Division of Nuclear Medicine and Molecular Imaging, University Hospitals of Leuven and KU Leuven, Leuven, Belgium.
Janssen Research and Development: Beerse, Beerse, Belgium.
Eur J Nucl Med Mol Imaging. 2019 Sep;46(10):2051-2064. doi: 10.1007/s00259-019-04369-6. Epub 2019 Jun 26.
The P2X7 receptor (P2X7R) is an ATP-gated ion channel predominantly expressed on activated microglia and is important in neurodegenerative diseases including Parkinson's disease (PD). In this first-in-human study, we investigated [C]JNJ54173717 ([C]JNJ717), a selective P2X7R tracer, in healthy volunteers (HV) and PD patients. Biodistribution, dosimetry, kinetic modelling and short-term test-retest variation (TRV), as well as possible genotype effects, were investigated.
Biodistribution and radiation dosimetry studies were performed in three HV (mean age 30 ± 2 years, two women) using whole-body PET/CT. The most appropriate kinetic model was determined in 11 HV (mean age 62 ± 10 years, six women) and 10 PD patients (mean age 64 ± 8 years, three women; mean UPDRS motor score 21 ± 8) using 90-min dynamic simultaneous PET/MR scans. The total volume of distribution (V) was calculated using a one-tissue and a two-tissue compartment model (1TCM, 2TCM) and Logan graphical analysis, and its time stability was assessed. Seven subjects underwent retest scans (mean age 60 ± 13 years, four HV, one woman). A group analysis was performed to compare PD patients and HV. Finally, 13 exons of P2X7R were genotyped in all subjects included in the second part of the study.
The mean effective dose was 4.47 ± 0.32 μSv/MBq, with the highest absorbed doses to the gallbladder, liver and small intestine. A reversible 2TCM was the most appropriate kinetic model with relatively homogeneous V values in the grey and white matter. Average V values were 3.4 ± 0.8 in HV and 3.3 ± 0.7 in PD patients, with no significant difference between the groups, but a possible genotype effect (rs3751143) was identified which can affect V. Average TRV was 10-15%. The stability of V over time allowed a reduction in scan time to 70 min.
[C]JNJ717 is safe and suitable for quantifying P2X7R expression in human brain. In this pilot study, no significant differences in P2X7R binding were found between HV and PD patients. The results also suggest that genotype effects need to be incorporated in future P2X7R PET analyses.
P2X7 受体（P2X7R）是一种主要表达于激活的小胶质细胞上的 ATP 门控离子通道，在包括帕金森病（PD）在内的神经退行性疾病中具有重要作用。在这项首次人体研究中，我们在健康志愿者（HV）和 PD 患者中研究了[C]JNJ54173717（[C]JNJ717），一种选择性 P2X7R 示踪剂。研究了其生物分布、剂量学、动力学模型和短期测试-再测试变异（TRV），以及可能的基因型影响。
使用全身 PET/CT 在 3 名 HV（平均年龄 30±2 岁，2 名女性）中进行了生物分布和辐射剂量学研究。在 11 名 HV（平均年龄 62±10 岁，6 名女性）和 10 名 PD 患者（平均年龄 64±8 岁，3 名女性；平均 UPDRS 运动评分 21±8）中使用 90 分钟动态同步 PET/MR 扫描，确定了最合适的动力学模型。使用单组织和双组织室模型（1TCM、2TCM）和 Logan 图形分析计算总分布容积（V），并评估其时间稳定性。7 名受试者接受了再测试扫描（平均年龄 60±13 岁，4 名 HV，1 名女性）。对 PD 患者和 HV 进行了组分析比较。最后，对研究第二部分纳入的所有受试者的 P2X7R 的 13 个外显子进行了基因分型。
平均有效剂量为 4.47±0.32 μSv/MBq，胆囊、肝脏和小肠的吸收剂量最高。可逆的 2TCM 是最合适的动力学模型，灰质和白质中的 V 值相对均匀。HV 的平均 V 值为 3.4±0.8，PD 患者的平均 V 值为 3.3±0.7，两组之间无显著差异，但发现了可能的基因型影响（rs3751143），它可以影响 V。平均 TRV 为 10-15%。V 随时间的稳定性允许将扫描时间缩短至 70 分钟。
[C]JNJ717 安全且适合于定量人类大脑中的 P2X7R 表达。在这项初步研究中，HV 和 PD 患者之间未发现 P2X7R 结合的显著差异。结果还表明，在未来的 P2X7R PET 分析中需要纳入基因型影响。
