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[C]GSK-189254，一种靶向 H 受体的 PET 示踪剂，在大鼠脑内的药代动力学建模。

Pharmacokinetic Modeling of [C]GSK-189254, PET Tracer Targeting H Receptors, in Rat Brain.

机构信息

University Medical Center Groningen, Department of Nuclear Medicine and Molecular Imaging, University of Groningen, Groningen 9700 RB, The Netherlands.

Symeres, Groningen 9747 AT, The Netherlands.

出版信息

Mol Pharm. 2022 Mar 7;19(3):918-928. doi: 10.1021/acs.molpharmaceut.1c00889. Epub 2022 Feb 16.

DOI:10.1021/acs.molpharmaceut.1c00889
PMID:35170965
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC8905578/
Abstract

The histamine H receptor has been considered as a target for the treatment of various central nervous system diseases. Positron emission tomography (PET) studies with the radiolabeled potent and selective histamine H receptor antagonist [C]GSK-189254 in rodents could be used to examine the mechanisms of action of novel therapeutic drugs or to assess changes of regional H receptor density in animal models of neurodegenerative disease. [C]GSK-189254 was intravenously administered to healthy Wistar rats ( = 10), and a 60 min dynamic PET scan was carried out. Arterial blood samples were obtained during the scan to generate a metabolite-corrected plasma input function. PET data were analyzed using a one-tissue compartment model (1T2k), irreversible (2T3k) or reversible two-tissue compartment models (2T4k), graphical analysis (Logan and Patlak), reference tissue models (SRTM and SRTM2), and standard uptake values (SUVs). The Akaike information criterion and the standard error of the estimated parameters were used to select the most optimal quantification method. This study demonstrated that the 2T4k model with a fixed blood volume fraction and Logan graphical analysis can best describe the kinetics of [C]GSK-189254 in the rat brain. SUV and the reference tissue-based measurements DVR(2T4k), BP(SRTM), and SUV ratio could also be used as a simplified method to estimate H receptor availability in case blood sampling is not feasible.

摘要

组胺 H 受体一直被认为是治疗各种中枢神经系统疾病的靶点。在啮齿动物中使用放射性标记的强效和选择性组胺 H 受体拮抗剂 [C]GSK-189254 的正电子发射断层扫描 (PET) 研究可用于检查新型治疗药物的作用机制，或评估神经退行性疾病动物模型中区域 H 受体密度的变化。将 [C]GSK-189254 静脉内给予健康的 Wistar 大鼠（n = 10），并进行 60 分钟的动态 PET 扫描。在扫描过程中采集动脉血样，以生成代谢校正的血浆输入函数。使用单组织室模型 (1T2k)、不可逆 (2T3k) 或可逆双组织室模型 (2T4k)、图形分析 (Logan 和 Patlak)、参考组织模型 (SRTM 和 SRTM2) 和标准摄取值 (SUV) 分析 PET 数据。Akaike 信息准则和估计参数的标准误差用于选择最优化的定量方法。这项研究表明，具有固定血液体积分数和 Logan 图形分析的 2T4k 模型可以最好地描述 [C]GSK-189254 在大鼠脑中的动力学。SUV 和基于参考组织的测量 DVR(2T4k)、BP(SRTM)和 SUV 比也可以作为一种简化方法，用于估计在不可行血液采样的情况下 H 受体的可用性。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ca3d/8905578/828489d13426/mp1c00889_0008.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ca3d/8905578/5e7683d311a2/mp1c00889_0002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ca3d/8905578/68fd0a6da7c3/mp1c00889_0003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ca3d/8905578/562f17aa386e/mp1c00889_0004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ca3d/8905578/b33d5cc8bd33/mp1c00889_0005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ca3d/8905578/7552f664b3de/mp1c00889_0006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ca3d/8905578/3242732fb23d/mp1c00889_0007.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ca3d/8905578/828489d13426/mp1c00889_0008.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ca3d/8905578/5e7683d311a2/mp1c00889_0002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ca3d/8905578/68fd0a6da7c3/mp1c00889_0003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ca3d/8905578/562f17aa386e/mp1c00889_0004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ca3d/8905578/b33d5cc8bd33/mp1c00889_0005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ca3d/8905578/7552f664b3de/mp1c00889_0006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ca3d/8905578/3242732fb23d/mp1c00889_0007.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ca3d/8905578/828489d13426/mp1c00889_0008.jpg

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