Beyond Phenylbutyric Acid: Evans Blue and Ibuprofen as Albumin- Binding Motifs for PSMA-Targeted Radioligand Therapy of Prostate Cancer.

INTRODUCTION: Radioligand Therapy (RLT) targeting Prostate-Specific Membrane Antigen (PSMA) reshapes the therapeutic landscape of metastatic castration-resistant prostate cancer. However, the rapid systemic clearance of small-molecule radioligands directly affects circulation time and tumor exposure. Reversible albumin binding emerged as a practical strategy to extend circulation and modulate biodistribution. Among drug-derived Albumin-Binding Moieties (ABMs), Evans Blue (EB) and ibuprofen (Ibu) offer distinct approaches to improve pharmacokinetics and the therapeutic index. METHODS: This review analyzes the design, synthesis, structure-activity relationships, and evaluation of PSMA radioligands incorporating EB- or Ibu-derived ABMs. Preclinical and clinical literature was examined, with emphasis on translational candidates. RESULTS: EB confers strong albumin binding and markedly prolongs tumor residence, whereas Ibu enables more finely tunable interactions with albumin. The impact of linker, radionuclide, and albumin affinity on biodistribution, dosimetry, and therapeutic efficacy are essential to consider. Available data suggest that albumin binding is a tunable pharmacokinetic parameter rather than a binary property. Clinical experience with EB-PSMA-617 and SibuDAB demonstrates that increasing tumor absorbed dose through prolonged circulation is achievable but may increase irradiation of kidneys, bone marrow, and salivary glands. DISCUSSION: These findings support the hypothesis that moderately strong, tunable albumin binding offers the most favorable therapeutic window. Stereochemical optimization of Ibu-derived ABMs and linker engineering illustrate how subtle structural changes can rebalance tumor uptake, clearance, and safety. Future radiopharmaceutical design will likely rely on iterative structure- pharmacokinetic optimization and dosimetry to define optimal albumin affinity. CONCLUSION: Overall, ABMs appear to be central tools for the design of next-generation PSMA radioligands and other radiopharmaceuticals.