Discovery of 18F Labeled AZD5213 Derivatives as Novel Positron Emission Tomography (PET) Radioligands Targeting Histamine Subtype-3 Receptor.

IF 2.6 4区生物学 Q3 BIOCHEMISTRY & MOLECULAR BIOLOGY

ChemBioChem Pub Date : 2024-09-20 DOI:10.1002/cbic.202400655

Zhendong Song, Yinlong Li, Kenneth Dahl, Ahmad Chaudhary, Zhenkun Sun, Xin Zhou, Jiahui Chen, Yabiao Gao, Jian Rong, Chunyu Zhao, Jimmy S Patel, Lee Collier, Chongzhao Ran, Chuangyan Zhai, Linqi Zhang, Ahmed Haider, Kim S Mühlfenzl, Hongjie Yuan, Charles S Elmore, Magnus Schou, Steven Liang

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Abstract

The histamine subtype 3 (H3) receptor is an important drug target in the central nervous system (CNS), and PET imaging offers a promising technique for the noninvasive evaluation of CNS disease related to the H3 receptor. In this study, we synthesized and evaluated the binding effects of [18F]H3-2404 and [18F]H3-2405 by modifying the structure of AZD5213, a selective H3 antagonist. These two radioligands were prepared in high radiochemical yields and displayed stability in serum. The in vitro autoradiographic study in rat brain tissue and the following in vivo PET studies in mice demonstrated sufficient brain uptake but predominantly non-specific distribution in rodent brain. Although these data suggest that [18F]H3-2404 and [18F]H3-2405 are unsuitable as PET tracers for brain imaging of the H3 receptor, this study provides a valuable attempt for optimizing 18F labeled radiotracers based on AZD5213.

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发现 18F 标记的 AZD5213 衍生物作为靶向组胺亚型-3 受体的新型正电子发射断层扫描 (PET) 放射配体。

组胺亚型 3（H3）受体是中枢神经系统（CNS）中的一个重要药物靶点，PET 成像为无创评估与 H3 受体相关的 CNS 疾病提供了一种很有前景的技术。在这项研究中，我们通过修改选择性 H3 拮抗剂 AZD5213 的结构，合成了 [18F]H3-2404 和 [18F]H3-2405 并评估了它们的结合效应。这两种放射性配体的制备具有较高的放射化学收率，并在血清中表现出稳定性。在大鼠脑组织中进行的体外自显影研究以及随后在小鼠体内进行的正电子发射计算机断层显像研究表明，啮齿类动物大脑对[18F]有足够的摄取，但主要是非特异性分布。虽然这些数据表明[18F]H3-2404 和 [18F]H3-2405 不适合作为 PET 示踪剂用于 H3 受体的脑成像，但这项研究为优化基于 AZD5213 的 18F 标记放射性示踪剂提供了宝贵的尝试。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

ChemBioChem 生物-生化与分子生物学

CiteScore

6.10

自引率

3.10%

发文量

407

审稿时长

1 months

期刊介绍： ChemBioChem (Impact Factor 2018: 2.641) publishes important breakthroughs across all areas at the interface of chemistry and biology, including the fields of chemical biology, bioorganic chemistry, bioinorganic chemistry, synthetic biology, biocatalysis, bionanotechnology, and biomaterials. It is published on behalf of Chemistry Europe, an association of 16 European chemical societies, and supported by the Asian Chemical Editorial Society (ACES).