Publication date: Jul 22, 2025

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 uSv/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.

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