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

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 Tc-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 Tc. 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, Tc-labeled peptide 1 had the highest binding affinity (K = 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). Tc-peptide 1 (Glu-urea-Lys-Gly-Ala-Asp-Naphthylalanine-HYNIC-Tc) exhibited the highest binding affinity, high radiochemical purity, the most stability and high specific accumulation in prostate tumour lesions. Tc-peptide 1 being of comparable efficacy and pharmacokinetic properties with the well-known PET tracer (Ga-PSMA-11) seems to be applied as a promising SPECT imaging agent to early diagnose of PCa and consequently increase survival rate of patients.