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

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.