Radionuclide Therapy of Prostate Cancer Using PSMA Ligands with a 4-Phenylbutyric Acid-Derived Albumin Binder: Recent Chemical and Clinical Advances.

Radioligand therapy (RLT) targeting the prostate-specific membrane antigen (PSMA) has become a key treatment modality for metastatic castration-resistant prostate cancer. However, the rapid clearance and suboptimal tumor uptake of current smallmolecule PSMA ligands limit their therapeutic index. Incorporating reversible albuminbinding moieties (ABM), particularly 4-phenylbutyric acid (PBA)-derived groups, has emerged as a powerful strategy to modulate pharmacokinetics by prolonging systemic circulation, enhancing tumor uptake, and improving radiation dose delivery. This review summarizes the chemical and translational advances of PSMA-targeting radiopharmaceuticals integrating PBA-type ABM. It details structure-activity relationships governing albumin affinity and linker design across all major chemical series. Emphasis is placed on the most clinically advanced candidates, i.e. PSMA-Trillium, HTK03170, Ludotadipep, P17-088, and CTT1403, highlighting their pharmacokinetics, tumor targeting, safety profiles, and early clinical outcomes. Key determinants of in vivo performance, including affinity for albumin and PSMA, polarity and length of linker elements, are examined in the context of tumor-to-kidney dose ratios and therapeutic efficacy. Collectively, PBA-derived ABM have proven highly effective but require careful tuning, as excessive albumin binding could lead to prolonged hematologic exposure and kidney irradiation, whereas insufficient affinity reduces therapeutic gains. The most successful ligands achieve a balanced interplay between albumin binding, PSMA affinity, and controlled renal clearance. As next-generation α- and β-emitters enter clinical development, optimized ABM-containing radiopharmaceuticals are expected to deliver higher tumor doses with improved safety, supporting their growing role in precision therapy for advanced prostate cancer.