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Bivalent Inhibitors of Prostate-Specific Membrane Antigen Conjugated to Desferrioxamine B Squaramide Labeled with Zirconium-89 or Gallium-68 for Diagnostic Imaging of Prostate Cancer.
Journal of Medicinal Chemistry ( IF 6.8 ) Pub Date : 2020-07-29 , DOI: 10.1021/acs.jmedchem.0c00291
Asif Noor 1 , Jessica K Van Zuylekom 2 , Stacey E Rudd 1 , Kelly Waldeck 2 , Peter D Roselt 2 , Mohammad B Haskali 2 , Michael P Wheatcroft 3 , Eddie Yan 3 , Rodney J Hicks 2, 4 , Carleen Cullinane 2, 4 , Paul S Donnelly 1
Journal of Medicinal Chemistry ( IF 6.8 ) Pub Date : 2020-07-29 , DOI: 10.1021/acs.jmedchem.0c00291
Asif Noor 1 , Jessica K Van Zuylekom 2 , Stacey E Rudd 1 , Kelly Waldeck 2 , Peter D Roselt 2 , Mohammad B Haskali 2 , Michael P Wheatcroft 3 , Eddie Yan 3 , Rodney J Hicks 2, 4 , Carleen Cullinane 2, 4 , Paul S Donnelly 1
Affiliation
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Prostate-specific membrane antigen (PSMA) is a carboxypeptidase that is overexpressed in prostate cancer and is an excellent candidate for targeted diagnostic imaging and therapy. Lysine-ureido-glutamate inhibitors of PSMA radiolabeled with positron-emitting radionuclides can be used for diagnostic imaging with positron emission tomography (PET). A squaramide ester derivative of desferrioxamine B (H3DFOSq) was used to prepare four new agents with either one or two lysine-ureido-glutamate pharmacophores. The H3DFOSq ligand can be used to form stable complexes with either of the positron-emitting radionuclides gallium-68 (t1/2 = 68 min) or zirconium-89 (t1/2 = 3.3 days). The complexes were evaluated in PSMA-positive xenograft mouse models. Bivalent inhibitors, where two pharmacophores are tethered to a single DFOSq ligand, have better tumor uptake than their monovalent analogues. The ligands presented here, which can be labeled with either gallium-68 or zirconium-89, have the potential to increase the number of clinical sites that can perform diagnostic PET imaging.
中文翻译：
前列腺特异性膜抗原的二价抑制剂与去铁胺B方酸酰胺共轭，用Zirconium-89或Gallium-68标记，用于前列腺癌的诊断成像。
前列腺特异性膜抗原（PSMA）是在前列腺癌中过表达的羧肽酶，是靶向诊断成像和治疗的极佳候选者。用正电子发射放射性核素进行放射性标记的PSMA的赖氨酸-脲基-谷氨酸抑制剂可用于正电子发射断层扫描（PET）的诊断成像。用去铁胺B的方酰胺酯衍生物（H 3 DFOSq）与一种或两种赖氨酸-脲基-谷氨酸药效基团一起制备四种新药。H 3 DFOSq配体可与发射正电子的放射性核素镓68（t 1/2 = 68 min）或锆89（t 1/2= 3.3天）。在PSMA阳性异种移植小鼠模型中评估了复合物。二价抑制剂将两个药效团束缚在一个DFOSq配体上，因此比其一价类似物具有更好的肿瘤吸收能力。此处显示的配体可以用镓68或锆89标记，可能会增加可执行诊断性PET成像的临床部位的数量。
更新日期：2020-09-10
中文翻译：
前列腺特异性膜抗原的二价抑制剂与去铁胺B方酸酰胺共轭，用Zirconium-89或Gallium-68标记，用于前列腺癌的诊断成像。
前列腺特异性膜抗原（PSMA）是在前列腺癌中过表达的羧肽酶，是靶向诊断成像和治疗的极佳候选者。用正电子发射放射性核素进行放射性标记的PSMA的赖氨酸-脲基-谷氨酸抑制剂可用于正电子发射断层扫描（PET）的诊断成像。用去铁胺B的方酰胺酯衍生物（H 3 DFOSq）与一种或两种赖氨酸-脲基-谷氨酸药效基团一起制备四种新药。H 3 DFOSq配体可与发射正电子的放射性核素镓68（t 1/2 = 68 min）或锆89（t 1/2= 3.3天）。在PSMA阳性异种移植小鼠模型中评估了复合物。二价抑制剂将两个药效团束缚在一个DFOSq配体上，因此比其一价类似物具有更好的肿瘤吸收能力。此处显示的配体可以用镓68或锆89标记，可能会增加可执行诊断性PET成像的临床部位的数量。
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