用于正电子发射断层扫描的 DREADD 的 F-标记放射性示踪剂。
F-labeled radiotracers for in vivo imaging of DREADD with positron emission tomography.
机构信息
Division of Nuclear Medicine and Molecular Imaging, Department of Radiology, Johns Hopkins School of Medicine, Baltimore, MD, 21205, USA.
Division of Preclinical Innovation, National Center for Advancing Translational Sciences, National Institutes of Health, Rockville, MD, 20850, USA.
出版信息
Eur J Med Chem. 2021 Mar 5;213:113047. doi: 10.1016/j.ejmech.2020.113047. Epub 2020 Nov 25.
Designer Receptors Exclusively Activated by Designer Drugs (DREADD) are a preclinical chemogenetic approach with clinical potential for various disorders. In vivo visualization of DREADDs has been achieved with positron emission tomography (PET) using C radiotracers. The objective of this study was to develop DREADD radiotracers labeled with F for a longer isotope half-life. A series of non-radioactive fluorinated analogs of clozapine with a wide range of in vitro binding affinities for the hM3Dq and hM4Di DREADD receptors has been synthesized for PET. Compound [F]7b was radiolabeled via a modified F-deoxyfluorination protocol with a commercial ruthenium reagent. [F]7b demonstrated encouraging PET imaging properties in a DREADD hM3Dq transgenic mouse model, whereas the radiotracer uptake in the wild type mouse brain was low. [F]7b is a promising long-lived alternative to the DREADD radiotracers [C]clozapine ([C]CLZ) and [C]deschloroclozapine ([C]DCZ).
设计者受体专门由设计者药物激活（DREADD）是一种具有临床潜力的临床前化学遗传方法，用于各种疾病。正电子发射断层扫描（PET）使用 C 放射性示踪剂已经实现了 DREADD 的体内可视化。本研究的目的是开发用 F 标记的 DREADD 放射性示踪剂，以获得更长的同位素半衰期。已经为 PET 合成了一系列具有广泛体外 hM3Dq 和 hM4Di DREADD 受体结合亲和力的非放射性氟化类似物。化合物 [F]7b 通过改良的 F-去氟化方案与商业钌试剂进行放射性标记。[F]7b 在 DREADD hM3Dq 转基因小鼠模型中表现出令人鼓舞的 PET 成像特性，而野生型小鼠大脑中的放射性示踪剂摄取量较低。[F]7b 是 DREADD 放射性示踪剂 [C]氯氮平（[C]CLZ）和 [C]去氯氯氮平（[C]DCZ）的有前途的长半衰期替代品。
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