First-in-Human Assessment of the Novel PDE2A PET Radiotracer 18F-PF-05270430
First-in-Human Assessment of the Novel PDE2A PET Radiotracer 18F-PF-05270430
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DOI：
10.2967/jnumed.115.166850
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发表时间：
2016-09-01
影响因子：
9.3
通讯作者：
Carson, Richard E.
中科院分区：
文献类型：
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作者：
Naganawa, Mika;Waterhouse, Rikki N.;Carson, Richard E.
这是对新型磷酸二酯酶2a (PDE2A) PET配体F-18-PF-05270430的首次人体研究。主要目的是确定适当的示踪剂动力学模型来量化脑摄取，并检查受试者内测试-重测试变异性。方法：在人类研究之前，对非人类灵长类动物进行了辐射剂量测定。6名健康男性受试者参与了一项带有动态扫描和代谢物校正输入功能的复测方案。研究了9个感兴趣的大脑区域，包括纹状体、白质、新皮质区和小脑。采用多种建模方法计算组织中不可置换示踪剂（BPND）、血浆中示踪剂（BPP）和组织中游离示踪剂（BPF）的体积分布（V-T）和结合电位。选择小脑作为计算结合电位的参考区域。结果：剂量学研究提供的有效剂量小于0.30 mSv/MBq，胆囊为关键器官；人体目标剂量为185 MBq。没有不良事件或临床可检测的药理作用的报道。示踪剂的摄取在纹状体中最高，其次是新皮质区和白质，在小脑中最低。通过多线性分析，区域时间活度曲线拟合良好，70 min的扫描时间足以量化V-T和结合电位。BPND的平均值在0.3 ~ 0.8之间，表现出受试者内部和受试者间的最佳变异性和可靠性。V-T、BPND和BPP全脑（不包括小脑）的重测变异性分别为8%、16%和17%。结论：F-18-PF-05270430显示了作为PDE2A PET配体的前景，尽管其结合电位值较低。
This was a first-in-human study of the novel phosphodiesterase-2A (PDE2A) PET ligand F-18-PF-05270430. The primary goals were to determine the appropriate tracer kinetic model to quantify brain uptake and to examine the within-subject test-retest variability. Methods: In advance of human studies, radiation dosimetry was determined in nonhuman primates. Six healthy male subjects participated in a test-retest protocol with dynamic scans and metabolite-corrected input functions. Nine brain regions of interest were studied, including the striatum, white matter, neocortical regions, and cerebellum. Multiple modeling methods were applied to calculate volume of distribution (V-T) and binding potentials relative to the nondisplaceable tracer in tissue (BPND), concentration of tracer in plasma (BPP), and free tracer in tissue (BPF). The cerebellum was selected as a reference region to calculate binding potentials. Results: The dosimetry study provided an effective dose of less than 0.30 mSv/MBq, with the gallbladder as the critical organ; the human target dose was 185 MBq. There were no adverse events or clinically detectable pharmacologic effects reported. Tracer uptake was highest in the striatum, followed by neocortical regions and white matter, and lowest in the cerebellum. Regional time activity curves were well fit by multilinear analysis-1, and a 70-min scan duration was sufficient to quantify V-T and the binding potentials. BPND, with mean values ranging from 0.3 to 0.8, showed the best intrasubject and intersubject variability and reliability. Test-retest variability in the whole brain (excluding the cerebellum) of V-T, BPND, and BPP were 8%, 16%, and 17%, respectively. Conclusion: F-18-PF-05270430 shows promise as a PDE2A PET ligand, albeit with low binding potential values.