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

The prostate-specific membrane antigen (PSMA) is a well-established target for radiotheranostics in prostate cancer. We previously demonstrated that 4-(<i>p</i>-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]<b>6</b>, 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]<b>6</b>, its radioiodinated analog [¹²⁵I]<b>5</b>, and [⁶⁷Ga]Ga-PSMA-617. To assess pharmacokinetic modulation, sodium 4-(<i>p</i>-iodophenyl)butanoate (IPBA), an albumin-binding competitor, was administered 1 h postinjection of [¹²⁵I]<b>5</b> and [²¹¹At]<b>6</b> at a 10-fold molar excess relative to blood albumin. The synthesis of [²¹¹At]<b>6</b> gave a radiochemical yield of 15.9 ± 7.7% and a radiochemical purity > 97%. The synthesized [²¹¹At]<b>6</b> exhibited time-dependent cellular uptake and internalization, with higher uptake levels than [⁶⁷Ga]Ga-PSMA-617. Biodistribution studies of [²¹¹At]<b>6</b> in normal mice revealed a prolonged blood retention similar to those of [¹²⁵I]<b>5</b>. Notably, post-administration of IPBA significantly reduced blood radioactivity and non-target tissue accumulation of [¹²⁵I]<b>5</b> and [²¹¹At]<b>6</b>. We found that ABM-mediated pharmacokinetic control was applicable to PSMA-targeted radiotherapeutics, broadening its potential for the optimization of radiotheranostics.