Synthesis and in Vivo Evaluation of a Novel PET Radiotracer for Imaging of Synaptic Vesicle Glycoprotein 2A (SV2A) in Nonhuman Primates.
Synthesis and in Vivo Evaluation of a Novel PET Radiotracer for Imaging of Synaptic Vesicle Glycoprotein 2A (SV2A) in Nonhuman Primates.
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DOI：
10.1021/acschemneuro.8b00526
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发表时间：
2019-03-20
影响因子：
5
通讯作者：
Huang Y
中科院分区：
文献类型：
--
作者：
Li S;Cai Z;Wu X;Holden D;Pracitto R;Kapinos M;Gao H;Labaree D;Nabulsi N;Carson RE;Huang Y
突触的结构破坏和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。我们先前已经开发了PET放射性示踪剂11 C-UCB-J，用于非人灵长类动物和人类中突触囊泡糖蛋白2A（SV 2A）和突触密度的成像和定量。本文报道了一种新型放射性示踪剂18F-SDM-8的合成及其在恒河猴体内的评价。SDM-8的体外结合测定显示高的SV 2A结合亲和力（Ki = 0.58 nM）。制备了高摩尔活性（241.7 MBq/nmol）和放射化学纯度（>98%）的18 F-SDM-8。在脑中，18F-SDM-8显示出非常高的摄取，峰值标准化摄取值（SVU）大于8，以及快速和可逆的动力学。左乙拉西坦的置换研究和UCB-J与左乙拉西坦的阻断研究证明了其对SV 2A的结合可逆性和特异性。计算区域结合电位值，范围从脑干中的0.8到扣带皮层中的4.5。通过与11 C-UCB-J比较，18F-SDM-8显示出相同的有吸引力的成像特性：非常高的脑摄取、适当的组织动力学和高水平的特异性结合。考虑到F-18的半衰期较长以及中枢产生和多位点分布的可行性，18F-SDM-8有望作为SV 2A的优良放射性示踪剂以及作为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。
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 11C-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 18F-SDM-8 and its in vivo evaluation in rhesus monkeys. The in vitro binding assay of SDM-8 showed high SV2A binding affinity (Ki = 0.58 nM). 18 F-SDM-8 was prepared in high molar activity (241.7 MBq/nmol) and radiochemical purity (>98%). In the brain, 18F-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 11C-UCB-J, 18F-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, 18F-SDM-8 holds promise as an excellent radiotracer for SV2A and as a biomarker for synaptic density measurement in neurodegenerative diseases and psychiatric disorders.
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影响因子：
17.1
作者：
Finnema, Sjoerd J.;Nabulsi, Nabeel B.;Carson, Richard E.
通讯作者：
Carson, Richard E.
影响因子：
6
作者：
Loescher, Wolfgang;Gillard, Michel;Sands, Zara A.;Kaminski, Rafal M.;Klitgaard, Henrik
通讯作者：
Klitgaard, Henrik
影响因子：
2
作者：
Hou, Zhongyu;Lei, Hao;Liu, Shuwei
通讯作者：
Liu, Shuwei
影响因子：
3.1
作者：
Constantinescu, Cristian C.;Tresse, Cedric;Barret, Olivier
通讯作者：
Barret, Olivier
影响因子：
29
作者：
Chen, Ming-Kai;Mecca, Adam P.;van Dyck, Christopher H.
通讯作者：
van Dyck, Christopher H.