Kinetics modeling and occupancy studies of a novel C-11 PET tracer for VAChT in nonhuman primates.
Kinetics modeling and occupancy studies of a novel C-11 PET tracer for VAChT in nonhuman primates.
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DOI：
10.1016/j.nucmedbio.2015.11.003
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发表时间：
2016-02
影响因子：
3.1
通讯作者：
Tu Z
中科院分区：
文献类型：
--
作者：
Jin H;Zhang X;Yue X;Liu H;Li J;Yang H;Flores H;Su Y;Parsons SM;Perlmutter JS;Tu Z
老年大脑和神经退行性疾病（包括阿尔茨海默病（AD）和帕金森病（PD））中都发现了胆碱能功能缺陷。囊泡乙酰胆碱转运蛋白 (VAChT) 是胆碱能系统的可靠生物标志物。我们之前报道了 (−)-[11C]TZ659 作为 VAChT 特异性配体的初步体外和离体表征。在这里，我们报告了非人类灵长类动物大脑中的体内特异性、示踪动力学和剂量占用研究。 (−)-[11C]TZ659 的 MicroPET 脑成像是在两只雄性猕猴的基线条件下进行的。使用具有动脉血输入功能的二组织室模型（2TCM）和洛根图以及无血液输入的简化参考组织模型（SRTM）和洛根图（LoganREF）进行示踪动力学建模。通过 (+)-喷他佐辛、(-)-维沙考或 S-(-)-艾氯必利预处理证明了 VAChT 的特异性。用递增剂量的 (−)-vesamicol 进行预处理后计算目标占有率 (Occ)。基线 PET 成像显示纹状体选择性保留，并从小脑半球作为参考区域快速清除。根据血液输入的 2TCM 和 Logan 分析得出的总分布容积 (VT) 值显示，纹状体中 (−)-[11C]TZ659 的水平比小脑半球高约 3 倍。注射 (−)-vesamicol 作为阻断剂或置换剂显着减少纹状体对 (−)-[11C]TZ659 的摄取。相反，用 sigma-1 配体 (+)-喷他佐辛预处理则没有影响。使用 S-(−)-艾氯必利（一种多巴胺 D2 样受体拮抗剂）进行预处理，可增加纹状体对 (−)-[11C]TZ659 的摄取。纹状体结合电位（BPND，范围为 0.33 – 1.6，以小脑半球为参考区域）显示 SRTM 和 LoganREF 之间具有良好的相关性 (r2 = 0.97)。占用研究发现，约 0.0057 mg/kg (−)-vesamicol 在纹状体中产生 50% VAChT 占用。 (−)-[11C]TZ659 表现出特异性和可逆的 VAChT 结合以及用于评估活体大脑中 VAChT 密度的有利药代动力学特性。
Deficits in cholinergic function have been found in the aged brain and in neurodegenerative diseases including Alzheimer’s disease (AD) and Parkinson’s disease (PD). The vesicular acetylcholine transporter (VAChT) is a reliable biomarker for the cholinergic system. We previously reported the initial in vitro and ex vivo characterization of (−)-[11C]TZ659 as a VAChT specific ligand. Here, we report the in vivo specificity, tracer kinetics, and dose-occupancy studies in the nonhuman primate brain are reported. MicroPET brain imaging of (−)-[11C]TZ659 was performed under baseline conditions in two male macaques. Tracer kinetic modeling was carried out using a two-tissue compartment model (2TCM) and Logan plot with arterial blood input function and using a simplified reference tissue model (SRTM) and Logan plot (LoganREF) without blood input. Specificity for VAChT was demonstrated by pretreatment with (+)-pentazocine, (−)-vesamicol, or S-(−)-eticlopride. Target occupancy (Occ) was calculated following pretreatment with escalating doses of (−)-vesamicol. Baseline PET imaging revealed selective retention in the striatum with rapid clearance from the cerebellar hemispheres as a reference region. Total volume of distribution (VT) values derived from both 2TCM and Logan analysis with blood input revealed ~3-fold higher levels of (−)-[11C]TZ659 in the striatum than the cerebellar hemispheres. Injection of (−)-vesamicol either as a blocking or displacing agent significantly reduced striatal uptake of (−)-[11C]TZ659. In contrast, pretreatment with the sigma-1 ligand (+)-pentazocine had no impact. Pretreatment with the S-(−)-eticlopride, a dopamine D2–like receptor antagonist, increased striatal uptake of (−)-[11C]TZ659. Striatal binding potential (BPND, range of 0.33 – 1.6 with cerebellar hemispheres as the reference region) showed good correlation (r2 = 0.97) between SRTM and LoganREF. Occupancy studies found that ~ 0.0057 mg/kg (−)-vesamicol produced 50% VAChT occupancy in the striatum. (−)-[11C]TZ659 demonstrated specific and reversible VAChT binding and favorable pharmacokinetic properties for assessing the density of VAChT in the living brain.