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

• 批准号: 9381138
• 负责人: Zhude Tu
• 金额: $ 60.29万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-06-15 至 2022-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9381138
• 关键词: Adult; Adverse effects; Age; Agonist; Alzheimer' s Disease; Animal Model; Autopsy; Autoradiography; Binding; Biological Markers; Brain; Brain Stem; Brain region; Cerebellar vermis structure; Cerebellum; Clinical; Corpus striatum structure; Cyclic GMP; Data; Dementia; Dependence; Dependency; Disease; Dopamine D2 Receptor; Dose; Female; Foundations; Functional disorder; Funding; Future; Gender; Goals; Grant; Hippocampus (Brain); Human; Image; Impaired cognition; Impairment; In Vitro; Injectable; Injection of therapeutic agent; Investigation; Kinetics; Label; Ligands; Macaca; Measures; Memory; Methodology; Modeling; Monitor; Monkeys; Motor; Nerve Degeneration; Neurodegenerative Disorders; Parkinson Disease; Parkinsonian Disorders; Pathologic; Pathology; Patients; Play; Positron-Emission Tomography; Production; Progressive Supranuclear Palsy; Quinpirole; Radiometry; Reproducibility; Research Subjects; Rodent; Role; Sampling; Severities; Severity of illness; Specificity; Syndrome; Testing; Thalamic structure; Therapeutic Intervention; Tissues; Toxic effect; Tracer; Treatment Efficacy; Validation; acetylcholine transporter; age group; brain tissue; cholinergic; cholinergic neuron; cholinergic synapse; clinical imaging; cognitive function; dosimetry; effective therapy; eticlopride; human subject; imaging agent; imaging probe; imaging study; in vivo; interest; male; nervous system disorder; nonhuman primate; novel; putamen; quantitative imaging; radiotracer; sex; sigma receptors; targeted agent; tool; translational study; uptake; validation studies; whole body imaging

A. Project Summary/Abstract Vesicular acetylcholine transporter (VAChT) is a reliable biomarker for studying the loss of cholinergic neurons and synapses. Cholinergic deficits are associated with impairment in memory, motor function and cognitive functions. A PET tracer for clinical imaging of VAChT will provide a critical noninvasive tool to measure cholinergic deficits and assess disease severity of patients with Alzheimer disease, Parkinson disease, progressive supranuclear palsy (PSP) and other dementias. It can also be used to monitor the efficacy of cholinergic therapies in neurological diseases. Under our previously funded R01 for the discovery of PET imaging agents for imaging the VAChT, we developed [18F]VAT and [11C]TZ659. Both have high potency (Ki ≤ 1.0 nM) and selectivity for VAChT versus sigma receptors (>1000-fold) and showed promise in rodent and nonhuman primate studies. More importantly, by the end of the five year funding period, we completed imaging dosimetry studies in nonhuman primates, rodent toxicity studies, and the SOP for automated production of [18F]VAT in our cGMP facilities. Approval of our eIND, IRB and RDRC applications for [18F]VAT enabled a pilot PET imaging in eight healthy human subjects that demonstrated: (a) high reproducibility and reliability of [18F]VAT production in the cGMP facility; (b) no observable adverse effects in research subjects; (c) high specificity for the VAChT-enriched striatal region with target: non-target ratio of 6.0; and (d) favorable kinetic with high striatal accumulation 20 min post-injection, and rapid washout from non-target cerebellar hemispheres. Therefore, the goal of this R01 renewal is to focus on translational studies of [18F]VAT in healthy control subjects to provide key measures of radiation dosimetry, variability within and between subjects, age-dependence and sex-dependence. These validation studies will provide the basis for future investigations of pathologic conditions. In addition, we will use nonhuman primates pre-treated with a D2 dopamine receptor agonist or antagonist to investigate their impact on brain VAChT expression assessed by PET with [18F]VAT. Finally, we will determine the feasibility of quantitatively imaging VAChT in patients with PSP-RS and compare the in vivo PET findings to in vitro autoradiography studies using [3H]VAT for postmortem brain tissues from cases with autopsy proven PSP.

A.项目摘要/摘要 囊泡乙酰胆碱转运蛋白（VACHT）是研究胆碱能神经元丧失的可靠生物标志物 和突触。胆碱能定义与记忆，运动功能和认知的损害有关 功能。用于VACHT临床成像的宠物示踪剂将提供一个关键的无创工具来测量 胆碱能缺乏症和评估阿尔茨海默氏病，帕金森病的患者的疾病严重程度， 进行性超级倾斜因麻痹（PSP）和其他痴呆症。它也可以用于监视 神经系统疾病中的胆碱能疗法。在我们以前资助的R01下发现宠物 用于成像VACHT的成像剂，我们开发了[18F]增值税和[11C] TZ659。两者都有很高的效力（ki≤ 1.0 nm）和VACHT与Sigma受体的选择性（> 1000倍），并在啮齿动物和 非人类灵长类研究。更重要的是，到五年资金期结束时，我们完成了成像 非人类隐私，啮齿动物毒性研究和自动产生的SOP的剂量学研究 [18F]我们的CGMP设施中的增值税。批准我们的EIND，IRB和RDRC应用程序[18F]增值税启用了飞行员 八个健康的人类受试者的宠物成像：（a）高可重复性和可靠性 [18F] CGMP设施中的增值税生产； （b）研究对象没有明显的不利影响； （c）高 富含VACHT的纹状体区域的特异性，其非目标比为6.0； （d）有利动力学 注射后20分钟，纹状体积聚高，非目标小脑半球的快速冲洗。 因此，此R01更新的目的是专注于健康对照对象中[18F]增值税的翻译研究 提供辐射剂量法，受试者内部和受试者之间的变异性的关键度量，年龄依赖性和 性别依赖性。这些验证研究将为将来的病理研究提供基础 状况。此外，我们将使用预先对D2多巴胺受体激动剂或 拮抗剂研究了通过[18F]增值税评估的PET评估的对脑VACHT表达的影响。最后，我们 将确定PSP-RS患者定量成像VACHT的可行性，并比较体内 使用[3H]增值税的宠物研究结果 尸检经过证明的PSP。