Purpose <p>Prostate-specific membrane antigen-targeted radioligand therapy (PSMA-RLT) is a promising approach to treating&#xa0;metastatic castration-resistant prostate cancer (mCRPC). With the emergence of oxalyldiaminopropionic acid urea (ODAP-Urea) based radioligands targeting PSMA, novel paradigms focused on PSMA-RLT are garnering attention. This study aims to assess potentially novel ODAP-Urea-based radioligands prepared for PSMA-RLT.</p> Methods <p>Albumin binding moieties (ABMs) were selected for optimization. Candidates were evaluated <i>in vitro</i> and subsequently investigated through biodistribution and imaging studies in 22Rv1 tumor-bearing mice.</p> Results <p>We synthesized five novel ODAP-Urea-based derivatives (CXY-18, CXY-19, CXY-20, CXY-21, CXY-23) with specific ABM. All compounds demonstrated high affinities for PSMA (<i>K</i>_i values ranging from 0.21&#xa0;nM to 3.6&#xa0;nM) and strong human albumin protein binding abilities (83.4 ± 1.6% to 94.6 ± 0.4%). [⁶⁸Ga]Ga-CXY-18 (CXY-18) PET/CT exhibited the highest tumor uptake and blood retention properties. Moreover, the internalization of [⁶⁸Ga]Ga-CXY-18 in the 22Rv1 cell line (23.81 ± 1.67%) exceeded that of [⁶⁸Ga]Ga-PSMA-617 (9.99 ± 0.98%). Biodistribution studies confirmed prolonged blood retention and enhanced tumor uptake with [¹⁷⁷Lu]Lu-CXY-18, peaking at 48&#xa0;h post-injection (4&#xa0;h: 27.22 ± 3.61%ID/g; 24&#xa0;h: 30.61 ± 4.96%ID/g; 48&#xa0;h: 33.92 ± 2.98%ID/g; 96&#xa0;h: 30.97 ± 1.87%ID/g; 192&#xa0;h: 9.03 ± 3.49%ID/g).</p> Conclusion <p>Our study indicates that CXY-18 possesses high PSMA specificity and tumor uptake, underscoring its promising potential for PSMA-RLT using 4-IBA.</p> Graphical Abstract <p></p>