Design, synthesis, radiolabeling and biological evaluation of new urea-based peptides targeting prostate specific membrane antigen

Bioorg Chem. 2020 Jun:99:103743. doi: 10.1016/j.bioorg.2020.103743. Epub 2020 Mar 13.

Abstract

Early diagnosis of Prostate cancer (PCa) plays a vital role in successful treatment increasing the survival rate of patients. Prostate Specific Membrane Antigen (PSMA) is over-expressed in almost all types of PCa. The goal of present study is to introduce new 99mTc-labeled peptides as a PSMA inhibitor for specific detection of PCa at early stages. Based on published PSMA-targeting compounds, a set of peptides bearing the well-known Glu-Urea-Lys pharmacophore and new non-urea containing pharmacophore were designed and assessed by in silico docking studies. The selected peptides were synthesized and radiolabeled with 99mTc. The in-vitro tests (log P, stability in normal saline and fresh human plasma, and affinity toward PSMA-positive LNCaP cell line) and in-vivo characterizations of radiopeptides (biodistribution and Single Photon Emission Computed Tomography-Computed Tomography (SPECT-CT) imaging in normal and tumour-bearing mice) were performed. The peptides 1-3 containing Glu-Urea-Lys and Glu-GABA-Asp as pharmacophores were efficiently interacted with crystal structure of PSMA and showed the highest binding energies range from -8 to -11.2 kcal/mol. Regarding the saturation binding test, 99mTc-labeled peptide 1 had the highest binding affinity (Kd = 13.58 nM) to PSMA-positive cells. SPECT-CT imaging and biodistribution studies showed high kidneys and tumour uptake 1 h post-injection of radiopeptide 1 and 2 (%ID/g tumour = 3.62 ± 0.78 and 1.8 ± 0.32, respectively). 99mTc-peptide 1 (Glu-urea-Lys-Gly-Ala-Asp-Naphthylalanine-HYNIC-99mTc) exhibited the highest binding affinity, high radiochemical purity, the most stability and high specific accumulation in prostate tumour lesions. 99mTc-peptide 1 being of comparable efficacy and pharmacokinetic properties with the well-known PET tracer (68Ga-PSMA-11) seems to be applied as a promising SPECT imaging agent to early diagnose of PCa and consequently increase survival rate of patients.

Keywords: PSMA; Peptide; Prostate cancer; Technetium-99m.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antigens, Surface / analysis*
  • Dose-Response Relationship, Drug
  • Drug Design*
  • Glutamate Carboxypeptidase II / analysis*
  • Humans
  • Male
  • Models, Molecular
  • Molecular Structure
  • Neoplasms, Experimental / diagnostic imaging
  • PC-3 Cells
  • Peptides / chemical synthesis
  • Peptides / chemistry*
  • Prostatic Neoplasms / diagnostic imaging*
  • Single Photon Emission Computed Tomography Computed Tomography
  • Structure-Activity Relationship
  • Technetium / chemistry*
  • Urea / analogs & derivatives
  • Urea / chemistry*

Substances

  • Antigens, Surface
  • Peptides
  • Technetium
  • Urea
  • FOLH1 protein, human
  • Glutamate Carboxypeptidase II