Optimization of the dipeptide motifs in the PSMA ligands linker structure: synthesis and in vitro evaluation

Synthesis of Prostate-Specific Membrane Antigen-Targeted Bimodal Conjugates of Cytotoxic Agents and Antiandrogens and Their Comparative Assessment with Monoconjugates

“…Phenylalanine or tyrosine were chosen as one of the amino acid residues in the peptide sequence. This choice was justified by a number of studies that examined in detail the effect of the chosen amino acid residues on the affinity to PSMA [25][26][27]. Thus, in [25], a glycine residue was inserted into the linker structure instead of one of the two phenylalanine residues, and this resulted in a significant decrease in the affinity of the resulting ligands.…”

“…To obtain the tripeptide fragment, a solid-phase synthesis method using 2-chlorotrityl chloride resin (2-CTC resin) was chosen. This approach was chosen because of the availability of established protocols for the synthesis of similar compounds [17,27]. Alternatively, liquid-phase synthesis can be used.…”

“…Sci. 2023, 24, x FOR PEER REVIEW 4 of 27 availability of established protocols for the synthesis of similar compounds [17,27]. Alternatively, liquid-phase synthesis can be used.…”

Synthesis and Preclinical Evaluation of Urea-Based Prostate-Specific Membrane Antigen-Targeted Conjugates Labeled with 177Lu

“…In previous studies, the development of PSMA ligands lacking three aromatic fragments, two in the peptide part and one at the ε-nitrogen atom of lysine, was carried out. , Extensive screening of these ligands revealed promising substituents that exhibit the best affinity to the receptor. In particular, the screening of various dipeptide motifs highlighted the effectiveness of l -Phe- l -Phe or l -Phe- l -Tyr fragments, along with certain modifications thereof, as optimal candidates for linker insertion . The dipeptide moieties provide interactions of the linker portion of the ligand with subpockets within the hydrophobic tunnel of PSMA.…”

“…This was achieved by variation of different substituents in the N-ε-Lys benzyl moiety along with variation of dipeptide linkers. These efforts were directed toward synthesizing fluorescent or therapeutic conjugates. − Based on the previous ligand screenings, the most potent benzyl moieties, such as m -Cl, p -Br-, and p -COOH-benzyl residues, were taken into account in this paper along with reference ligands, containing a nonsubstituted-benzyl moiety and ligand without benzyl group. To evaluate the effect of the molecular structure of the linker on the properties of a small-molecule PSMA inhibitor, we introduce 6 polypeptides based on N -[ N -[( S )-1,3-dicarboxypropyl]­carbamoyl]-( S )- l -lysine (DCL) with most standard linkers containing the Phe-Phe or Phe-Tyr peptide sequences and an aromatic fragment at the ε-NH 2 K 2 group of the DCL fragment.…”