Engineering a Radiohybrid PSMA Ligand with an Albumin-Binding Moiety and Pharmacokinetic Modulation via an Albumin-Binding Competitor for Radiotheranostics

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The prostate-specific membrane antigen (PSMA) is a well-established target for radiotheranostics in prostate cancer. We previously demonstrated that 4-(p-astatophenyl)butyric acid (APBA), an albumin-binding moiety (ABM) labeled with astatine-211 (211At), enables the modulation of pharmacokinetics and enhancement of therapeutic efficacy when combined with the post-administration of an albumin-binding competitor. However, this strategy has not been explored in PSMA-targeting ligands. We designed and synthesized [211At]6, a novel PSMA ligand structurally analogous to PSMA-617 with APBA. The compound was obtained via a tin–halogen exchange reaction from the corresponding tributylstannyl precursor. Comparative cellular uptake and biodistribution studies were conducted with [211At]6, its radioiodinated analog [125I]5, and [67Ga]Ga-PSMA-617. To assess pharmacokinetic modulation, sodium 4-(p-iodophenyl)butanoate (IPBA), an albumin-binding competitor, was administered 1 h postinjection of [125I]5 and [211At]6 at a 10-fold molar excess relative to blood albumin. The synthesis of [211At]6 gave a radiochemical yield of 15.9 ± 7.7% and a radiochemical purity > 97%. The synthesized [211At]6 exhibited time-dependent cellular uptake and internalization, with higher uptake levels than [67Ga]Ga-PSMA-617. Biodistribution studies of [211At]6 in normal mice revealed a prolonged blood retention similar to those of [125I]5. Notably, post-administration of IPBA significantly reduced blood radioactivity and non-target tissue accumulation of [125I]5 and [211At]6. We found that ABM-mediated pharmacokinetic control was applicable to PSMA-targeted radiotherapeutics, broadening its potential for the optimization of radiotheranostics.