Abstract::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.