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Theranostic Study of PSMA-Targeted Radioligands Modified with Enhancer SNAC.

Tao Zhang1, Qinglin Zhang1, Zhexin He1

  • 1State Key Laboratory of Vaccines for Infectious Diseases, Xiang An Biomedicine Laboratory, National Innovation Platform for Industry-Education Integration in Vaccine Research, Fujian Engineering Research Center of Molecular Theranostic Technology, Center for Molecular Imaging and Translational Medicine, School of Public Health, Xiamen University, Xiamen, Fujian 361102, China.

Journal of Medicinal Chemistry
|May 13, 2026
PubMed
Summary

We developed novel prostate cancer radioligands using SNAC conjugation for enhanced PSMA targeting. The lead compound, PDB3-1, showed promising tumor uptake and therapeutic efficacy, suggesting a new theranostic strategy.

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Area of Science:

  • Nuclear medicine
  • Radiopharmaceutical chemistry
  • Oncology

Background:

  • Prostate-specific membrane antigen (PSMA) is a key target for prostate cancer (PCa) theranostics.
  • Conventional radioligand designs often rely on albumin binding for improved pharmacokinetics.
  • A novel approach is needed to optimize PSMA-targeted agents.

Purpose of the Study:

  • To develop and evaluate novel PSMA-targeted radioligands using SNAC conjugation for enhanced prostate cancer theranostics.
  • To investigate the binding affinity, pharmacokinetic properties, and therapeutic efficacy of SNAC-modified ligands.
  • To assess the safety profile of the lead candidate.

Main Methods:

  • Three SNAC-modified ligands (PSA3-1, PDA3-1, PDB3-1) with quinoline/naphthalene linkers were synthesized.
  • Ligands were radiolabeled with Gallium-68 (68Ga) for PET imaging and Lutetium-177 (177Lu) for therapy.
  • In vitro binding affinity and in vivo PET imaging and biodistribution studies were performed in PC-3 PIP tumor models.
  • Therapeutic efficacy and toxicity were evaluated in preclinical studies.

Main Results:

  • SNAC-modified ligands were successfully radiolabeled with high purity (>98%) and hydrophilicity.
  • PDB3-1 exhibited the highest PSMA binding affinity (IC50 = 19.1 nM).
  • [68Ga]Ga-PDB3-1 demonstrated high tumor uptake and low background in PET imaging.
  • [177Lu]Lu-PDB3-1 showed favorable biodistribution with rapid renal clearance and low systemic retention.
  • Therapeutic administration of [177Lu]Lu-PDB3-1 resulted in significant tumor inhibition and survival benefits comparable to [177Lu]Lu-PSMA-617 at a reduced dose.
  • High-dose studies confirmed the safety and tolerability of the compound.

Conclusions:

  • SNAC conjugation represents a novel and effective strategy for optimizing PSMA-targeted radioligands.
  • PDB3-1 is a promising theranostic candidate for prostate cancer.
  • This approach offers potential advantages over conventional albumin-binding designs for PSMA-targeted theranostics.