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Design, synthesis, radiolabeling and biological evaluation of new urea-based peptides targeting prostate specific membrane antigen.
Bioorganic Chemistry ( IF 4.5 ) Pub Date : 2020-03-13 , DOI: 10.1016/j.bioorg.2020.103743 Mona Mosayebnia 1 , Zahra Hajimahdi 1 , Davood Beiki 2 , Maliheh Rezaeianpour 3 , Maliheh Hajiramezanali 4 , Parham Geramifar 2 , Omid Sabzevari 5 , Mohsen Amini 6 , Dara Hatamabadi 1 , Soraya Shahhosseini 7
Bioorganic Chemistry ( IF 4.5 ) Pub Date : 2020-03-13 , DOI: 10.1016/j.bioorg.2020.103743 Mona Mosayebnia 1 , Zahra Hajimahdi 1 , Davood Beiki 2 , Maliheh Rezaeianpour 3 , Maliheh Hajiramezanali 4 , Parham Geramifar 2 , Omid Sabzevari 5 , Mohsen Amini 6 , Dara Hatamabadi 1 , Soraya Shahhosseini 7
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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.
中文翻译：
设计，合成，放射性标记和针对前列腺特异膜抗原的新型基于尿素的肽的生物学评估。
前列腺癌（PCa）的早期诊断在成功治疗，提高患者生存率方面起着至关重要的作用。前列腺特异性膜抗原（PSMA）在几乎所有类型的PCa中均过表达。本研究的目标是引入新的99mTc标记的肽作为PSMA抑制剂，用于早期阶段PCa的特异性检测。基于公开的PSMA靶向化合物，通过计算机对接研究设计和评估了一组带有著名的Glu-Urea-Lys药效团和新的不含尿素的药效团的肽。合成所选的肽，并用99mTc进行放射性标记。体外测试（log P，在生理盐水和新鲜人血浆中的稳定性，以及对PSMA阳性LNCaP细胞系的亲和力）和放射性肽的体内表征（正常小鼠和荷瘤小鼠的生物分布和单光子发射计算机断层扫描计算机断层扫描（SPECT-CT）成像）。含有Glu-Urea-Lys和Glu-GABA-Asp作为药效基团的肽1-3与PSMA的晶体结构有效相互作用，并显示出最高的结合能，范围为-8至-11.2 kcal / mol。关于饱和结合测试，99mTc标记的肽1对PSMA阳性细胞具有最高的结合亲和力（Kd = 13.58 nM）。SPECT-CT成像和生物分布研究显示，在注射放射性肽1和2后1小时，肾脏和肿瘤的摄取较高（％ID / g肿瘤分别为3.62±0.78和1.8±0.32）。99mTc-肽1（Glu-尿素-Lys-Gly-Ala-Asp-萘丙氨酸-HYNIC-99mTc）在前列腺肿瘤病变中表现出最高的结合亲和力，高放射化学纯度，最稳定和最高的特异性积累。99mTc肽1具有与众所周知的PET示踪剂（68Ga-PSMA-11）相当的功效和药代动力学特性，似乎已被用作有前途的SPECT显像剂，可用于PCa的早期诊断，从而提高了患者的生存率。
更新日期：2020-04-20
中文翻译：
设计，合成，放射性标记和针对前列腺特异膜抗原的新型基于尿素的肽的生物学评估。
前列腺癌（PCa）的早期诊断在成功治疗，提高患者生存率方面起着至关重要的作用。前列腺特异性膜抗原（PSMA）在几乎所有类型的PCa中均过表达。本研究的目标是引入新的99mTc标记的肽作为PSMA抑制剂，用于早期阶段PCa的特异性检测。基于公开的PSMA靶向化合物，通过计算机对接研究设计和评估了一组带有著名的Glu-Urea-Lys药效团和新的不含尿素的药效团的肽。合成所选的肽，并用99mTc进行放射性标记。体外测试（log P，在生理盐水和新鲜人血浆中的稳定性，以及对PSMA阳性LNCaP细胞系的亲和力）和放射性肽的体内表征（正常小鼠和荷瘤小鼠的生物分布和单光子发射计算机断层扫描计算机断层扫描（SPECT-CT）成像）。含有Glu-Urea-Lys和Glu-GABA-Asp作为药效基团的肽1-3与PSMA的晶体结构有效相互作用，并显示出最高的结合能，范围为-8至-11.2 kcal / mol。关于饱和结合测试，99mTc标记的肽1对PSMA阳性细胞具有最高的结合亲和力（Kd = 13.58 nM）。SPECT-CT成像和生物分布研究显示，在注射放射性肽1和2后1小时，肾脏和肿瘤的摄取较高（％ID / g肿瘤分别为3.62±0.78和1.8±0.32）。99mTc-肽1（Glu-尿素-Lys-Gly-Ala-Asp-萘丙氨酸-HYNIC-99mTc）在前列腺肿瘤病变中表现出最高的结合亲和力，高放射化学纯度，最稳定和最高的特异性积累。99mTc肽1具有与众所周知的PET示踪剂（68Ga-PSMA-11）相当的功效和药代动力学特性，似乎已被用作有前途的SPECT显像剂，可用于PCa的早期诊断，从而提高了患者的生存率。
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