Albumin-Binding PSMA Ligands: Implications for Expanding the Therapeutic Window.

Despite significant gains in the treatment of metastatic castration-resistant prostate cancer by radioligands targeting PSMA, 30% of patients never respond to therapy. One possible explanation is insufficient dose delivery to the tumor, which is related to suboptimal pharmacokinetics. We have recently described RPS-063, a trifunctional ligand targeting PSMA with high uptake in LNCaP xenograft tumors, but also in kidneys. We aimed to use structural modifications to increase the tumor-to-kidney ratio through increased albumin binding and tumor uptake and reduction of kidney activity. Methods: Four structurally-related trifunctional PSMA-targeting small molecules were prepared by either varying the albumin binding group or by inserting a PEG8 linker into a common structure. The compounds were ranked by PSMA affinity and albumin affinity, radiolabeled with 68 Ga and 177 Lu, and tissue kinetics determined in male BALB/C nu/nu mice bearing LNCaP xenograft tumors. Results: Each of the compounds binds PSMA with IC50 < 10 nM. The albumin binding group had a minimal effect on PSMA affinity, but changed albumin affinity by an order of magnitude. However, the addition of a PEG8 spacer weakened affinity for albumin in each case. Increased affinity for albumin corresponded with delayed blood clearance and modified uptake kinetics in the tumor and kidney. Uptake of 177 Lu-RPS-072 (34.9 ± 2.4 %ID/g) and 177 Lu-RPS-077 (27.4 ± 0.6 %ID/g) increased up to 24 h post injection, and washout by 96 h was not significant. As a result, the area under the curve (AUC) in the tumor was in the order 177 Lu-RPS-072>177 Lu-RPS-077>177 Lu-RPS-063>177 Lu-RPS-071. Increased linker length corresponded with more rapid clearance from kidneys. Consequently, the ratio of tumor AUC and kidney AUC was 4.7 ± 0.3 for 177 Lu-RPS-072. Conclusion: The AUC in the tumor and tumor-to-kidney ratio of 177 Lu-RPS-072 are superior to any small molecule investigated in a LNCaP xenograft model to date. In comparison to other PSMA-targeting radioligands that have been evaluated in a PC3-PIP model, activity in kidneys is reduced and activity in tumors compares favorably when the different PSMA expression levels in LNCaP and PC3-PIP cells are taken into account. RPS-072 therefore exhibits an increased therapeutic index, shows the potential to increase the dose delivered to tumors and is a highly promising candidate for targeted radioligand therapy.