Structure-affinity-pharmacokinetics relationships of In-labeled PSMA-targeted ligands with different albumin binders.

Introduction: Prostate-specific membrane antigen (PSMA) is a promising target for treating metastatic castration-resistant prostate cancer. Our previous report presented In- or Ac-labeled PSMA-NAT-DA1 (PNT-DA1) as a PSMA-targeted ligand. To improve its therapeutic efficiency, PNT-DA1 contains 4-(p-iodophenyl)butyric acid (IPBA), which is known as an albumin binder (ALB) moiety. However, few reports have examined the relationship between the chemical modification of the ALB moiety and pharmacokinetics of PSMA-targeted radioligands. To assess this relationship, we designed, synthesized, and evaluated four [In]In-PNT-DA1 analogues with ALB moieties different from IPBA.

Methods: The [In]In-PNT-DA1 analogues were synthesized from their corresponding precursors through ligand substitution reaction. The stability of [In]In-PNT-DA1 analogues in mouse plasma, their affinity for human serum albumin (HSA), their binding to mouse plasma proteins, and their affinity for PSMA were evaluated in vitro. The tissue distribution profile of the radioligands was assessed in biodistribution studies using LNCaP tumor-bearing nude mice.

Results: All [In]In-PNT-DA1 analogues were obtained at a high radiochemical yield and purity. These analogues were highly stable in mouse plasma after 24 h. The binding affinity for HSA significantly varied among the different ALB moieties. Moreover, high affinity for mouse plasma proteins was observed for all [In]In-PNT-DA1 analogues compared with their counterparts without an ALB moiety. The affinity for PSMA was comparable for all radioligands. In the biodistribution assay, the pharmacokinetics of [In]In-PNT-DA1 analogues varied markedly depending on the type of ALB moiety. In particular, tumor area under the curve (AUC) values were increased for radioligands with higher blood retention, while some previous studies reported that compounds with moderate blood retention exhibited the highest tumor AUC values.

Conclusion: The introduction of an appropriate ALB moiety into the ligand may lead to the development of more useful PSMA-targeted radioligands with higher tumor accumulation.