Division of Nuclear Medicine, Leuven University Hospitals and UZ Leuven, Leuven, Belgium.
Translational Imaging Biomarkers, Merck & Co., Inc., 770 Sumneytown Pike, Mailstop WP44D-216, West Point, PA, 19486, USA.
Mol Imaging Biol. 2020 Feb;22(1):173-180. doi: 10.1007/s11307-019-01367-w.
[F]MK-6240 is a selective, high-affinity positron emission tomography tracer for imaging neurofibrillary tangles, a key pathological signature that correlates with cognitive decline in Alzheimer disease. This report provides safety information from preclinical toxicology studies and first-in-human whole-body biodistribution and dosimetry studies of [F]MK-6240 for its potential application in human brain imaging studies.
MK-6240 was administered intravenously (IV) in a 7-day rat toxicity study at × 50, × 100, and × 1000 dose margins relative to projected highest clinical dose of 0.333 μg/kg. The IV formulation of MK-6240 for clinical use and the formulation used in the 7-day rat toxicity study was tested for hemolysis potential in human and Wistar rat whole blood. Sequential whole-body positron emission tomography scans were performed in three healthy young subjects after IV bolus injection of 180 ± 0.3 MBq [F]MK-6240 to characterize organ biodistribution and estimate whole-body radiation exposure (effective dose).
MK-6240 administered IV in a 7-day rat toxicity study did not show any test article-related changes. The no-observed-adverse-effect level in rats was ≥ 333 μg/kg/day which provides a margin 1000-fold over an anticipated maximum clinical dose of 0.333 μg/kg. Additionally, the MK-6240 formulation was not hemolytic in human or Wistar rat blood. [F]MK-6240 activity was widely distributed to the brain and the rest of the body, with organ absorbed doses largest for the gall bladder (202 μGy/MBq). The average (±SD) effective dose was 29.4 ± 0.6 μSv/MBq, which is in the typical range for F-18 radiolabeled ligands.
Microdoses of [F]MK-6240 are safe for clinical positron emission tomography imaging studies. Single IV administration of 185 MBq (5 mCi) [F]MK-6240 is anticipated to result in a total human effective dose of 5.4 mSv and thus allows multiple positron emission tomography scans of the same subject per year.
[F]MK-6240 是一种选择性的、高亲和力的正电子发射断层扫描示踪剂，可用于成像神经原纤维缠结，这是阿尔茨海默病认知能力下降的关键病理标志物。本报告提供了来自临床前毒理学研究和人体全身生物分布和剂量学研究的安全性信息，这些研究旨在评估 [F]MK-6240 应用于人体脑成像研究的潜力。
在一项为期 7 天的大鼠毒性研究中，以预测的最高临床剂量 0.333μg/kg 的 50 倍、100 倍和 1000 倍剂量间隔静脉内（IV）给予 MK-6240。用于临床的 MK-6240 的 IV 制剂和用于 7 天大鼠毒性研究的制剂在人全血和 Wistar 大鼠全血中进行了溶血潜力测试。在 3 名健康年轻受试者中，静脉推注 180±0.3MBq [F]MK-6240 后，进行了连续全身正电子发射断层扫描，以描述器官的生物分布并估计全身辐射暴露（有效剂量）。
在为期 7 天的大鼠毒性研究中，静脉内给予 MK-6240 未显示任何与试验药物相关的变化。大鼠的无观察到不良效应水平≥333μg/kg/天，这为预期的 0.333μg/kg 的最大临床剂量提供了 1000 倍的安全边际。此外，MK-6240 制剂在人或 Wistar 大鼠血液中没有溶血。[F]MK-6240 活性广泛分布于大脑和身体其他部位，胆囊吸收剂量最大（202μGy/MBq）。平均（±SD）有效剂量为 29.4±0.6μSv/MBq，这在 F-18 放射性配体的典型范围内。
微量 [F]MK-6240 用于临床正电子发射断层扫描成像研究是安全的。单次静脉注射 185MBq（5mCi）[F]MK-6240 预计会使人体总有效剂量达到 5.4mSv，因此允许每年对同一受试者进行多次正电子发射断层扫描。
