PET Imaging Evaluation of Four σ1 Radiotracers in Nonhuman Primates
PET Imaging Evaluation of Four σ1 Radiotracers in Nonhuman Primates
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DOI：
10.2967/jnumed.116.188052
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发表时间：
2017-06-01
影响因子：
9.3
通讯作者：
Huang, Yiyun
中科院分区：
文献类型：
--
作者：
Baum, Evan;Cai, Zhengxin;Huang, Yiyun
sigma（1）受体（S1 Rs）与多种疾病有关，包括阿尔茨海默病和癌症。以前的PET S1 R放射性示踪剂的特征在于缓慢的动力学或脱靶结合，这阻碍了它们在人类中的使用。在这里，我们报告了第一次PET成像评价恒河猴的4个F-18标记的螺环哌啶为基础的PET放射性示踪剂（F-18-1至F-18-4）。方法：在成年雄性恒河猴上获得4种放射性示踪剂的基线扫描。用S1 R选择性激动剂SA 4503进行阻断扫描，以评估F-18-2和F-18-4的结合特异性。测量动脉输入功能，并通过动力学建模分析确定结合参数。结果：4种放射性示踪剂在恒河猴脑内均表现出高、快的摄取。F-18-2和F-18-4的组织活性洗脱迅速，而F-18-1和F-18-3的组织活性洗脱慢得多，这与它们各自的体外S1 R结合亲和力一致。1-组织室和多线性分析-1动力学模型均提供了时间-活性曲线的良好拟合和分布体积的可靠估计。所有放射性示踪剂的区域分布体积值在扣带皮层最高，在丘脑最低。F-18-4显示出比F-18-2更大的跨脑区域的差异摄取和3倍更高的结合潜力。0.5 mg/kg剂量的SA 4503阻断了约85%（F-18-2）和95%（F-18-4）的放射性示踪剂结合。结论：示踪剂F-18-2和F-18-4显示出高脑摄取和快速组织动力学，在同一只猴中，F-18-4具有比F-18-2更高的特异性结合信号。总而言之，这些数据表明F-18-2和F-18-4都具有作为可行的PET示踪剂对人脑中的S1 R进行成像所需的动力学和成像特性。
The sigma(1) receptors (S1Rs) are implicated in a variety of diseases including Alzheimer disease and cancer. Previous PET S1R radiotracers are characterized by slow kinetics or off-target binding that impedes their use in humans. Here, we report the first PET imaging evaluation in rhesus monkeys of 4 F-18-labeled spirocyclic piperidine-based PET radiotracers (F-18-1 to F-18-4). Methods: Baseline scans for the 4 radiotracers were obtained on an adult male rhesus monkey. Blocking scans were obtained with the S1R-selective agonist SA4503 to assess binding specificity of F-18-2 and F-18-4. Arterial input functions were measured, and binding parameters were determined with kinetic modeling analysis. Results: In the rhesus brain, all 4 radiotracers showed high and fast uptake. Tissue activity washout was rapid for F-18-2 and F-18-4, and much slower for F-18-1 and F-18-3, in line with their respective in vitro S1R-binding affinities. Both the 1-tissue-compartment and multilinear analysis-1 kinetic models provided good fits of time-activity curves and reliable estimates of distribution volume. Regional distribution volume values were highest in the cingulate cortex and lowest in the thalamus for all radiotracers. F-18-4 showed greater differential uptake across brain regions and 3-fold-higher binding potential than F-18-2. SA4503 at the dose of 0.5 mg/kg blocked approximately 85% (F-18-2) and 95% (F-18-4) of radiotracer binding. Conclusion: Tracers F-18-2 and F-18-4 displayed high brain uptake and fast tissue kinetics, with F-18-4 having higher specific binding signals than F-18-2 in the same monkey. Taken together, these data indicate that both F-18-2 and F-18-4 possess the requisite kinetic and imaging properties as viable PET tracers for imaging S1R in the human brain.