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Purpose <p>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 [<sup>18</sup>F]JNJ-64511070 in healthy volunteers including biodistribution, dosimetry and kinetic modelling.</p> Methods <p>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<sub>T</sub>). Both 1- and 2-tissue compartment models (1-2TCM) as well as Logan graphical analysis (LGA) were considered to assess regional V<sub>T</sub>.</p> Results <p>The average ED (± SD) was 15.6 ± 1.0 µSv/MBq. Brain uptake of [<sup>18</sup>F]JNJ-64511070 was fast and showed slow clearance from brain. The intact parent tracer fraction was 80% after 80&#xa0;min. 2TCM was the most appropriate kinetic model to estimate regional V<sub>T</sub>, with LGA showing very similar estimates. Regional V<sub>T</sub> 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<sub>T</sub> 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&#xa0;min, while further time reduction induced bias and increased variability in the medial temporal cortex. </p> Conclusion <p>[<sup>18</sup>F]JNJ-64511070 is the first <sup>18</sup>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.</p> Trial registration <p>ClinicalTrials.gov database with clinical trial number NCT03270579, Registered 31 August 2017.</p>

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Dosimetry and kinetic modelling of [18F]JNJ-64511070, a novel PET ligand to quantify AMPA-associated TARP-γ8 receptors in the human brain

  • 期刊论文

  • 发表日期：

    2025年7月22日

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  • Michel Koole,
  • Mark E. Schmidt,
  • Anja Hijzen,
  • Marie Cohilis,
  • Corinne Vandermeulen,
  • Kim Serdons,
  • Sofie Celen,
  • Guy Bormans,
  • Michael Maher,
  • Anna Katrin Szardenings,
  • Wei Zhang,
  • Hartmuth Kolb,
  • Jan de Hoon,
  • Koen Van Laere

摘要

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.