In Vivo Imaging of Human Cholinergic Nerve Terminals with (-)-5-18F-Fluoroethoxybenzovesamicol: Biodistribution, Dosimetry, and Tracer Kinetic Analyses
In Vivo Imaging of Human Cholinergic Nerve Terminals with (-)-5-18F-Fluoroethoxybenzovesamicol: Biodistribution, Dosimetry, and Tracer Kinetic Analyses
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DOI：
10.2967/jnumed.113.124792
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发表时间：
2014-03-01
影响因子：
9.3
通讯作者：
Koeppe, Robert A.
中科院分区：
文献类型：
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作者：
Petrou, Myria;Frey, Kirk A.;Koeppe, Robert A.
（-）-5-F-18-fluoroethoxybenzovesamicol（F-18-FEOBV）是一种选择性结合囊泡乙酰胆碱转运蛋白（VAChT）的vesamicol衍生物，已用于临床前研究以定量突触前胆碱能神经末梢。据我们所知，这项研究首次在人体内使用F-18-FEOBV，包括人体受试者的辐射剂量测定、生物分布、耐受性和安全性，以及F-18-FEOBV的脑动力学和定量分析方法。方法：对3名健康志愿者进行全身F-18-FEOBV扫描。另外7名受试者在推注F-18-FEOBV后0-120、150-180和210-240分钟进行了动态脑成像。用色谱法鉴定真实的F-18-FEOBV进行动脉血采样，以确定动脉血浆输入功能。分析方法包括2-组织房室模型的非线性最小二乘拟合、参考组织建模和晚期单扫描成像。结果：静脉注射高达1.3 μ g F-18-FEOBV后，未观察到药理学或生理学变化。辐射剂量测定估计表明，超过400 MBq的管理可能不会超过监管辐射剂量限值。动力学分析表明，脑摄取相对较高，单程提取率为25%-35%。VAChT结合的估计值变化的因素大于30之间的纹状体和皮质。k（3）估计值的变异系数为15%~ 30%。分布量测量产生的动态范围约为15，但变异性几乎没有减少。参考组织方法产生了更稳定的分布体积比（1 + BPND）估计值，变异系数范围从纹状体的20%到皮质区域的6%-12%。F-18-FEOBV的晚期静态分布与参考组织模型的分布体积比估计值高度相关（r = 0.993）。结论：F-18-FEOBV PET证实示踪剂与VAChT结合，具有预期的体内人脑分布。参考组织建模和后期静态扫描方法都提供了VAChT结合的稳健指数。
(-)-5-F-18-fluoroethoxybenzovesamicol (F-18-FEOBV) is a vesamicol derivative that binds selectively to the vesicular acetylcholine transporter (VAChT) and has been used in preclinical studies to quantify presynaptic cholinergic nerve terminals. This study presents, to our knowledge, the first-in-human experience with F-18-FEOBV, including radiation dosimetry, biodistribution, tolerability and safety in human subjects, and brain kinetics and methods for quantitative analysis of F-18-FEOBV. Methods: Whole-body F-18-FEOBV scans were obtained in 3 healthy human volunteers. Seven additional subjects underwent dynamic brain imaging 0-120, 150-180, and 210-240 min after bolus injection of F-18-FEOBV. Arterial blood sampling was performed with chromatographic identification of authentic F-18-FEOBV to determine the arterial plasma input function. Analysis methods included nonlinear least-squares fitting of a 2-tissue-compartmental model, reference tissue modeling, and late single-scan imaging. Results: No pharmacologic or physiologic changes were observed after intravenous administration of up to 1.3 mu g of F-18-FEOBV. Radiation dosimetry estimates indicate that more than 400 MBq may be administered without exceeding regulatory radiation dose limits. Kinetic analysis showed brain uptake to be relatively high with single-pass extraction of 25%-35%. VAChT binding estimates varied by a factor of greater than 30 between the striatum and cortex. Coefficients of variation in k(3) estimates varied from 15% to 30%. Volume of distribution measures yielded a dynamic range of approximately 15 but with little reduction in variability. Reference tissue approaches yielded more stable estimates of the distribution volume ratio (1 + BPND), with coefficients of variation ranging from 20% in the striatum to 6%-12% in cortical regions. The late static distribution of F-18-FEOBV correlated highly with the distribution volume ratio estimates from reference tissue models (r = 0.993). Conclusion: F-18-FEOBV PET confirms that the tracer binds to VAChT with the expected in vivo human brain distribution. Both reference tissue modeling and late static scanning approaches provide a robust index of VAChT binding.