PET Probes for Imaging the Vesicular Acetylcholine Transporter

用于囊泡乙酰胆碱转运蛋白成像的 PET 探针

基本信息

批准号：
8470733
负责人：
Zhude Tu
金额：
$ 33.56万
依托单位：
WASHINGTON UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2011
资助国家：
美国
起止时间：
2011-06-15 至 2016-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8470733
关键词：
Accounting Affinity Alzheimer&apos s Disease American Americas Applications Grants Area Autoradiography Binding Biodistribution Biological Biological Assay Biological Markers Blood Blood - brain barrier anatomy Blood specimen Brain Clinic Clinical Clinical Research Clinical assessments Corpus striatum structure Data Dementia Dose Drug Psychoses Drug abuse Early Diagnosis Elderly Evaluation Female Funding Future Goals Human Image Impaired cognition In Vitro Individual Institutional Review Boards Isomerism Kinetics Label Lead Ligands Macaca Measurement Measures Metabolic Metabolism Monitor Monkeys Nerve Neurodegenerative Disorders New Agents Organ Patients Phase Play Positron-Emission Tomography Prevalence Property Proteins Radiation Radio Radioactive Radiolabeled Rattus Recovery Reporting Research Research Contracts Research Project Grants Rodent Role Series Severities Specificity Structure Testing Time Toxic effect Tracer Treatment Efficacy United States Validation acetylcholine transporter analog base carbonyl group cholinergic cholinergic neuron cholinergic synapse cost dosimetry drug abuse therapy enantiomer imaging probe in vivo inhibitor/antagonist male metabolic abnormality assessment neurodegenerative dementia nonhuman primate novel presynaptic programs radiation absorbed dose radiotracer receptor screening sigma receptors social tool uptake vesamicol whole body imaging

项目摘要

DESCRIPTION (provided by applicant): The goal of this research project is to develop a PET radiotracer to quantify the vesicular acetylcholine transporter (VAChT). VAChT is a novel protein expressed in presynaptic cholinergic nerve terminals. This protein is a key biomarker for studying the loss of cholinergic neurons and synapses, which plays a major role in the cognitive dysfunction of dementia and is associated with a number of neurodegenerative diseases. A PET tracer for VAChT will provide a unique tool to measure the loss of cholinergic neurons and assess the severity of cognitive dysfunction of dementia associated with neurodegenerative diseases. In addition, it has been found that the level of VAChT in the brain is altered during treatment of drug abuse and psychosis. Therefore, a PET tracer for VAChT also will provide a new tool to monitor treatment of drug abuse and psychosis. Currently, PET measurement of brain VAChT in the brain has been hampered due to the lack of a suitable PET tracer. Therefore, it is extremely important to develop in vivo PET imaging agents for VAChT. To develop a PET radiotracer for imaging VAChT, we propose to explore a series of new novel carbonyl containing VAChT inhibitors and identify the more potent isomers of the lead compounds with nanomolar affinity (Ki < 10 nM) and high selectivity for VAChT by in vitro bioactivity determination. The identified isomers will be radiosynthesized with C-11 or F-18 and then will be validated in vivo rats and non-human primates. In addition, (-)-[18F]FBBV, a lead radio agent that belongs in this new class of VAChT inhibitors will be further evaluated to determine if it will be a suitable PET tracer for clinical imaging studies of VAChT. The initial in vivo validation of (-)-[18F]FBBV demonstrated high specific binding affinity in the VAChT enriched striatum of the brain. In the current project, we propose to further evaluate (-)[18F]FBBV and several structural congeners. There are five specific aims in this grant application: Specific Aim 1, Synthesis and Radiosynthesis. We will first resolve the racemic mixtures of 5 new lead compounds to determine which enantiomeric isomers are more potent and more selective using in vitro binding affinity screening assays; the more potent enantiomers will then be radiosynthesized with C-11 or F-18. Specific Aim 2, Biological evaluation in rats. Rat biodistribution and autoradiography studies will be conducted to determine if the radiotracers bind to VAChT-enriched striatum of the brain. Specific Aim 3, MicroPET imaging and blood metabolite analysis in nonhuman primates. Baseline studies, test-retest variability studies, specificity studies and reversibility/irreversibility studies of the 18F or 11C-labeled radiotracers will be conducted in macaques including metabolite analysis of arterial blood samples. Specific Aim 4, Dosimetry Studies. Whole body microPET imaging studies will be conducted in macaques to estimate the dose of radiation absorbed by different organs in human. Specific Aim 5, Toxicity Studies. Toxicity studies of the unlabeled form of the most promising PET radiotracer will be conducted. Specific Aims 4 and 5 are prerequisite steps for future PET imaging studies in humans.

描述（由申请人提供）：该研究项目的目标是开发一种 PET 放射性示踪剂来量化囊泡乙酰胆碱转运蛋白 (VAChT)。 VAChT 是一种在突触前胆碱能神经末梢表达的新型蛋白质。这种蛋白质是研究胆碱能神经元和突触损失的关键生物标志物，胆碱能神经元和突触损失在痴呆症的认知功能障碍中发挥着重要作用，并与许多神经退行性疾病相关。 VAChT 的 PET 示踪剂将提供一种独特的工具来测量胆碱能神经元的损失并评估与神经退行性疾病相关的痴呆症认知功能障碍的严重程度。此外，研究还发现，在药物滥用和精神病治疗过程中，大脑中 VAChT 的水平会发生改变。因此，VAChT 的 PET 示踪剂也将提供一种新工具来监测药物滥用和精神病的治疗。目前，由于缺乏合适的 PET 示踪剂，PET 对大脑中 VAChT 的测量受到了阻碍。因此，开发VAChT体内PET显像剂极为重要。为了开发用于 VAChT 成像的 PET 放射性示踪剂，我们建议探索一系列新型含羰基 VAChT 抑制剂，并通过体外生物活性鉴定具有纳摩尔亲和力 (Ki < 10 nM) 和对 VAChT 高选择性的先导化合物的更有效异构体决心。鉴定出的异构体将与 C-11 或 F-18 进行放射合成，然后在大鼠和非人类灵长类动物体内进行验证。此外，(-)-[18F]FBBV（属于此类新型 VAChT 抑制剂的主要放射剂）将得到进一步评估，以确定其是否适合用于 VAChT 临床成像研究的 PET 示踪剂。 (-)-[18F]FBBV 的初步体内验证表明，在富含 VAChT 的大脑纹状体中具有高特异性结合亲和力。在当前项目中，我们建议进一步评估 (-)[18F]FBBV 和几种结构同系物。本次资助申请有五个具体目标：具体目标 1、合成和放射合成。我们将首先解析 5 种新先导化合物的外消旋混合物，以确定哪些对映体异构体更有效且更具选择性，使用体外结合亲和力筛选测定；然后用 C-11 或 F-18 放射合成更有效的对映体。具体目标 2，大鼠生物学评价。将进行大鼠生物分布和放射自显影研究，以确定放射性示踪剂是否与富含 VAChT 的大脑纹状体结合。具体目标 3，非人类灵长类动物的 MicroPET 成像和血液代谢物分析。 18F或11C标记放射性示踪剂的基线研究、重测变异性研究、特异性研究和可逆性/不可逆性研究将在猕猴中进行，包括动脉血样本的代谢物分析。具体目标 4，剂量测定研究。将对猕猴进行全身 microPET 成像研究，以估计人体不同器官吸收的辐射剂量。具体目标 5，毒性研究。将针对最有前途的 PET 放射性示踪剂的未标记形式进行毒性研究。具体目标 4 和 5 是未来人类 PET 成像研究的先决步骤。