Methodology for PET Imaging of Role of Dopamine D3 Receptor in Addiction

多巴胺 D3 受体在成瘾中的作用的 PET 成像方法

基本信息

批准号：
9109775
负责人：
Robert Kenneth Doot
金额：
$ 16.08万
依托单位：
UNIVERSITY OF PENNSYLVANIA
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-04-01 至 2021-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9109775
关键词：
Address Affinity Atlases Autoradiography Basal Ganglia Behavior Biology Blood Blood specimen Brain Brain Diseases Brain Neoplasms Brain imaging Brain region Brain scan Breast Cocaine Cocaine Dependence Computers Computing Methodologies Controlled Study Data Development Dopamine Dopamine Receptor Drug Targeting Exposure to FDA approved Faculty Functional Magnetic Resonance Imaging Funding Human Image Image Analysis Kinetics Laboratories Lead Learning Measurement Measures Memory Mentors Methodology Methods Modeling Molecular Neuroanatomy Neurosciences Neurotransmitters Nicotine Pathway interactions Patients Pattern Pharmaceutical Preparations Pharmacology Placebos Positron-Emission Tomography Psychostimulant dependence Public Health Recommendation Relapse Research Research Personnel Rewards Role Rosa Running Scanning Selection Criteria Signal Transduction Smoking Structure Techniques Testing Thalamic structure Tissues Tracer Training Universities Ursidae Family Work addiction base cancer risk clinical predictors diagnostic biomarker dopamine D3 receptor drug efficacy experience formycin triphosphate human study imaging biomarker imaging probe in vivo insight instrumentation interest malignant breast neoplasm member neuroimaging novel phase 2 study predicting response public health relevance putamen quantitative imaging radioligand radiotracer receptor receptor binding response targeted treatment tool uptake

项目摘要

DESCRIPTION (provided by applicant): The training will augment my experience in Positron Emission Tomography (PET) instrumentation and image analyses of breast cancer to enable me to become an independent investigator of PET methodology for neuroimaging addiction and establish a neuroimaging analysis laboratory patterned after the neuroimaging analysis laboratory established by my co-mentor Dr. Dean F. Wong at John Hopkins University. My interest in neuroimaging addiction work is an outgrowth of my exposure to addiction research since moving to Penn as a faculty member, and an understanding of what molecular neuroimaging can bring to bear on this important public health problem. I now want to study addiction, but first must fill 3 training gaps in (1) novel radiotracer imaging, (2) human addictio neuroscience, and (3) advanced computer-based quantitative image analysis. Dopamine D3 receptors are localized in reward-relevant brain regions; imaging them will elucidate their role in addiction relapse, leading to more effective cessation therapy, including D3-selective agents. Until now, determining the role of D3 receptors in addiction and relapse has not been feasible, as current PET radioligands are not sufficiently selective for distinguishing D2 versus D3 receptor subtypes. In response to this need, my mentor Dr. Robert Mach has created the first D3-specific tracer, [18F]fluortriopride ([18F]FTP). Preliminary data from our recent first-in-human PET scan of [18F]FTP uptake shows concentration in the expected D3-rich thalamus, putamen, and caudate regions and in brain regions involved in memory. This new tracer stimulates Aim 1, and addresses my first training gap: I will devise methods for quantitating [18F]FTP uptake for first-in-human studies of controls under mentor Dr. Mach and co-mentor Dr. Wong. Though there is no FDA-approved drug for stimulant addiction, co-mentor Dr. Anna Rose Childress was recently funded to study whether a new D3-targeted drug engages relapse-relevant brain targets (with fMRI). This study offers a natural opportunity to address training gap 2: Dr. Childress will provide mentored experience in human addiction neuroscience in the context of adding D3-specific [18F]FTP scans to her human study - allowing us in Aim 2 to examine D3-receptor occupancy in cocaine patients before and during D3- targeted medication. These D3 studies would be the first of their kind in cocaine patients. Dr. Caryn Lerman will mentor training on other forms of addiction (i.e. nicotine), for which the role of D3 receptor is also relevant. Training in deformable atlas computational methods for localization of brain structures and multivariate pattern analysis identification of imaging markers by co-mentor Dr. Christos Davatzikos will fill training gap 3 and through Aim 3's mentored research allow refinement of image markers of addiction via pattern analyses. The mentored research will create valuable tools for quantitating in vivo availability of dopamine D3 receptors to study efficacy of a cocaine cessation therapy and reveal underlying mechanisms of addiction.

描述（通过应用程序提供）：培训将增强我在正电子发射断层扫描（PET）仪器和图像分析方面的经验，使我能够成为神经影像成瘾的宠物方法论的独立研究者，并建立神经影像学分析实验室，并在我的联合委员Dean F. dean F. wong john john hopkins aT John hopkins hopkins Ath hopkins hopkins hopkins dean f.我对神经影像成瘾工作的兴趣是我对成瘾研究的接触的产物，因为搬到宾夕法尼亚州作为教职员工，并且了解分子神经影像学可以在这一重要的公共卫生问题上带来什么。我现在想研究成瘾，但首先必须填补（1）新颖的放射性示意剂成像，（2）人类添加剂神经科学和（3）（3）先进的基于计算机的定量图像分析中的3个训练空白。多巴胺D3受体位于与奖励相关的大脑区域中；成像它们将阐明他们在成瘾继电器，导致更有效的停止疗法，包括D3选择剂。到目前为止，确定D3受体在成瘾和浮雕中的作用一直是不可行的，因为当前的PET放射线不足以将D2与D3受体亚型区分开。为了应对这一需求，我的心理罗伯特·马赫（Robert Mach）博士创建了第一个D3特异性示踪剂[18F]氟替代（[18F] FTP）。我们最近的第一个人类的初步数据 [18F] FTP摄取的PET扫描显示出预期的D3富丘脑，pe骨和尾状区域以及与记忆相关的大脑区域的浓度。这个新的示踪剂刺激了目标1，并解决了我的第一个训练差距：我将设计用于定量[18F] FTP摄取的方法，以在心理博士Mach和Co-Machor Dr. Wong博士下对控制措施进行首次人工研究。尽管没有FDA批准的药物用于兴奋性成瘾，但联合注册者Anna Rose Childress博士最近获得了资助，以研究新的D3靶向药物是否涉及与脑靶标相关的大脑靶标（使用fMRI）。这项研究提供了一个自然的机会来解决培训第2条：Childress博士将在人类研究中添加D3特异性[18F] FTP扫描的背景下提供人类成瘾神经科学的经验 - 使我们在AIM 2中允许我们在D3靶向药物之前和期间检查可卡因患者的D3受体占用。这些D3研究将是可卡因患者中的第一个研究。 Caryn Lerman博士将指导培训在其他形式的成瘾（即尼古丁）上，D3受体的作用也很重要。培训对大脑结构的定位和多变量模式分析识别成像标记的培训，Christos Davatzikos博士将填补培训差距3，并通过AIM 3的指导研究允许通过模式分析对成瘾的图像标记进行改进。这项指导的研究将创建有价值的工具，以定量多巴胺D3受体的体内可用性来研究可卡因的效率停止疗法和揭示成瘾的潜在机制。