Quantitative receptor occupancy PET

定量受体占用 PET

• 批准号: 10024082
• 负责人: Marc David Normandin
• 金额: $ 19.89万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-09-25 至 2022-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10024082
• 关键词: 3-Dimensional; Adopted; Algorithms; Anatomy; Animal Model; Antipsychotic Agents; Binding; Biological Assay; Brain; Brain region; Central Nervous System Agents; Central Nervous System Diseases; Clozapine; Data; Data Set; Development; Dopamine D2 Receptor; Dose; Evaluation; Failure; Image; Joints; Kinetics; Ligand Binding; Ligands; Maps; Measures; Methodology; Methods; Modeling; Monkeys; Monte Carlo Method; Neuraxis; Noise; Patients; Penetration; Performance; Pharmaceutical Preparations; Pharmacologic Substance; Pharmacology; Phase; Plasma; Play; Positron-Emission Tomography; Radiation exposure; Research; Risk; Role; Sample Size; Scanning; Signal Transduction; Site; Techniques; Technology; Time; Tracer; Translating; base; clinical development; cost; detector; drug candidate; drug development; drug discovery; drug testing; human subject; image reconstruction; improved; in vivo; kinetic model; nonhuman primate; novel; novel therapeutics; receptor; receptor density; reconstruction; stem

PROJECT SUMMARY Positron emission tomography (PET) receptor occupancy imaging plays an increasingly important role in the development of central nervous system (CNS) drugs, providing critical information on drug brain penetration, target engagement and dosing. The conventional approach to measure occupancy of a CNS drug is to scan a subject twice, at baseline and after administration of the drug, independently apply image reconstruction and kinetic modeling to the data of each scan, and compute occupancy by measuring fractional reductions in specific ligand binding between the scans. The drawback of this approach, however, is the low precision of the estimated occupancy values. We propose to develop a novel parametric reconstruction approach that jointly reconstructs and analyzes the dynamic projections measured in the baseline and post-drug scans, leading to direct, quantitative estimation of receptor occupancy maps with a drastically higher signal-to-noise ratio. We expect our approach to significantly improve the precision and accuracy of occupancy quantification, allowing more robust characterization of dose-occupancy relationships and thereby greatly improving the quality of the information extracted from PET occupancy studies. The proposed methodology will be evaluated in an animal model.

项目摘要 正电子发射断层扫描（PET）受体占用成像在肿瘤治疗中发挥着越来越重要的作用。 中枢神经系统（CNS）药物的发展，提供药物脑的关键信息 穿透、目标接合和剂量。测量CNS药物占有率的常规方法 在基线和给药后扫描受试者两次， 对每次扫描的数据进行重建和动力学建模，并通过测量分数 减少扫描之间的特异性配体结合。然而，这种方法的缺点是低 估计占用值的精度。我们提出了一种新的参数化重建 联合重建和分析基线中测量的动态预测的方法， 药物后扫描，导致直接，定量估计受体占有率图， 更高的信噪比。我们希望我们的方法能够显着提高精度和准确性， 占用定量，允许更稳健地表征剂量-占用关系，从而 大大提高了从PET占用研究中提取的信息的质量。拟议 将在动物模型中评价方法学。