Koole Michel, Schmidt Mark E, Hijzen Anja, Cohilis Marie, Vandermeulen Corinne, Serdons Kim, Celen Sofie, Bormans Guy, Maher Michael, Szardenings Anna Katrin, Zhang Wei, Kolb Hartmuth, de Hoon Jan, Van Laere Koen
Nuclear Medicine and Molecular Imaging, Dept. Imaging and Pathology, KU Leuven, Leuven, Belgium.
Janssen Research and Development, Beerse, Belgium.
Eur J Nucl Med Mol Imaging. 2025 Jul 22. doi: 10.1007/s00259-025-07428-3.
The α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors (AMPA-R) are the primary determinants of synaptic strength in most glutamatergic neurons. Inhibition or negative modulation of AMPA-Rs is an attractive strategy for therapeutic intervention in central nervous system (CNS) disorders characterized by excessive neuronal activity. We report the clinical qualification of a AMPA-R associated TARP-γ8 specific PET ligand [F]JNJ-64511070 in healthy volunteers including biodistribution, dosimetry and kinetic modelling.
Whole body dosimetry was performed in 3 healthy male subjects (22-41y). Upon estimation of the normalized cumulated activity (NCA), the effective dose (ED) was calculated using OLINDA v1.1. In a second part, 120-minute dynamic brain scanning with arterial blood sampling was done in five healthy males (25-53y) to determine the appropriate kinetic model and evaluate time stability of total distribution volume (V). Both 1- and 2-tissue compartment models (1-2TCM) as well as Logan graphical analysis (LGA) were considered to assess regional V.
The average ED (± SD) was 15.6 ± 1.0 µSv/MBq. Brain uptake of [F]JNJ-64511070 was fast and showed slow clearance from brain. The intact parent tracer fraction was 80% after 80 min. 2TCM was the most appropriate kinetic model to estimate regional V, with LGA showing very similar estimates. Regional V values were similar across cortical brain regions (4.49 ± 0.66) with higher values for the hippocampus and amygdala (7.03 ± 1.64 and 5.76 ± 1.10 respectively) and lower values for cerebellum, striatum, thalamus and brain stem (2.82 ± 0.49, 2.84 ± 0.38, 1.12 ± 0.18 and 0.91 ± 0.16 respectively). Inter-subject V variability was limited with a Coefficient of Variation (CoV) of 14.5% and 23.3% for cortical and medio-temporal regions respectively. The acquisition time could be reduced to 90 min, while further time reduction induced bias and increased variability in the medial temporal cortex.
[F]JNJ-64511070 is the first F-labelled selective PET ligand for quantification of AMPA-R TARP-γ8 expression in human brain and can be used for testing target engagement of AMPA-R TARP-γ8 specific drug compounds, assisting in guiding dose selection and providing insight into the AMPA-R TARP-γ8 expression in healthy and diseased individuals.
ClinicalTrials.gov database with clinical trial number NCT03270579, Registered 31 August 2017.
α-氨基-3-羟基-5-甲基-4-异恶唑丙酸受体（AMPA-R）是大多数谷氨酸能神经元突触强度的主要决定因素。抑制或负向调节AMPA-R是治疗以神经元活动过度为特征的中枢神经系统（CNS）疾病的一种有吸引力的策略。我们报告了一种与AMPA-R相关的TARP-γ8特异性PET配体[F]JNJ-64511070在健康志愿者中的临床鉴定，包括生物分布、剂量学和动力学建模。
对3名健康男性受试者（22 - 41岁）进行全身剂量学研究。在估算归一化累积活度（NCA）后，使用OLINDA v1.1计算有效剂量（ED）。在第二部分，对5名健康男性（25 - 53岁）进行120分钟的动态脑扫描并采集动脉血样，以确定合适的动力学模型并评估总分布容积（V）的时间稳定性。同时考虑单组织和双组织室模型（1 - 2TCM）以及洛根图形分析（LGA）来评估区域V。
平均有效剂量（±标准差）为15.6 ± 1.0 µSv/MBq。[F]JNJ-64511070在脑中的摄取迅速，且从脑中清除缓慢。80分钟后完整母体示踪剂的比例为80%÷。2TCM是估算区域V最合适的动力学模型，LGA显示的估算结果非常相似。整个皮质脑区的区域V值相似（4.49 ± 0.66），海马体和杏仁核的值较高（分别为7.03 ± 1.64和5.76 ± 1.10），小脑、纹状体、丘脑和脑干的值较低（分别为2.82 ± 0.49、2.84 ± 0.38、1.12 ± 0.18和0.91 ± 0.16）。受试者间V的变异性有限，皮质和颞中区域的变异系数（CoV）分别为14.5%和23.3%。采集时间可缩短至90分钟，而进一步缩短时间会导致内侧颞叶皮质出现偏差并增加变异性。
[F]JNJ-64511070是首个用于定量人脑AMPA-R TARP-γ8表达的F标记选择性PET配体，可用于测试AMPA-R TARP-γ8特异性药物化合物的靶点结合情况，协助指导剂量选择，并深入了解健康个体和患病个体中AMPA-R TARP-γ8的表达情况。
ClinicalTrials.gov数据库，临床试验编号NCT03270579，于2017年8月31日注册。
