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[F]FE-OTS964：一种针对 TOPK 的小分子药物，用于胶质母细胞瘤异种移植模型的体内 PET 成像。

[F]FE-OTS964: a Small Molecule Targeting TOPK for In Vivo PET Imaging in a Glioblastoma Xenograft Model.

机构信息

Department of Radiology, Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, New York, NY, 10065, USA.

CRUK/MRC Oxford Institute for Radiation Oncology, University of Oxford, Oxford, UK.

出版信息

Mol Imaging Biol. 2019 Aug;21(4):705-712. doi: 10.1007/s11307-018-1288-6.

DOI:10.1007/s11307-018-1288-6
PMID:30357568
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC6482100/
Abstract

PURPOSE

Lymphokine-activated killer T cell-originated protein kinase (TOPK) is a fairly new cancer biomarker with great potential for clinical applications. The labeling of a TOPK inhibitor with F-18 can be exploited for positron emission tomography (PET) imaging allowing more accurate patient identification, stratification, and disease monitoring.

PROCEDURES

[F]FE-OTS964 was produced starting from OTS964, a preclinical drug which specifically binds to TOPK, and using a two-step procedure with [F]fluoroethyl p-toluenesulfonate as a prosthetic group. Tumors were generated in NSG mice by subcutaneous injection of U87 glioblastoma cells. Animals were injected with [F]FE-OTS964 and PET imaging and ex vivo biodistribution analysis was carried out.

RESULTS

[F]FE-OTS964 was successfully synthesized and validated in vivo as a PET imaging agent. The labeling reaction led to 15.1 ± 7.5 % radiochemical yield, 99 % radiochemical purity, and high specific activity. Chemical identity of the radiotracer was confirmed by co-elution on an analytical HPLC with a cold-labeled standard. In vivo PET imaging and biodistribution analysis showed tumor uptake of 3.06 ± 0.30 %ID/cc, which was reduced in animals co-injected with excess blocking dose of OTS541 to 1.40 ± 0.42 %ID/cc.

CONCLUSIONS

[F]FE-OTS964 is the first TOPK inhibitor for imaging purposes and may prove useful in the continued investigation of the pharmacology of TOPK inhibitors and the biology of TOPK in cancer patients.

摘要

目的

淋巴因子激活的杀伤 T 细胞衍生的蛋白激酶（TOPK）是一种极具临床应用潜力的新型癌症生物标志物。TOPK 抑制剂与 F-18 标记后可用于正电子发射断层扫描（PET）成像，从而更准确地识别、分层和监测患者，以及疾病监测。

程序

[F]FE-OTS964 是从 OTS964 开始生产的，OTS964 是一种专门与 TOPK 结合的临床前药物，并使用两步法，以 [F]氟乙基对甲苯磺酸盐作为前体。通过皮下注射 U87 胶质母细胞瘤细胞在 NSG 小鼠中生成肿瘤。向动物注射 [F]FE-OTS964，并进行 PET 成像和离体生物分布分析。

结果

[F]FE-OTS964 已成功合成并在体内验证为 PET 成像剂。标记反应导致 15.1±7.5%放射性化学产率、99%放射性化学纯度和高比活度。通过与冷标记标准品在分析型 HPLC 上共洗脱，确认了示踪剂的化学同一性。体内 PET 成像和生物分布分析显示肿瘤摄取率为 3.06±0.30%ID/cc，在与过量 OTS541 阻断剂量共注射的动物中降低至 1.40±0.42%ID/cc。

