Radiosynthesis of [18F]brequinar for in vivo PET imaging of hDHODH for potential studies of acute myeloid leukemia and cancers†

IF 3.597 Q2 Pharmacology, Toxicology and Pharmaceutics MedChemComm Pub Date : 2024-07-22 DOI:10.1039/D4MD00433G
Vinay Kumar Banka, Stefano Sainas, Elena Martino, Jiacheng Wang, Marco Lucio Lolli and Yu-Shin Ding
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Abstract

Dihydroorotate dehydrogenase (DHODH), an enzyme that plays a critical role in the de novo pyrimidine biosynthesis, has been recognized as a promising target for the treatment of diseases that involve cellular proliferation, such as autoimmune diseases and cancers. Pharmacological inhibition of human DHODH (hDHODH) that offers a potential therapeutic strategy for the treatment in adult subjects with acute myeloid leukemia (AML) has recently been supported by phase I/II clinical trials for the treatment of patients with relapsed/refractory AML. To facilitate the development of optimized hDHODH inhibitors, the presence of an in vivo imaging probe that is able to demonstrate in vivo target engagement is critical and desirable. Brequinar is one of the most potent hDHODH inhibitors so far discovered. In this work, we use a copper-mediated radiofluorination (CMRF) strategy and compare the chemical design and radiosynthesis starting from either pinacole boronate p-nitrobenzyl ester (4) or tributylstannate (tin) p-nitrobenzyl ester (5), chosen for their suitability as a precursor to [18F]brequinar. We report here the design, synthesis, radiolabeling and characterization of [18F]brequinar, and a preliminary PET imaging study of DHODH in vivo. This study provides the strategies to create [18F]brequinar, the first hDHODH inhibitor PET radiotracer, which will facilitate its use as a tool (theranostics) for hDHODH drug development and for diagnosis and monitoring therapeutic efficacy in AML and cancers.

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用于 hDHODH 体内 PET 成像的[18F]brequinar 的放射合成,可用于急性髓性白血病和癌症的潜在研究。
二氢烟酸脱氢酶(DHODH)是一种在嘧啶从头生物合成过程中发挥关键作用的酶,已被公认为是治疗自身免疫性疾病和癌症等涉及细胞增殖的疾病的一个很有前景的靶点。药理抑制人类 DHODH(hDHODH)为治疗急性髓性白血病(AML)成人患者提供了一种潜在的治疗策略,最近治疗复发/难治性 AML 患者的 I/II 期临床试验支持了这一策略。为了促进优化的 hDHODH 抑制剂的开发,体内成像探针的存在至关重要,它能够证明体内靶点的参与。Brequinar 是迄今为止发现的最有效的 hDHODH 抑制剂之一。在这项工作中,我们采用了铜介导的放射性氟化(CMRF)策略,并比较了从硼酸频哪醇对硝基苯甲酯(4)或锡酸三丁酯(锡)对硝基苯甲酯(5)开始的化学设计和放射性合成。我们在此报告[18F]brequinar 的设计、合成、放射性标记和表征,以及 DHODH 在体内的 PET 成像初步研究。这项研究提供了创建[18F]brequinar--首个 hDHODH 抑制剂 PET 放射性示踪剂的策略,这将有助于将其作为一种工具(治疗学)用于 hDHODH 药物开发以及急性髓细胞性白血病和癌症的诊断和疗效监测。
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来源期刊
MedChemComm
MedChemComm BIOCHEMISTRY & MOLECULAR BIOLOGY-CHEMISTRY, MEDICINAL
CiteScore
4.70
自引率
0.00%
发文量
0
审稿时长
2.2 months
期刊介绍: Research and review articles in medicinal chemistry and related drug discovery science; the official journal of the European Federation for Medicinal Chemistry. In 2020, MedChemComm will change its name to RSC Medicinal Chemistry. Issue 12, 2019 will be the last issue as MedChemComm.
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