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: 10159311
• 负责人: Zhude Tu
• 金额: $ 57.46万
• 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 2024-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10159311
• 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; Disease; Dopamine Agonists; Dopamine D2 Receptor; Dose; Female; Foundations; Functional disorder; Funding; Future; Gender; Goals; Grant; Hippocampus (Brain); Human; Image; Impaired cognition; Impairment; In Vitro; Injections; Institutional Review Boards; Investigation; Kinetics; Label; Ligands; Macaca; Measures; Memory; Methodology; 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; kinetic model; male; nervous system disorder; non-invasive monitor; 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 囊泡乙酰胆碱转运体（VAChT）是研究胆碱能神经元丢失的可靠生物标志物 和突触。胆碱能缺陷与记忆、运动功能和认知功能障碍有关。 功能协调发展的PET示踪剂的临床成像VAChT将提供一个重要的非侵入性工具，以衡量 胆碱能缺陷和评估阿尔茨海默病，帕金森病， 进行性核上性麻痹（PSP）和其他痴呆。它也可以用来监测疗效 神经系统疾病的胆碱能疗法。在我们之前资助的R 01中， 为了使VAChT成像，我们开发了[18 F]VAT和[11 C] TZ 659。两者都具有高效力（Ki ≤ 1.0 nM）和对VAChT相对于σ受体的选择性（>1000倍），并在啮齿动物和哺乳动物中显示出前景。 非人类灵长类动物研究。更重要的是，在五年的资助期结束时，我们完成了成像， 非人灵长类动物的剂量测定研究、啮齿动物毒性研究和自动化生产的SOP [18F] cGMP设施的增值税。我们的eIND、IRB和RDRC申请获得[18 F]增值税的批准， 在八名健康人类受试者中进行的PET成像证明：（a） [18 F] cGMP设施中的VAT生产;（B）在研究受试者中无可观察到的不良反应;（c）高 对富含VAChT的纹状体区域的特异性，靶：非靶比率为6.0;和（d）有利的动力学 在注射后20分钟具有高的纹状体积累，并且从非靶小脑半球快速洗脱。 因此，本次R 01更新的目标是关注健康对照受试者中[18 F]VAT的转化研究 提供辐射剂量测定、受试者内和受试者之间的变异性、年龄依赖性和 性依赖这些验证研究将为将来的病理学研究提供基础。 条件此外，我们将使用用D2多巴胺受体激动剂或 拮抗剂，研究其对脑VAChT表达的影响，通过PET与[18 F]VAT评估。最后我们 将确定在PSP-RS患者中定量成像VAChT的可行性，并比较体内 使用[3 H]VAT对尸检脑组织进行体外放射自显影研究的PET结果， 尸检证明是PSP

项目成果

Structure-activity relationship studies and bioactivity evaluation of 1,2,3-triazole containing analogues as a selective sphingosine kinase-2 inhibitors.

1,2,3-三唑含有选择性鞘氨醇激酶-2抑制剂的1,2,3-三唑的生物活性研究和生物活性评估。

• DOI: 10.1016/j.ejmech.2020.112713
• 发表时间: 2020-11-15
• 期刊: European journal of medicinal chemistry
• 影响因子: 6.7
• 作者: Tangadanchu VKR;Jiang H;Yu Y;Graham TJA;Liu H;Rogers BE;Gropler R;Perlmutter J;Tu Z
• 通讯作者: Tu Z

Absorbed radiation dosimetry of the D3-specific PET radioligand [18F]FluorTriopride estimated using rodent and nonhuman primate.

使用啮齿动物和非人类灵长类动物估算 D3 特异性 PET 放射性配体 [18F]FluorTriopride 的吸收辐射剂量测定。

• 发表时间: 2016
• 期刊: American journal of nuclear medicine and molecular imaging
• 影响因子: 2.5
• 作者: Laforest,Richard;Karimi,Morvarid;Moerlein,StephenM;Xu,Jinbin;Flores,HubertP;Bognar,Christopher;Li,Aixiao;Mach,RobertH;Perlmutter,JoelS;Tu,Zhude
• 通讯作者: Tu,Zhude

Chiral resolution of serial potent and selective σ1 ligands and biological evaluation of (-)-[18F]TZ3108 in rodent and the nonhuman primate brain.

啮齿类动物和非人类灵长类动物脑中连续有效和选择性 α1 配体的手性拆分以及 (-)-[18F]TZ3108 的生物学评估。

• DOI: 10.1016/j.bmc.2017.01.017
• 发表时间: 2017
• 期刊: Bioorganic & medicinal chemistry
• 影响因子: 3.5
• 作者: Yue,Xuyi;Jin,Hongjun;Luo,Zonghua;Liu,Hui;Zhang,Xiang;McSpadden,EthanD;Tian,Linlin;Flores,HubertP;Perlmutter,JoelS;Parsons,StanleyM;Tu,Zhude
• 通讯作者: Tu,Zhude

Kinetics modeling and occupancy studies of a novel C-11 PET tracer for VAChT in nonhuman primates.

• DOI: 10.1016/j.nucmedbio.2015.11.003
• 发表时间: 2016-02
• 期刊: Nuclear medicine and biology
• 影响因子: 3.1
• 作者: Jin H;Zhang X;Yue X;Liu H;Li J;Yang H;Flores H;Su Y;Parsons SM;Perlmutter JS;Tu Z
• 通讯作者: Tu Z

Synthesis of Fluorine-Containing Phosphodiesterase 10A (PDE10A) Inhibitors and the In Vivo Evaluation of F-18 Labeled PDE10A PET Tracers in Rodent and Nonhuman Primate.

含氟磷酸二酯酶10a（PDE10A）抑制剂的合成以及在啮齿动物和非人类灵长类动物中对F-18标记的PDE10A PET示踪剂的体内评估。

• DOI: 10.1021/acs.jmedchem.5b01205
• 发表时间: 2015-11-12
• 期刊: Journal of medicinal chemistry
• 影响因子: 7.3
• 作者: Li J;Zhang X;Jin H;Fan J;Flores H;Perlmutter JS;Tu Z
• 通讯作者: Tu Z