Preclinical Development of Novel PSMA-Targeting Radioligands: Modulation of Albumin-Binding Properties To Improve Prostate Cancer Therapy.

The treatment of metastatic castration-resistant prostate cancer (mCRPC) remains challenging with current treatment options. The development of more effective therapies is, therefore, urgently needed. Targeted radionuclide therapy with prostate-specific membrane antigen (PSMA)-targeting ligands has revealed promising clinical results. In an effort to optimize this concept, it was the aim of this study to design and investigate PSMA ligands comprising different types of albumin binders. PSMA-ALB-53 and PSMA-ALB-56 were designed by combining the glutamate-urea-based PSMA-binding entity, a DOTA chelator and an albumin binder based on the 4-( p-iodophenyl)-moiety or p-(tolyl)-moiety. The compounds were labeled with 177Lu (50 MBq/nmol) resulting in radioligands of high radiochemical purity (≥98%). Both radioligands were stable (≥98%) over 24 h in the presence of l-ascorbic acid. The uptake into PSMA-positive PC-3 PIP tumor cells in vitro was in the same range (54-58%) for both radioligands; however, 177Lu-PSMA-ALB-53 showed a 15-fold enhanced binding to human plasma proteins. Biodistribution studies performed in PC-3 PIP/flu tumor-bearing mice revealed high tumor uptake of 177Lu-PSMA-ALB-53 and 177Lu-PSMA-ALB-56, respectively, demonstrated by equal areas under the curves (AUCs) for both radioligands. The increased retention of 177Lu-PSMA-ALB-53 in the blood resulted in almost 5-fold lower tumor-to-blood AUC ratios when compared to 177Lu-PSMA-ALB-56. Kidney clearance of 177Lu-PSMA-ALB-56 was faster, and hence, the tumor-to-kidney AUC ratio was 3-fold higher than in the case of 177Lu-PSMA-ALB-53. Due to the more favorable tissue distribution profile, 177Lu-PSMA-ALB-56 was selected for a preclinical therapy study in PC-3 PIP tumor-bearing mice. The tumor growth delay after application of 177Lu-PSMA-ALB-56 and 177Lu-PSMA-617 applied at the same activities (2 or 5 MBq per mouse) revealed better antitumor effects in the case of 177Lu-PSMA-ALB-56. As a consequence, the survival of mice treated with 177Lu-PSMA-ALB-56 was prolonged when compared to the mice, which received the same activity of 177Lu-PSMA-617. Our results demonstrated the superiority of 177Lu-PSMA-ALB-56 over 177Lu-PSMA-ALB-53 indicating that the p-(tolyl)-moiety was more suited as an albumin binder to optimize the tissue distribution profile. 177Lu-PSMA-ALB-56 was more effective to treat tumors than 177Lu-PSMA-617 resulting in complete tumor remission in four out of six mice. This promising results warrant further investigations to assess the potential for clinical application of 177Lu-PSMA-ALB-56.