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

化学 药效团 LNCaP公司 体内分布 尿素 体内 前列腺癌 体外 显像剂 生物化学 癌症 内科学 医学 生物 生物技术
作者
Mona Mosayebnia,Zahra Hajimahdi,Davood Beiki,Maliheh Rezaeianpour,Maliheh Hajiramezanali,Parham Geramifar,Omid Sabzevari,Mohsen Amini,Dara Hatamabadi,Soraya Shahhosseini
出处
期刊:Bioorganic Chemistry [Elsevier]
卷期号:99: 103743-103743 被引量:17
标识
DOI:10.1016/j.bioorg.2020.103743
摘要

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.
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