maintain or even improve tumor targeting while exhibiting a more rapid renal clearance rate than [ 68 Ga]Ga- PSMA-617 . With average renal uptake of less than 10%ID/g, as opposed to 25%ID/g for [ 68 Ga]Ga- PSMA-617, this substantial decrease in renal accumulation translates to a significantly improved safety profile by minimizing nephrotoxic risks. Our findings establish (2 S,3 R ) β-branched aromatic α-amino acids as multifunctional pharmacophores that simultaneously enhance two critical performance parameters: target-binding affinity and renal clearance efficiency. Notably, [ 68 Ga]Ga- PSMA-Y55 emerged as the lead compound, exhibiting an optimal balance of high tumor uptake and low renal accumulation, rendering it a promising candidate for next-generation prostate cancer radioligand therapy.