新型磷酸二酯酶2A（PDE2A）正电子发射断层显像（PET）放射性示踪剂18F-PF-05270430的首次人体评估。
First-in-Human Assessment of the Novel PDE2A PET Radiotracer 18F-PF-05270430.
作者信息
Naganawa Mika, Waterhouse Rikki N, Nabulsi Nabeel, Lin Shu-Fei, Labaree David, Ropchan Jim, Tarabar Sanela, DeMartinis Nicholas, Ogden Adam, Banerjee Anindita, Huang Yiyun, Carson Richard E
机构信息
Department of Radiology and Biomedical Imaging, PET Center, Yale School of Medicine, New Haven, Connecticut; and
Pfizer Worldwide Research and Development, Cambridge, Massachusetts.
出版信息
J Nucl Med. 2016 Sep;57(9):1388-95. doi: 10.2967/jnumed.115.166850. Epub 2016 Apr 21.
UNLABELLED
This was a first-in-human study of the novel phosphodiesterase-2A (PDE2A) PET ligand (18)F-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 (VT) 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 VT 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 VT, BPND, and BPP were 8%, 16%, and 17%, respectively.
CONCLUSION
(18)F-PF-05270430 shows promise as a PDE2A PET ligand, albeit with low binding potential values.
未标记
这是一项关于新型磷酸二酯酶-2A（PDE2A）正电子发射断层显像（PET）配体（18）F-PF-05270430的首次人体研究。主要目标是确定合适的示踪剂动力学模型以量化脑摄取，并检查受试者内重测变异性。
方法
在人体研究之前，在非人类灵长类动物中确定辐射剂量学。六名健康男性受试者参与了一项重测方案，包括动态扫描和代谢物校正输入函数。研究了九个脑感兴趣区域，包括纹状体、白质、新皮质区域和小脑。应用多种建模方法计算分布容积（VT）以及相对于组织中不可置换示踪剂的结合电位（BPND）、血浆中示踪剂浓度（BPP）和组织中游离示踪剂（BPF）。选择小脑作为参考区域来计算结合电位。
结果
剂量学研究显示有效剂量小于0.30 mSv/MBq，胆囊为关键器官；人体目标剂量为185 MBq。未报告不良事件或临床可检测到的药理作用。示踪剂摄取在纹状体中最高，其次是新皮质区域和白质，在小脑中最低。区域时间-活性曲线通过多线性分析-1拟合良好，70分钟的扫描持续时间足以量化VT和结合电位。BPND的平均值范围为0.3至0.8，显示出最佳的受试者内和受试者间变异性及可靠性。VT、BPND和BPP在全脑（不包括小脑）中的重测变异性分别为8%、16%和17%。
结论
（18）F-PF-05270430作为一种PDE2A PET配体显示出前景，尽管结合电位值较低。
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