Epilepsy Clinic, Copenhagen University Hospital Rigshospitalet, Blegdamsvej 9, Copenhagen O, 2100, Denmark.
Neurobiology Research Unit, Copenhagen University Hospital Rigshospitalet, Rigshospitalet, Building 8057, Blegdamsvej 9, Copenhagen, 8057, DK-2100, Denmark.
Eur J Nucl Med Mol Imaging. 2024 Sep;51(11):3292-3304. doi: 10.1007/s00259-024-06759-x. Epub 2024 May 17.
Here, we evaluate a PET displacement model with a Single-step and Numerical solution in healthy individuals using the synaptic vesicle glycoprotein (SV2A) PET-tracer [C]UCB-J and the anti-seizure medication levetiracetam (LEV). We aimed to (1) validate the displacement model by comparing the brain LEV-SV2A occupancy from a single PET scan with the occupancy derived from two PET scans and the Lassen plot and (2) determine the plasma LEV concentration-SV2A occupancy curve in healthy individuals.
Eleven healthy individuals (five females, mean age 35.5 [range: 25-47] years) underwent two 120-min [C]UCB-J PET scans where an LEV dose (5-30 mg/kg) was administered intravenously halfway through the first PET scan to partially displace radioligand binding to SV2A. Five individuals were scanned twice on the same day; the remaining six were scanned once on two separate days, receiving two identical LEV doses. Arterial blood samples were acquired to determine the arterial input function and plasma LEV concentrations. Using the displacement model, the SV2A-LEV target engagement was calculated and compared with the Lassen plot method. The resulting data were fitted with a single-site binding model.
SV2A occupancies and V estimates derived from the displacement model were not significantly different from the Lassen plot (p = 0.55 and 0.13, respectively). The coefficient of variation was 14.6% vs. 17.3% for the Numerical and the Single-step solution in Bland-Altman comparisons with the Lassen plot. The average half maximal inhibitory concentration (IC), as estimated from the area under the curve of the plasma LEV concentration, was 12.5 µg/mL (95% CI: 5-25) for the Single-Step solution, 11.8 µg/mL (95% CI: 4-25) for the Numerical solution, and 6.3 µg/mL (95% CI: 0.08-21) for the Lassen plot. Constraining Emax to 100% did not significantly improve model fits.
Plasma LEV concentration vs. SV2A occupancy can be determined in humans using a single PET scan displacement model. The average concentration of the three computed IC values ranges between 6.3 and 12.5 µg/mL. The next step is to use the displacement model to evaluate LEV occupancy and corresponding plasma concentrations in relation to treatment efficacy.
NCT05450822. Retrospectively registered 5 July 2022 https://clinicaltrials.gov/ct2/results? term=NCT05450822&Search=Search.
在这里，我们使用突触小泡糖蛋白 (SV2A) PET 示踪剂 [C]UCB-J 和抗癫痫药物左乙拉西坦 (LEV) 在健康个体中评估具有单步和数值解的 PET 置换模型。我们旨在 (1) 通过比较单次 PET 扫描的脑 LEV-SV2A 占有率与来自两次 PET 扫描和 Lassen 图的占有率来验证置换模型，(2) 确定健康个体中的血浆 LEV 浓度-SV2A 占有率曲线。
11 名健康个体（5 名女性，平均年龄 35.5 [范围：25-47] 岁）接受了两次 120 分钟 [C]UCB-J PET 扫描，在第一次 PET 扫描进行到一半时静脉内给予 LEV 剂量（5-30 mg/kg）以部分置换放射性配体与 SV2A 的结合。五人在同一天扫描两次；其余六人在两天内各扫描一次，接受两次相同的 LEV 剂量。采集动脉血样以确定动脉输入函数和血浆 LEV 浓度。使用置换模型计算 SV2A-LEV 靶标占有率，并与 Lassen 图法进行比较。根据单站点结合模型拟合所得数据。
置换模型得出的 SV2A 占有率和 V 估计值与 Lassen 图法无显著差异（p = 0.55 和 0.13，分别）。Bland-Altman 比较中，数值解和单步解的变异系数分别为 14.6% 和 17.3%。从血浆 LEV 浓度的曲线下面积估计的平均半最大抑制浓度 (IC) ，对于单步解为 12.5 µg/mL（95%CI：5-25），对于数值解为 11.8 µg/mL（95%CI：4-25），对于 Lassen 图为 6.3 µg/mL（95%CI：0.08-21）。将 Emax 约束为 100%并不会显著改善模型拟合度。
可以使用单次 PET 扫描置换模型在人体中确定血浆 LEV 浓度与 SV2A 占有率之间的关系。三个计算的 IC 值的平均浓度范围在 6.3 和 12.5 µg/mL 之间。下一步是使用置换模型来评估 LEV 占有率及其与治疗效果相关的相应血浆浓度。
NCT05450822。2022 年 7 月 5 日回顾性注册 https://clinicaltrials.gov/ct2/results?term=NCT05450822&Search=Search。
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