Prostate-specific membrane antigen (PSMA) targeted radioligand therapy (TRT) for metastatic castration-resistant prostate cancer has demonstrated significant potential. This study aimed to develop an optimal radiotherapeutic agent suitable for high-level PSMA expression by optimizing the ligand structure with albumin-binding zwitterionic strategies to increase tumor uptake and retention time and to explore the effects of these strategies on the in vitro and in vivo properties of PSMA inhibitors. All precursors were synthesized based on PSMA-targeting agent Flu-1. The radioligands were investigated for their physicochemical properties, imaging, and biodistribution by means of gallium and lutetium labeling to evaluate their pharmacokinetic properties, as well as their affinity and specificity for PSMA. The therapeutic effect of radioligands was systematically evaluated in [Lu-177]Lu-Flu-1, [Lu-177]Lu-BWD, [Lu-177]Lu-P4-BWD, and [Lu-177]Lu-P4-PND. All PSMA ligands were of chemical purity >95%. The final radiochemical purity of the radioligands was achieved up to 99%. The cell-based and imaging study results showed that BWD had a high affinity for PSMA (IC50 = 35.86 +/- 0.56) and was significantly superior to the other radioligands in terms of tumor uptake and retention. The biodistribution study further confirmed that the tumor uptake of [Lu-177]Lu-BWD (64.28 +/- 12.46%ID/g) was significantly higher than that of other [Lu-177]Lu-radioligands at 4 h postinjection, including [Lu-177]Lu-PSMA-617 (47.64 +/- 11.39%ID/g). The TRT results showed that a single injection of 7.4 MBq of [Lu-177]Lu-BWD significantly inhibited the growth of PC3-PIP tumors, and it was superior to that of [Lu-177]Lu-PSMA-617 under the same conditions. [Lu-177]Lu-BWD with greatly enhanced tumor uptake and retention demonstrated remarkable therapeutic efficacy using significantly lower dosages for clinical translation to treat PCa with high level of PSMA expression.