SV2A PET Imaging in Healthy Subjects and Epilepsy Patients

 描述(申请人提供)：突触前神经元终末中的小泡通过与突触前膜融合来分泌神经递质。突触囊泡糖蛋白2(SV2)是一种重要的囊泡膜蛋白，它的一个亚型SV2a在几乎所有突触中都有表达。临床和实验数据表明，SV2A参与了癫痫的发生，致痫区域的SV2A受体密度降低。癫痫的动物模型表明，SV2A的缺失可能与癫痫的发生和药物耐药性有关。此外，SV2a被发现是抗惊厥剂左乙拉西坦(Lev)的作用部位。我们最近开发了11C-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SV2A。在我们对健康受试者进行的首个人类SV2APET研究中，我们发现11C-UCB-J具有成为人脑中SV2APET定量成像的优秀PET示踪剂的潜力。此外，这种示踪剂有可能成为测量突触小泡的通用工具。 密度。我们建议完全开发和验证11C-UCB-J供人类使用，并进行癫痫的初步临床研究。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/输注对SV2A进行量化，并在一天内对年轻的健康对照组进行配对测试/复测扫描。在一个单独的队列中，我们将通过基线和静脉注射LEV后的配对研究来确定年轻健康对照中特异性结合的大小。这些实验的数据将确定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11C-UCB-J的特异性和非特异性结合来评估年龄对SV2A的影响。将进行基于MR的部分体积校正，以消除任何皮质萎缩的伪影影响。这些结果对于解释任何与疾病相关的变化将是重要的，例如，由于神经退化，作为年龄的函数。第三个目的是评估有药物难治性局灶性癫痫的癫痫患者中SV2A的密度，这些患者是手术切除的候选对象。我们将比较这些患者与年龄和性别匹配的健康对照组的11C-UCB-J结合，并评估癫痫发作起始处的SV2A密度是否降低。我们将通过测量手术切除的组织样本中SV2A的表达来验证这些结果。在相同的患者中，11C-UCB-J结合也将与18F-FDG的结合进行比较，以评估11C-UCB-J在确定癫痫灶方面是否比FDG更有价值。

 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.