Combined Application of Albumin-Binding [ 177 Lu]Lu-PSMA-ALB-56 and Fast-Cleared PSMA Inhibitors: Optimization of the Pharmacokinetics.

The strategy of using radioligands for targeting the prostate-specific membrane antigen (PSMA) revealed to be promising for the treatment of metastatic castration-resistant prostate cancer (mCRPC). Recently developed albumin-binding PSMA radioligands showed a remarkably increased tumor uptake because of the enhanced blood circulation, but higher accumulation of activity was also observed in off-target organs and tissues. The aim of this study was to investigate the option of using fast-cleared, small-molecular-weight PSMA inhibitors (PSMA-11, 2-PMPA, and ZJ-43) to reduce the kidney uptake of [ ¹⁷⁷ Lu]Lu-PSMA-ALB-56, a previously developed albumin-binding PSMA radioligand. Dual-isotope SPECT/CT imaging was performed with tumor-bearing mice coinjected with [ ¹⁷⁷ Lu]Lu-PSMA-ALB-56 and a 2.5-fold molar excess of [ ⁶⁷ Ga]Ga-PSMA-11. At early timepoints after injection, the high renal uptake of [ ⁶⁷ Ga]Ga-PSMA-11 reduced the accumulation of [ ¹⁷⁷ Lu]Lu-PSMA-ALB-56 in the kidneys substantially, whereas the tumor uptake of [ ¹⁷⁷ Lu]Lu-PSMA-ALB-56 was only slightly affected. These findings were confirmed in biodistribution studies, which revealed reduced uptake of [ ¹⁷⁷ Lu]Lu-PSMA-ALB-56 in the kidneys due to coadministered unlabeled PSMA-11 (9.1 ± 0.8% IA/g vs 46 ± 11% IA/g; 1 h p.i.). The tumor uptake of [ ¹⁷⁷ Lu]Lu-PSMA-ALB-56 was almost the same at 1 h p.i., irrespective of whether or not PSMA-11 was coinjected (24 ± 6% IA/g vs 27 ± 7% IA/g). The application of [ ¹⁷⁷ Lu]Lu-PSMA-ALB-56 with 2-PMPA or ZJ-43, respectively, showed similar results in biodistribution studies. Among all three tested PSMA inhibitors, 2-PMPA, applied at a 2.5-fold molar excess relative to [ ¹⁷⁷ Lu]Lu-PSMA-ALB-56, was most effective to improve the tumor-to-kidney ratios over the first hours after injection of [ ¹⁷⁷ Lu]Lu-PSMA-ALB-56. The concept of using a PSMA inhibitor together with [ ¹⁷⁷ Lu]Lu-PSMA-ALB-56 appears promising in view of a clinical translation of this and possibly other long-circulating PSMA radioligands.