PET PROBES FOR IMAGING THE VESICULAR ACETYLCHOLINE TRANSPORTER

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

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.