PET PROBES FOR IMAGING THE VESICULAR ACETYLCHOLINE TRANSPORTER

A.项目摘要/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、运动功能和认知障碍有关 功能。一种用于Vacht临床成像的PET示踪剂将提供一种关键的无创性测量工具 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。它还可以用来监测 神经疾病中的胆碱能疗法。在我们之前为发现PET而资助的R01项下 为了对Vacht进行成像，我们开发了[18F]VAT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(&gt；1000倍)，并在啮齿动物和 非人灵长类动物研究。更重要的是，在五年资助期结束时，我们完成了成像 非人灵长类动物的剂量学研究，啮齿动物毒性研究，以及用于自动化生产的SOP [18F]我们的cGMP设施中的增值税。我们的EIND、IRB和RDRC[18F]增值税申请获得批准，使飞行员能够 在8名健康人身上进行的PET成像显示：(A)高重复性和可靠性 [18F]cGMP设施的增值税生产；(B)研究对象没有明显的不利影响；(C)高 Vacht丰富的纹状体区域的特异性与靶：非靶比为6.0；以及(D)有利的动力学 注射后20min纹状体积聚较高，非靶区小脑半球迅速消失。 因此，R01更新的目标是专注于健康对照受试者中[18F]增值税的翻译研究 提供辐射剂量测定、受试者内和受试者之间的可变性、年龄相关性和 性依赖。这些验证研究将为今后的病理学研究提供基础。 条件。此外，我们将使用经过D2多巴胺受体激动剂或D2受体激动剂处理的非人类灵长类动物 拮抗剂研究它们对脑Vacht表达的影响，通过PET和[18F]VAT评估。最后，我们 将确定对PSP-RS患者进行Vacht定量成像的可行性，并在体内比较 脑血管疾病患者死后脑组织[~3H]VAT体外放射自显影的PET表现 尸检证实是PSP。

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.