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. 项目总结/摘要 囊泡乙酰胆碱转运蛋白 (VAChT) 是研究胆碱能神经元损失的可靠生物标志物 和突触缺陷与记忆、运动功能和认知障碍有关。 用于 VAChT 临床成像的 PET 示踪剂将提供一种重要的非侵入性测量工具。 胆碱能缺陷并评估阿尔茨海默病、帕金森病、 也可用于监测进行性核上性麻痹（PSP）和其他痴呆症的疗效。 神经系统疾病的胆碱能疗法是我们之前资助的 R01 项目，用于发现 PET。 用于 VAChT 成像的显像剂，我们开发了 [18F]VAT 和 [11C]TZ659 两者都具有高效力（Ki ≤）。 1.0 nM）和 VAChT 相对于 sigma 受体的选择性（>1000 倍），并在啮齿类动物和 更重要的是，在五年资助期结束时，我们完成了成像。 非人类灵长类动物的剂量测定研究、啮齿动物毒性研究以及自动化生产的 SOP [18F]我们的 cGMP 设施中的增值税 [18F]增值税的 eIND、IRB 和 RDRC 申请获得批准，启用了试点。 对八名健康人类受试者进行的 PET 成像证明：(a) [18F]cGMP 设施中的增值税生产；(b) 对研究对象没有可观察到的不利影响；(c) 高 富含 VAChT 的纹状体区域的特异性，目标：非目标比率为 6.0；(d) 有利的动力学； 注射后 20 分钟纹状体积累量较高，并且从非目标小脑半球快速冲洗。 因此，本次R01更新的目标是专注于[18F]VAT在健康对照受试者中的转化研究 提供辐射剂量测定、受试者内部和受试者之间的变异性、年龄依赖性和 这些验证研究将为未来的病理学研究提供基础。 此外，我们将使用经过 D2 多巴胺受体激动剂或预处理的非人类灵长类动物。 拮抗剂以研究其对通过 PET 和 [18F]VAT 评估的大脑 VAChT 表达的影响。 将确定对 PSP-RS 患者进行 VAChT 定量成像的可行性，并比较体内结果 使用[3H]VAT对来自患有以下疾病的病例的死后脑组织进行体外放射自显影研究的PET结果 尸检证明PSP。