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
(2S, 3R) 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 [68Ga]Ga-PSMA-617. With average renal uptake of less than 10%ID/g, as opposed to 25%ID/g
for [68Ga]Ga-PSMA-617, this substantial decrease
in renal accumulation translates to a significantly improved safety
profile by minimizing nephrotoxic risks. Our findings establish (2S,3R) 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-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.