SV2A PET Imaging in Healthy Subjects and Epilepsy Patients

 描述（由申请人提供）：突触前神经元末梢中的囊泡通过与突触前膜融合来分泌神经递质。一种必需的囊泡膜蛋白是突触囊泡糖蛋白2（SV 2），其同种型之一SV 2A在几乎所有突触中普遍表达。临床和实验数据表明，SV 2A参与癫痫，在致痫区发现SV 2A受体密度降低。癫痫动物模型表明，SV 2A的缺失可能有助于癫痫发生和药物抗性。此外，已发现SV 2A是抗惊厥药左乙拉西坦（LEV）的作用部位。我们最近开发了11 C-UCB-J作为一种有前途的放射性配体，用于正电子发射断层扫描（PET）定量测量SV 2A。在我们在健康受试者中进行的首次人体SV 2A PET试验研究中，我们发现11 C-UCB-J有可能成为人脑中SV 2A定量成像的优秀PET示踪剂。此外，这种示踪剂有可能成为一种通用的工具，用于测量突触囊泡 密度的我们建议全面开发和验证11 C-UCB-J用于人体，并在癫痫中进行初步临床研究。在第一个目标中，我们将在高分辨率研究断层扫描（HRRT）上使用推注/输注递送定量SV 2A，并在一天内对年轻健康对照进行配对测试/重新测试扫描。在一个单独的队列中，我们将通过配对研究在基线和静脉注射LEV后确定年轻健康对照中特异性结合的程度。来自这些实验的数据将定义最佳扫描方案和最合适的定量方法。在第二个目标中，我们将通过评估11 C-UCB-J的特异性和非特异性结合来评估年龄对SV 2A的影响。将进行基于MR的部分容积校正，以消除皮质萎缩的任何人为影响。这些结果对于解释任何疾病相关的变化都很重要，例如，因为神经退化，随着年龄的增长第三个目的是评估SV 2A密度的癫痫患者与医学难治性局灶性癫痫谁是手术切除的候选人。我们将比较这些患者与年龄和性别匹配的健康对照组的11 C-UCB-J结合，并评估癫痫发作起源部位的SV 2A密度是否降低。我们将通过测量手术切除的组织样本中的SV 2A表达来验证这些结果。还将在相同患者中比较11 C-UCB-J与18F-FDG的结合，以评价11 C-UCB-J在癫痫灶确定方面是否比FDG更有诊断价值。

 DESCRIPTION (provided by applicant): Vesicles in presynaptic neuron terminals secrete neurotransmitters by fusing with the presynaptic membrane. One essential vesicle membrane protein is the synaptic vesicle glycoprotein 2 (SV2), with one of its isoforms, SV2A, ubiquitously expressed in virtually all synapses. Clinical and experimental data have suggested that SV2A is involved in epilepsy with decreased SV2A receptor density found in the epileptogenic zone. Animal models of epilepsy suggest that loss of SV2A could contribute to epileptogenesis and pharmacoresistance. Furthermore, SV2A has been found to be the site of action of the anticonvulsant Levetiracetam (LEV). We recently developed 11C-UCB-J as a promising radioligand for quantitative measurement of SV2A with positron emission tomography (PET). In our pilot first-in-human SV2A PET studies in healthy subjects, we found that 11C-UCB-J has the potential to be an excellent PET tracer for quantitative imaging of SV2A in the human brain. In addition, this tracer has the potential to be a general-purpose tool for measuring synaptic vesicle density. We propose to fully develop and validate 11C-UCB-J for human use and perform an initial clinical study in epilepsy. In the first aim, we will quantify SV2A using bolus/infusion delivery on the High Resolution Research Tomography (HRRT) and perform paired test/retest scans in one day in young healthy controls. In a separate cohort, we will determine the magnitude of specific binding in young healthy controls by paired studies at baseline and following IV administration of LEV. Data from these experiments will define the optimal scanning protocol and the most appropriate quantitative method. In the second aim, we will assess age effects on SV2A by assessing specific and nonspecific binding of 11C-UCB-J. MR-based partial volume correction will be performed to eliminate any artifactual effects of cortical atrophy. Such results will be important to interpret any disease-related changes, e.g., due to neurodegeneration, as a function of age. The third aim is to assess SV2A density in epilepsy patients with medically refractory focal epilepsies who are candidates for surgical resection. We will compare 11C-UCB-J binding in these patients to age- and sex-matched healthy controls and assess whether SV2A density is decreased at the site of origin of seizures. We will validate these results with measurements of SV2A expression in surgically removed tissue samples. 11C-UCB-J binding will also be compared to that of 18F-FDG in the same patients, to evaluate if 11C-UCB-J is more diagnostically useful than FDG for seizure focus determination.