Department of Nuclear Medicine, Yonsei University College of Medicine, Seoul, 03722, Republic of Korea; Department of Nuclear Medicine, Molecular Imaging & Therapeutic Medicine Research Center, Biomedical Research Institute, Jeonbuk National University Medical School and Hospital, Jeonju, 54907, Republic of Korea.
Radiation Instrumentation Research Division, Korea Atomic Energy Research Institute, Jeongeup, 56212, Republic of Korea.
Eur J Med Chem. 2020 Mar 1;189:112099. doi: 10.1016/j.ejmech.2020.112099. Epub 2020 Jan 25.
Prostate cancer is one of the most frequently found cancers in men worldwide. Prostate-specific membrane antigen (PSMA) is typically highly expressed in prostate cancer, and the Glu-Urea-Lys (GUL) structure has recently received considerable attention as a key unit of PSMA-targeting agents. Additionally, one of the common characteristics of many solid tumors, such as prostate cancer, is hypoxia. In this study, novel multifunctional PSMA inhibitors containing a PSMA-targeting moiety either with or without a hypoxia-sensitive moiety (F-PEG-ADIBOT-2NI-GUL and F-PEG-ADIBOT-GUL, respectively; ADIBOT: azadibenzocyclooctatriazole, 2NI: 2-nitroimidazole) were designed and synthesized, and their feasibility as PET tracers for prostate cancer imaging studies was examined. The compounds labelled with F via the copper-free click reaction were stable in human serum and showed nanomolar binding affinities in in vitro PSMA binding assays. Micro-PET and biodistribution studies indicate that both F-labelled inhibitors successfully accumulated in prostate cancer regions, and F-PEG-ADIBOT-2NI-GUL showed a 2-fold higher tumor-to-total non-target organ ratio than that of F-PEG-ADIBOT-GUL, suggesting that the synergistic effects of the PSMA-targeting GUL moiety and the hypoxia-sensitive 2-nitroimidazole moiety can increase tumor uptake of the novel PET tracers in prostate cancer. These findings suggest that this novel multifunctional PET tracer with an F-labelled PSMA inhibitor and a 2-nitroimidazole moiety is a potent candidate to provide better diagnosis of prostate cancer via PET imaging studies.
前列腺癌是全球男性中最常见的癌症之一。前列腺特异性膜抗原（PSMA）通常在前列腺癌中高度表达，而 Glu-Urea-Lys（GUL）结构最近作为 PSMA 靶向剂的关键单元受到了相当多的关注。此外，许多实体瘤（如前列腺癌）的一个共同特征是缺氧。在这项研究中，设计并合成了含有 PSMA 靶向部分的新型多功能 PSMA 抑制剂，无论是否含有缺氧敏感部分（分别为 F-PEG-ADIBOT-2NI-GUL 和 F-PEG-ADIBOT-GUL；ADIBOT：氮杂二苯并环辛三烯，2NI：2-硝基咪唑），并研究了它们作为前列腺癌成像研究的 PET 示踪剂的可行性。通过无铜点击反应用 F 标记的化合物在人血清中稳定，并且在体外 PSMA 结合测定中表现出纳摩尔结合亲和力。微 PET 和生物分布研究表明，两种 F 标记的抑制剂都成功地在前列腺癌区域积聚，并且 F-PEG-ADIBOT-2NI-GUL 比 F-PEG-ADIBOT-GUL 具有 2 倍更高的肿瘤与总非靶器官比值，表明 PSMA 靶向 GUL 部分和缺氧敏感的 2-硝基咪唑部分的协同作用可以增加新型 PET 示踪剂在前列腺癌中的肿瘤摄取。这些发现表明，这种具有 F 标记的 PSMA 抑制剂和 2-硝基咪唑部分的新型多功能 PET 示踪剂是通过 PET 成像研究提供更好的前列腺癌诊断的有力候选者。
