t Bu 4 octapa-alkyl-NHS for metalloradiopeptide preparation

Dalton Trans. 2020 Jun 9;49(22):7605-7619. doi: 10.1039/d0dt00845a.

Abstract

The peptide is an important class of biological targeting molecule; herein, a new bifunctional octadentate non-macrocyclic H4octapa, tBu4octapa-alkyl-NHS, which is compatible with solid-phase peptide synthesis and thus useful for radiopeptide preparation, has been synthesized. To preserve denticity, the alkyl-N-hydroxylsuccinimide linker was covalently attached to the methylene-carbon on one of the acetate arms, yielding a chiral carbon center. According to density-functional theory (DFT) calculations using [Lu(octapa-alkyl-benzyl-ester)]- as a simulation model, the chirality has minimal effects on the complex geometry; regardless of the S-/R-stereochemistry, DFT calculations revealed two possible geometric isomers, distorted bicapped trigonal antiprism (DBTA) and distorted square antiprism (DSA), due to the asymmetry in the chelator. To evaluate the biological behavior of the new bifunctionalization, two well-studied PSMA (prostate-specific membrane antigen)-targeting peptidomimetics of varying hydrophobicity were chosen as proof-of-principle targeting vector molecules. Radiolabeling both bioconjugates with lutetium-177 was highly efficient at room temperature in 15 min at micromolar chelator concentration pH = 7. Both the in vitro serum challenge and the lanthanum(iii) challenge studies revealed complex lability, and notably, progressive bone accumulation was only observed with the more hydrophobic linker (i.e. H4octapa-alkyl-PSMA617). This in vivo result informs potential alterations exerted by the linker on the complex geometry and stability, with an appropriate biological targeting vector adopted for such evaluations.

MeSH terms

  • Alkanes / chemistry*
  • Density Functional Theory
  • Molecular Structure
  • Organometallic Compounds / chemical synthesis*
  • Organometallic Compounds / chemistry
  • Peptides / chemical synthesis*
  • Peptides / chemistry
  • Radiopharmaceuticals / chemical synthesis*
  • Radiopharmaceuticals / chemistry
  • Solid-Phase Synthesis Techniques*
  • Stereoisomerism

Substances

  • Alkanes
  • Organometallic Compounds
  • Peptides
  • Radiopharmaceuticals