Fundamental evaluation regarding the relationship between albumin-binding and tumor accumulation of PSMA-targeting radioligands

Objective

The marked success of prostate-specific membrane antigen (PSMA)-targeting radioligands with albumin binder (ALB) is attributed to the improvement of blood retention and tumor accumulation. [¹¹¹In]In-PNT-DA1, our PSMA-targeting radioligand with ALB, also achieved improved tumor accumulation due to its prolonged blood retention. Although the advantage of ALBs is related to their reversible binding to albumin, the relationship between albumin-binding and tumor accumulation of PSMA-targeting radioligands remains unclear because of the lack of information about radioligands with stronger albumin-binding than ALBs. In this study, we designed and synthesized [¹¹¹In]In-PNT-DM-HSA, a new radioligand that consists of a PSMA-targeting radioligand covalently bound to albumin. The pharmacokinetics of [¹¹¹In]In-PNT-DM-HSA was compared with those of [¹¹¹In]In-PNT-DA1 and [¹¹¹In]In-PSMA-617, a non-ALB-conjugated radioligand, to evaluate the relationship between albumin-binding and tumor accumulation.

Method

The [¹¹¹In]In-PNT-DM-HSA was prepared by incubation of [¹¹¹In]In-PNT-DM, a PSMA-targeting radioligand including a maleimide group, and human serum albumin (HSA). The ability of [¹¹¹In]In-PNT-DM-HSA was evaluated by in vitro assays. A biodistribution study using LNCaP tumor-bearing mice was conducted to compare the pharmacokinetics of [¹¹¹In]In-PNT-DM-HSA, [¹¹¹In]In-PNT-DA1, and [¹¹¹In]In-PSMA-617.

Results

The [¹¹¹In]In-PNT-DM-HSA was obtained at a favorable radiochemical yield and high radiochemical purity. In vitro assays revealed that [¹¹¹In]In-PNT-DM-HSA had fundamental characteristics as a PSMA-targeting radioligand interacting with albumin covalently. In a biodistribution study, [¹¹¹In]In-PNT-DM-HSA and [¹¹¹In]In-PNT-DA1 showed higher blood retention than [¹¹¹In]In-PSMA-617. On the other hand, the tumor accumulation of [¹¹¹In]In-PNT-DA1 was much higher than [¹¹¹In]In-PNT-DM-HSA and [¹¹¹In]In-PSMA-617.

Conclusions

These results indicate that the moderate reversible binding of ALB with albumin, not covalent binding, may play a critical role in enhancing the tumor accumulation of PSMA-targeting radioligands.