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用于诱导型一氧化氮合酶 PET/MR 成像的(4'-氨基-5',8'-二氟-1'H-螺[哌啶-4,2'-喹唑啉]-1-基](4-[F]氟苯基)甲酮的自动化合成及初步评价。

Automated Synthesis and Initial Evaluation of (4'-Amino-5',8'-difluoro-1'H-spiro[piperidine-4,2'-quinazolin]-1-yl)(4-[F]fluorophenyl)methanone for PET/MR Imaging of Inducible Nitric Oxide Synthase.

机构信息

Brain Research Center, National Yang Ming Chiao Tung University, Taipei, Taiwan.

Department of Nuclear Medicine, Taipei Medical University Hospital, Taipei, Taiwan.

出版信息

Mol Imaging. 2021 Jul 8;2021:9996125. doi: 10.1155/2021/9996125. eCollection 2021.

Abstract

BACKGROUND

Inducible nitric oxide synthase (iNOS) plays a crucial role in neuroinflammation, especially microglial activity, and may potentially represent a useful biomarker of neuroinflammation. In this study, we carefully defined a strategic plan to develop iNOS-targeted molecular PET imaging using (4'-amino-5',8'-difluoro-1'H-spiro[piperidine-4,2'-quinazolin]-1-yl)(4-fluorophenyl)methanone ([F]FBAT) as a tracer in a mouse model of lipopolysaccharide- (LPS-) induced brain inflammation.

METHODS

An model, murine microglial BV2 cell line, was used to assess the uptake of [F]FBAT in response to iNOS induction at the cellular level. whole-body dynamic PET/MR imaging was acquired in LPS-treated (5 mg/kg) and control mice. Standard uptake value (SUV), total volume of distribution ( ), and area under the curve (AUC) based on the [F]FBAT PET signals were determined. The expression of iNOS was confirmed by immunohistochemistry (IHC) of brain tissues.

RESULTS

At the end of synthesis, the yield of [F]FBAT was 2.2-3.1% (EOS), radiochemical purity was >99%, and molar radioactivity was 125-137 GBq/mol. , [F]FBAT rapidly and progressively accumulated in murine microglial BV2 cells exposed to LPS; however, [F]FBAT accumulation was inhibited by aminoguanidine, a selective iNOS inhibitor. biodistribution studies of [F]FBAT showed a significant increase in the liver and kidney on LPS-treated mice. At 3 h postinjection of LPS, , the [F]FBAT accumulation ratios at 30 min post intravenous (i.v.) radiotracer injection for the whole brain, cortex, cerebellum, and brainstem were 2.16 ± 0.18, 1.53 ± 0.25, 1.41 ± 0.21, and 1.90 ± 0.12, respectively, compared to those of mice not injected with LPS. The mean area under the curve (AUC), total volume of distribution ( , mL/cm), and (influx rate) of [F]FBAT were 1.9 ± 0.21- and 1.4 ± 0.22-fold higher in the 3 h LPS group, respectively, than in the control group. In the pharmacokinetic two-compartment model, the whole brain of [F]FBAT was significantly higher in mice injected with LPS compared to the control group. Aminoguanidine, selective iNOS inhibitor, pretreatment significantly reduced the AUC and values in LPS-induced mice. Quantitative analysis of immunohistochemically stained brain sections confirmed iNOS was preferentially upregulated in the cerebellum and cortex of mice injected with LPS.

CONCLUSION

An automated robotic method was established for radiosynthesis of [F]FBAT, and the preliminary and results demonstrated the feasibility of detecting iNOS activity/expression in LPS-treated neuroinflammation by noninvasive imaging with [F]FBAT PET/MRI.

摘要

背景

诱导型一氧化氮合酶(iNOS)在神经炎症中起着至关重要的作用,尤其是小胶质细胞的活性,并且可能潜在地代表神经炎症的有用生物标志物。在这项研究中,我们仔细制定了一项战略计划,使用(4'-氨基-5',8'-二氟-1'H-螺[哌啶-4,2'-喹唑啉]-1-基)(4-氟苯基)甲酮([F]FBAT)作为示踪剂,在脂多糖(LPS)诱导的脑炎症小鼠模型中开发针对 iNOS 的分子 PET 成像。

方法

使用 模型,即小鼠小胶质细胞 BV2 细胞系,评估 [F]FBAT 在细胞水平上响应 iNOS 诱导的摄取情况。在 LPS 处理(5mg/kg)和对照小鼠中进行了全身体动态 PET/MR 成像。根据 [F]FBAT PET 信号确定标准摄取值(SUV)、总分布体积( )和曲线下面积(AUC)。通过脑组织的免疫组织化学(IHC)证实了 iNOS 的表达。

结果

在合成结束时,[F]FBAT 的产率为 2.2-3.1%(EOS),放射化学纯度>99%,摩尔放射性为 125-137GBq/mol。 ,[F]FBAT 在暴露于 LPS 的小鼠小胶质细胞 BV2 细胞中迅速且逐渐积累;然而,[F]FBAT 的积累被选择性 iNOS 抑制剂氨基胍抑制。[F]FBAT 的生物分布研究表明,LPS 处理的小鼠的肝脏和肾脏中的放射性明显增加。在 LPS 注射后 3 小时, ,静脉(i.v.)放射性示踪剂注射后 30 分钟时,整个大脑、皮质、小脑和脑干的 [F]FBAT 积累比分别为 2.16±0.18、1.53±0.25、1.41±0.21 和 1.90±0.12,与未注射 LPS 的小鼠相比。LPS 组的平均曲线下面积(AUC)、总分布体积( ,mL/cm)和 (流入率)分别是对照组的 1.9±0.21-和 1.4±0.22 倍。在药代动力学双室模型中,与对照组相比,LPS 注射小鼠的全脑 明显更高。选择性 iNOS 抑制剂氨基胍预处理显著降低了 LPS 诱导的小鼠的 AUC 和 值。免疫组化染色脑切片的定量分析证实,LPS 注射的小鼠小脑和皮质中 iNOS 优先上调。

结论

建立了 [F]FBAT 的自动化机器人合成方法,初步的 和 结果表明,通过 [F]FBAT PET/MRI 非侵入性成像检测 LPS 诱导的神经炎症中的 iNOS 活性/表达是可行的。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/c8fd/8328489/d3aaf6c93fbe/MOI2021-9996125.sch.001.jpg

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