PET Center, Department of Radiology and Biomedical Imaging , Yale University School of Medicine , New Haven , Connecticut 06520 , United States.
Department of Nuclear Medicine, West China Hospital, Laboratory of Clinical Nuclear Medicine, West China Hospital , Sichuan University , Chengdu 610041 , Sichuan Province , China.
ACS Chem Neurosci. 2019 Mar 20;10(3):1544-1554. doi: 10.1021/acschemneuro.8b00526. Epub 2018 Nov 16.
Structural disruption and alterations of synapses are associated with many brain disorders including Alzheimer's disease, epilepsy, depression, and schizophrenia. We have previously developed the PET radiotracer C-UCB-J for imaging and quantification of synaptic vesicle glycoprotein 2A (SV2A) and synaptic density in nonhuman primates and humans. Here we report the synthesis of a novel radiotracer F-SDM-8 and its in vivo evaluation in rhesus monkeys. The in vitro binding assay of SDM-8 showed high SV2A binding affinity ( K = 0.58 nM). F-SDM-8 was prepared in high molar activity (241.7 MBq/nmol) and radiochemical purity (>98%). In the brain, F-SDM-8 displayed very high uptake with peak standardized uptake value (SVU) greater than 8 and fast and reversible kinetics. A displacement study with levetiracetam and blocking studies with UCB-J and levetiracetam demonstrated its binding reversibility and specificity toward SV2A. Regional binding potential values were calculated and ranged from 0.8 in the brainstem to 4.5 in the cingulate cortex. By comparing to C-UCB-J, F-SDM-8 displayed the same attractive imaging properties: very high brain uptake, appropriate tissue kinetics, and high levels of specific binding. Given the longer half-life of F-18 and the feasibility for central production and multisite distribution, F-SDM-8 holds promise as an excellent radiotracer for SV2A and as a biomarker for synaptic density measurement in neurodegenerative diseases and psychiatric disorders.
结构破坏和突触改变与许多脑部疾病有关，包括阿尔茨海默病、癫痫、抑郁症和精神分裂症。我们之前开发了 PET 示踪剂 C-UCB-J，用于在非人类灵长类动物和人类中对突触小泡糖蛋白 2A（SV2A）和突触密度进行成像和定量。在这里，我们报告了新型示踪剂 F-SDM-8 的合成及其在恒河猴体内的评估。SDM-8 的体外结合测定显示出高 SV2A 结合亲和力（K = 0.58 nM）。F-SDM-8 以高摩尔活性（241.7 MBq/nmol）和放射性化学纯度（>98%）制备。在大脑中，F-SDM-8 显示出非常高的摄取，峰值标准化摄取值（SVU）大于 8，具有快速和可逆的动力学。用左乙拉西坦进行的置换研究和用 UCB-J 和左乙拉西坦进行的阻断研究证明了其对 SV2A 的结合可逆性和特异性。计算了区域结合潜能值，范围从脑干的 0.8 到扣带皮层的 4.5。与 C-UCB-J 相比，F-SDM-8 显示出相同的有吸引力的成像特性：非常高的大脑摄取、适当的组织动力学和高水平的特异性结合。鉴于 F-18 的半衰期较长，以及中央生产和多站点分布的可行性，F-SDM-8 有望成为 SV2A 的优秀示踪剂，以及神经退行性疾病和精神障碍中突触密度测量的生物标志物。
