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. [ 111 In]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 [ 111 In]In-PNT-DM-HSA, a new radioligand that consists of a PSMA-targeting radioligand covalently bound to albumin. The pharmacokinetics of [ 111 In]In-PNT-DM-HSA was compared with those of [ 111 In]In-PNT-DA1 and [ 111 In]In-PSMA-617, a non-ALB-conjugated radioligand, to evaluate the relationship between albumin-binding and tumor accumulation. Method The [ 111 In]In-PNT-DM-HSA was prepared by incubation of [ 111 In]In-PNT-DM, a PSMA-targeting radioligand including a maleimide group, and human serum albumin (HSA). The ability of [ 111 In]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 [ 111 In]In-PNT-DM-HSA, [ 111 In]In-PNT-DA1, and [ 111 In]In-PSMA-617. Results The [ 111 In]In-PNT-DM-HSA was obtained at a favorable radiochemical yield and high radiochemical purity. In vitro assays revealed that [ 111 In]In-PNT-DM-HSA had fundamental characteristics as a PSMA-targeting radioligand interacting with albumin covalently. In a biodistribution study, [ 111 In]In-PNT-DM-HSA and [ 111 In]In-PNT-DA1 showed higher blood retention than [ 111 In]In-PSMA-617. On the other hand, the tumor accumulation of [ 111 In]In-PNT-DA1 was much higher than [ 111 In]In-PNT-DM-HSA and [ 111 In]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.