2. Academic Validation
  3. Zwitterionic Modification of PSMA Ligands Reduces Off-Target Binding and Tissue Retention

Zwitterionic Modification of PSMA Ligands Reduces Off-Target Binding and Tissue Retention

  • J Med Chem. 2026 Mar 26;69(6):7364-7376. doi: 10.1021/acs.jmedchem.5c03849.
Lennart F V Spickschen 1,  Roland Thünauer 2,  Aleksander J Swierzewski 1,  John M Van Wazer 3,  Amanda Fears 3,  Matthew D Silva 4,  Daniel L J Thorek 3,  Elke Oetjen 5,  Wolfgang Maison 1
Affiliations

Affiliations

  • 1 Department of Chemistry, Institute of Pharmacy, University of Hamburg, Bundesstrasse 45, Hamburg 20146, Germany.
  • 2 Technology Platform Light Microscopy (TPLM), University of Hamburg and Advanced Light and Fluorescence Microscopy (ALFM) Facility, Centre of Structural Systems Biology, Notkestrasse 85, Hamburg 22607, Germany.
  • 3 Department of Radiology, Washington University, School of Medicine, 510 S. Kingshighway Blvd., Saint Louis, Missouri 63110, United States.
  • 4 EMIT Imaging, Inc.12 Michigan Drive, Natick, Massachusetts 01760, United States.
  • 5 Institute of Clinical Pharmacology and Toxicology, University Medical Center Hamburg-Eppendorf, Martinistrasse 52, Hamburg 20246, Germany.
PMID: 41824001 DOI: 10.1021/acs.jmedchem.5c03849
Abstract

Off-target tissue retention is a serious limitation for prostate-specific membrane antigen (PSMA)-targeted drugs. This study addresses key questions regarding the role of zwitterionic modifications in PSMA-ligand design for tissue distribution. A series of fluorescent PSMA-ligands was synthesized and evaluated with respect to PSMA-binding, tumor uptake, and biodistribution in cell experiments and in mice. The data revealed that the introduction of two zwitterionic groups into the linker domain of the PSMA-specific conjugates was particularly advantageous. The resulting compound 10 combined high and specific PSMA-binding affinity (IC50 = 4.39 ± 1.69 nM) and good uptake in tumor cells and tumor xenografts with extremely low off-target tissue retention. A major practical advantage of this strategy is its simple synthetic realization using solid-phase peptide synthesis with commercial building blocks and their modification using click-chemistry. Zwitterionization is therefore easily transferable to Other targeting vectors and alternative effector molecules, for example in radiopharmaceuticals.

Keywords

PSMA targeting; PSMA-617; off-target toxicity; prostate cancer; zwitterions.

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