腹腔注射[18F]-FDOPA用于小鼠显微PET成像的评估以及亚慢性氯胺酮剂量对多巴胺合成能力的影响评估

IF 2.2 4区 医学 Q3 BIOCHEMICAL RESEARCH METHODS
Molecular Imaging Pub Date : 2022-10-28 eCollection Date: 2022-01-01 DOI:10.1155/2022/4419221
Els F Halff, Sridhar Natesan, David R Bonsall, Mattia Veronese, Anna Garcia-Hidalgo, Michelle Kokkinou, Sac-Pham Tang, Laura J Riggall, Roger N Gunn, Elaine E Irvine, Dominic J Withers, Lisa A Wells, Oliver D Howes
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引用次数: 0

摘要

使用放射性示踪剂 [18F]-FDOPA 的正电子发射断层扫描(PET)是研究动物和人类大脑多巴胺合成能力的一种工具。此前,我们已在小鼠体内标准化了一种微观 PET 方法,即通过颈静脉插管静脉注射 [18F]-FDOPA 并评估纹状体多巴胺合成能力(以 [18F]-FDOPA 的流入率常数 K i Mod 为指标),使用扩展的 Patlak 图形分析法,以小脑为参考区域。这样就能直接比较临床前和临床输出值。然而,慢性静脉导管在技术上难以维持纵向研究。因此,在本研究中,我们评估了腹腔注射[18F]-FDOPA这种有助于纵向成像的微创替代方法。我们的实验包括以下评估:(i) 比较静脉注射和腹腔注射放射性示踪剂对[18F]-FDOPA的摄取,并优化用于扩展帕特拉克分析的时间窗,(ii) 比较两种给药途径在受试者内设计中的Ki Mod、(iv) 在亚慢性氯胺酮诱导的小鼠多巴胺功能亢进模型中比较两种给药途径,验证 Ki Mod 估计值。我们的研究结果表明,腹腔注射[18F]-FDOPA具有良好的脑摄取效果,给药途径对Ki Mod估计值无显著影响(腹腔注射:0.024 ± 0.0047 min-1;静脉注射:0.022 ± 0.0041 min-1,p = 0.42),变异系数相似(腹腔注射:19.6%;静脉注射:18.4%)。该技术具有中等程度的测试-重复有效性(类内相关系数 (ICC) = 0.52,N = 6),因此支持纵向研究。亚慢性氯胺酮给药后,与对照组相比,两种方法均测得K i Mod升高,且效应大小较大(腹腔:Cohen's d = 1.3;静脉:Cohen's d = 0.9),进一步证明氯胺酮对多巴胺系统具有持久影响,这可能有助于其治疗作用和/或滥用责任。
本文章由计算机程序翻译,如有差异,请以英文原文为准。

Evaluation of Intraperitoneal [<sup>18</sup>F]-FDOPA Administration for Micro-PET Imaging in Mice and Assessment of the Effect of Subchronic Ketamine Dosing on Dopamine Synthesis Capacity.

Evaluation of Intraperitoneal [<sup>18</sup>F]-FDOPA Administration for Micro-PET Imaging in Mice and Assessment of the Effect of Subchronic Ketamine Dosing on Dopamine Synthesis Capacity.

Evaluation of Intraperitoneal [<sup>18</sup>F]-FDOPA Administration for Micro-PET Imaging in Mice and Assessment of the Effect of Subchronic Ketamine Dosing on Dopamine Synthesis Capacity.

Evaluation of Intraperitoneal [18F]-FDOPA Administration for Micro-PET Imaging in Mice and Assessment of the Effect of Subchronic Ketamine Dosing on Dopamine Synthesis Capacity.

Positron emission tomography (PET) using the radiotracer [18F]-FDOPA provides a tool for studying brain dopamine synthesis capacity in animals and humans. We have previously standardised a micro-PET methodology in mice by intravenously administering [18F]-FDOPA via jugular vein cannulation and assessment of striatal dopamine synthesis capacity, indexed as the influx rate constant K i Mod of [18F]-FDOPA, using an extended graphical Patlak analysis with the cerebellum as a reference region. This enables a direct comparison between preclinical and clinical output values. However, chronic intravenous catheters are technically difficult to maintain for longitudinal studies. Hence, in this study, intraperitoneal administration of [18F]-FDOPA was evaluated as a less-invasive alternative that facilitates longitudinal imaging. Our experiments comprised the following assessments: (i) comparison of [18F]-FDOPA uptake between intravenous and intraperitoneal radiotracer administration and optimisation of the time window used for extended Patlak analysis, (ii) comparison of Ki Mod in a within-subject design of both administration routes, (iii) test-retest evaluation of Ki Mod in a within-subject design of intraperitoneal radiotracer administration, and (iv) validation of Ki Mod estimates by comparing the two administration routes in a mouse model of hyperdopaminergia induced by subchronic ketamine. Our results demonstrate that intraperitoneal [18F]-FDOPA administration resulted in good brain uptake, with no significant effect of administration route on Ki Mod estimates (intraperitoneal: 0.024 ± 0.0047 min-1, intravenous: 0.022 ± 0.0041 min-1, p = 0.42) and similar coefficient of variation (intraperitoneal: 19.6%; intravenous: 18.4%). The technique had a moderate test-retest validity (intraclass correlation coefficient (ICC) = 0.52, N = 6) and thus supports longitudinal studies. Following subchronic ketamine administration, elevated K i Mod as compared to control condition was measured with a large effect size for both methods (intraperitoneal: Cohen's d = 1.3; intravenous: Cohen's d = 0.9), providing further evidence that ketamine has lasting effects on the dopamine system, which could contribute to its therapeutic actions and/or abuse liability.

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来源期刊
Molecular Imaging
Molecular Imaging Biochemistry, Genetics and Molecular Biology-Biotechnology
自引率
3.60%
发文量
21
期刊介绍: Molecular Imaging is a peer-reviewed, open access journal highlighting the breadth of molecular imaging research from basic science to preclinical studies to human applications. This serves both the scientific and clinical communities by disseminating novel results and concepts relevant to the biological study of normal and disease processes in both basic and translational studies ranging from mice to humans.
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