Abstract[¹⁷⁷Lu]Lu-Ibu-DAB-PSMA was previously characterized with moderate albumin-binding properties enabling high tumor accumulation but reasonably low retention in the blood. The aim of this study was to investigate [¹⁷⁷Lu]Lu-Ibu-DAB-PSMA in preclinical in vivo experiments and compare its therapeutic efficacy and potential undesired side effects with those of [¹⁷⁷Lu]Lu-PSMA-617 and the previously developed [¹⁷⁷Lu]Lu-PSMA-ALB-56. BALB/c nude mice without tumors were investigated on Day 10 and 28 after injection of 10 MBq radioligand. It was revealed that most plasma parameters were in the same range for all groups of mice and histopathological examinations of healthy tissue did not show any alternations in treated mice as compared to untreated controls. Based on these results, a therapy study over twelve weeks was conducted with PC-3 PIP tumor-bearing mice for comparison of the radioligands’s therapeutic efficacy up to an activity of 10 MBq (1 nmol) per mouse. In agreement with the increased mean absorbed tumor dose, [¹⁷⁷Lu]Lu-Ibu-DAB-PSMA (~ 6.6 Gy/MBq) was more effective to inhibit tumor growth than [¹⁷⁷Lu]Lu-PSMA-617 (~ 4.5 Gy/MBq) and only moderately less potent than [¹⁷⁷Lu]Lu-PSMA-ALB-56 (~ 8.1 Gy/MBq). As a result, the survival of mice treated with 2 MBq of an albumin-binding radioligand was significantly increased (p < 0.05) compared to that of mice injected with [¹⁷⁷Lu]Lu-PSMA-617 or untreated controls. The majority of mice treated with 5 MBq or 10 MBq [¹⁷⁷Lu]Lu-Ibu-DAB-PSMA or [¹⁷⁷Lu]Lu-PSMA-ALB-56 were still alive at study end. Hemograms of immunocompetent mice injected with 30 MBq [¹⁷⁷Lu]Lu-Ibu-DAB-PSMA or 30 MBq [¹⁷⁷Lu]Lu-PSMA-617 showed values in the same range as untreated controls. This was, however, not the case for mice treated with [¹⁷⁷Lu]Lu-PSMA-ALB-56 which revealed a drop in lymphocytes and hemoglobin at Day 10 and Day 28 after injection. The data of this study demonstrated a significant therapeutic advantage of [¹⁷⁷Lu]Lu-Ibu-DAB-PSMA over [¹⁷⁷Lu]Lu-PSMA-617 and a more favorable safety profile as compared to that of [¹⁷⁷Lu]Lu-PSMA-ALB-56. Based on these results, [¹⁷⁷Lu]Lu-Ibu-DAB-PSMA may has the potential for a clinical translation.