A Novel Type of PSMA-Targeting Ligands via β-Branched Aromatic α-Amino Acid Modification, Bearing Enhanced Tumor Targeting and Reduced Renal Toxicity

We designed and synthesized a novel type of PSMA radioligand incorporating (2<i>S</i>, 3<i>R</i>) β-branched aromatic α-amino acids within the linker segment of its structure. <i>In vivo</i> 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 [⁶⁸Ga]Ga-<b>PSMA-617</b>. With average renal uptake of less than 10%ID/g, as opposed to 25%ID/g for [⁶⁸Ga]Ga-<b>PSMA-617</b>, this substantial decrease in renal accumulation translates to a significantly improved safety profile by minimizing nephrotoxic risks. Our findings establish (2<i>S</i>,3<i>R</i>) β-branched aromatic α-amino acids as multifunctional pharmacophores that simultaneously enhance two critical performance parameters: target-binding affinity and renal clearance efficiency. Notably, [⁶⁸Ga]Ga-<b>PSMA-Y55</b> 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.