Thibault Marin, Vasily Belov, Yanis Chemli, Jinsong Ouyang, Yassir Najmaoui, Georges El Fakhri, Sridhar Duvvuri, Philip Iredale, Nicolas J Guehl, Marc D Normandin, Yoann Petibon
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The proposed method is also evaluated in preclinical in-vivo experiments using 11C-MK6884 and a muscarinic acetylcholine receptor 4 positive allosteric modulator drug, showing improved estimation of receptor occupancy as compared to traditional estimators.</p><p><strong>Conclusion: </strong>The proposed joint direct estimation framework improves RO estimation compared to conventional methods, especially in intermediate to low-binding regions.</p><p><strong>Significance: </strong>This work could potentially facilitate the evaluation of new drug candidates targeting the CNS.</p>","PeriodicalId":13245,"journal":{"name":"IEEE Transactions on Biomedical Engineering","volume":"PP ","pages":""},"PeriodicalIF":4.4000,"publicationDate":"2024-10-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"PET mapping of receptor occupancy using joint direct parametric reconstruction.\",\"authors\":\"Thibault Marin, Vasily Belov, Yanis Chemli, Jinsong Ouyang, Yassir Najmaoui, Georges El Fakhri, Sridhar Duvvuri, Philip Iredale, Nicolas J Guehl, Marc D Normandin, Yoann Petibon\",\"doi\":\"10.1109/TBME.2024.3486191\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p><p>Receptor occupancy (RO) studies using PET neuroimaging play a critical role in the development of drugs targeting the central nervous system (CNS). 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引用次数: 0
摘要
利用 PET 神经成像技术进行的受体占位(RO)研究在开发针对中枢神经系统(CNS)的药物方面发挥着至关重要的作用。估算药物受体占据率的传统方法包括估算两次 PET 扫描(基线扫描和药物注射后扫描)之间的结合电位变化。这种估算通常是通过首先重建动态 PET 扫描数据,然后将动力学模型拟合到时间活动曲线上,从而分别对每次扫描进行估算。这种方法无法正确模拟 PET 测量中的噪声,导致 RO 估计结果不佳,尤其是在低受体密度区域:在这项工作中,我们评估了一种新颖的联合直接参数重建框架,该框架可直接从一对基线和药物注射后动态 PET 扫描中估算大脑中 RO 和其他动力学参数的分布:方法:所提出的方法将RO图的正则化与交替优化相结合,即使在低结合区域也能估计占据率:模拟结果表明,与传统方法相比,该方法在占据率的准确性和精确性方面有了定量改进。在使用 11C-MK6884 和毒蕈碱乙酰胆碱受体 4 阳性异位调节剂药物进行的临床前体内实验中,也对所提出的方法进行了评估,结果表明与传统估计方法相比,受体占据率的估计有所改进:结论:与传统方法相比,拟议的联合直接估算框架改进了受体占有率估算,尤其是在中低结合区域:意义:这项工作可能有助于评估以中枢神经系统为靶点的候选新药。
PET mapping of receptor occupancy using joint direct parametric reconstruction.
Receptor occupancy (RO) studies using PET neuroimaging play a critical role in the development of drugs targeting the central nervous system (CNS). The conventional approach to estimate drug receptor occupancy consists in estimation of binding potential changes between two PET scans (baseline and post-drug injection). This estimation is typically performed separately for each scan by first reconstructing dynamic PET scan data before fitting a kinetic model to time activity curves. This approach fails to properly model the noise in PET measurements, resulting in poor RO estimates, especially in low receptor density regions.
Objective: In this work, we evaluate a novel joint direct parametric reconstruction framework to directly estimate distributions of RO and other kinetic parameters in the brain from a pair of baseline and postdrug injection dynamic PET scans.
Methods: The proposed method combines the use of regularization on RO maps with alternating optimization to enable estimation of occupancy even in low binding regions.
Results: Simulation results demonstrate the quantitative improvement of this method over conventional approaches in terms of accuracy and precision of occupancy. The proposed method is also evaluated in preclinical in-vivo experiments using 11C-MK6884 and a muscarinic acetylcholine receptor 4 positive allosteric modulator drug, showing improved estimation of receptor occupancy as compared to traditional estimators.
Conclusion: The proposed joint direct estimation framework improves RO estimation compared to conventional methods, especially in intermediate to low-binding regions.
Significance: This work could potentially facilitate the evaluation of new drug candidates targeting the CNS.
期刊介绍:
IEEE Transactions on Biomedical Engineering contains basic and applied papers dealing with biomedical engineering. Papers range from engineering development in methods and techniques with biomedical applications to experimental and clinical investigations with engineering contributions.