European journal of nuclear medicine and molecular imaging · 2025
Dosimetry and kinetic modelling of [18F]JNJ-64511070, a novel PET ligand to quantify AMPA-associated TARP-γ8 receptors in the human brain.
Клиническое исследование I фазыСтатьяНазвание и аннотация: Перевод в очереди
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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
Аннотация
PURPOSE: 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 [18F]JNJ-64511070 in healthy volunteers including biodistribution, dosimetry and kinetic modelling.
METHODS: 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 (VT). Both 1- and 2-tissue compartment models (1-2TCM) as well as Logan graphical analysis (LGA) were considered to assess regional VT.
RESULTS: The average ED (± SD) was 15.6 ± 1.0 µSv/MBq. Brain uptake of [18F]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 VT, with LGA showing very similar estimates. Regional VT 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 VT 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.
CONCLUSION: [18F]JNJ-64511070 is the first 18F-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.
TRIAL REGISTRATION: ClinicalTrials.gov database with clinical trial number NCT03270579, Registered 31 August 2017.
METHODS: 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 (VT). Both 1- and 2-tissue compartment models (1-2TCM) as well as Logan graphical analysis (LGA) were considered to assess regional VT.
RESULTS: The average ED (± SD) was 15.6 ± 1.0 µSv/MBq. Brain uptake of [18F]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 VT, with LGA showing very similar estimates. Regional VT 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 VT 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.
CONCLUSION: [18F]JNJ-64511070 is the first 18F-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.
TRIAL REGISTRATION: ClinicalTrials.gov database with clinical trial number NCT03270579, Registered 31 August 2017.