结论

[F]FE-OTS964 是首个用于成像目的的 TOPK 抑制剂，可能有助于进一步研究 TOPK 抑制剂的药理学和癌症患者中 TOPK 的生物学。

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本文引用的文献

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T-lymphokine-activated killer cell-originated protein kinase (TOPK) as a prognostic factor and a potential therapeutic target in glioma.T淋巴细胞激活的杀伤细胞源蛋白激酶（TOPK）作为胶质瘤的预后因素和潜在治疗靶点。
Oncotarget. 2017 Dec 26;9(8):7782-7795. doi: 10.18632/oncotarget.23674. eCollection 2018 Jan 30.
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Targeting the T-Lak cell originated protein kinase by OTS964 shrinks the size of power-law coded heterogeneous glioma stem cell populations.OTS964靶向T淋巴细胞衍生蛋白激酶可缩小幂律编码的异质性胶质瘤干细胞群体的规模。
Oncotarget. 2017 Dec 9;9(3):3043-3059. doi: 10.18632/oncotarget.23077. eCollection 2018 Jan 9.
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Front Pharmacol. 2021 Feb 15;12:620874. doi: 10.3389/fphar.2021.620874. eCollection 2021.
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Improved radiosynthesis of I-MAPi, an auger theranostic agent.改进 I-MAPi 的放射合成，一种增效治疗的放射性药物。
Int J Radiat Biol. 2023;99(1):70-76. doi: 10.1080/09553002.2020.1781283. Epub 2020 Jul 2.
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PET/CT Imaging with an F-Labeled Galactodendritic Unit in a Galectin-1-Overexpressing Orthotopic Bladder Cancer Model.在过表达半乳糖凝集素-1 的原位膀胱癌模型中进行 F 标记的半乳糖树突单元的 PET/CT 成像。
J Nucl Med. 2020 Sep;61(9):1369-1375. doi: 10.2967/jnumed.119.236430. Epub 2020 Jan 31.
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TOPKi-NBD: a fluorescent small molecule for tumor imaging.TOPKi-NBD：一种用于肿瘤成像的荧光小分子。
Eur J Nucl Med Mol Imaging. 2020 Apr;47(4):1003-1010. doi: 10.1007/s00259-019-04608-w. Epub 2019 Nov 16.
7
T-LAK cell-originated protein kinase (TOPK): an emerging target for cancer-specific therapeutics.T-LAK 细胞来源的蛋白激酶（TOPK）：一种新兴的癌症特异性治疗靶点。
Cell Death Dis. 2018 Oct 24;9(11):1089. doi: 10.1038/s41419-018-1131-7.
TOPK modulates tumour-specific radiosensitivity and correlates with recurrence after prostate radiotherapy.
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Br J Cancer. 2017 Aug 8;117(4):503-512. doi: 10.1038/bjc.2017.197. Epub 2017 Jul 4.
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Biochem Biophys Res Commun. 2017 Jun 24;488(2):247-252. doi: 10.1016/j.bbrc.2017.03.162. Epub 2017 Mar 31.
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Clin Cancer Res. 2016 Dec 15;22(24):6110-6117. doi: 10.1158/1078-0432.CCR-16-0207. Epub 2016 Jun 22.
8
Pantoprazole, an FDA-approved proton-pump inhibitor, suppresses colorectal cancer growth by targeting T-cell-originated protein kinase.泮托拉唑是一种经美国食品药品监督管理局（FDA）批准的质子泵抑制剂，它通过靶向T细胞起源的蛋白激酶来抑制结直肠癌的生长。
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Combined expressional analysis, bioinformatics and targeted proteomics identify new potential therapeutic targets in glioblastoma stem cells.联合表达分析、生物信息学和靶向蛋白质组学鉴定胶质母细胞瘤干细胞中的新潜在治疗靶点。
Oncotarget. 2015 Sep 22;6(28):26192-215. doi: 10.18632/oncotarget.4613.
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PBK/TOPK enhances aggressive phenotype in prostate cancer via β-catenin-TCF/LEF-mediated matrix metalloproteinases production and invasion.PBK/TOPK通过β-连环蛋白-TCF/LEF介导的基质金属蛋白酶产生和侵袭增强前列腺癌的侵袭性表型。
Oncotarget. 2015 Jun 20;6(17):15594-609. doi: 10.18632/oncotarget.3709.