RT Journal Article SR Electronic T1 18F-JNJ-64413739, a Novel PET Ligand for the P2X7 Ion Channel: Radiation Dosimetry, Kinetic Modeling, Test-Retest Variability, and Occupancy of the P2X7 Antagonist JNJ-54175446 JF Journal of Nuclear Medicine JO J Nucl Med FD Society of Nuclear Medicine SP 683 OP 690 DO 10.2967/jnumed.118.216747 VO 60 IS 5 A1 Michel Koole A1 Mark E. Schmidt A1 Anja Hijzen A1 Paulien Ravenstijn A1 Corinne Vandermeulen A1 Donatienne Van Weehaeghe A1 Kim Serdons A1 Sofie Celen A1 Guy Bormans A1 Marc Ceusters A1 Wei Zhang A1 Luc Van Nueten A1 Hartmuth Kolb A1 Jan de Hoon A1 Koen Van Laere YR 2019 UL http://jnm.snmjournals.org/content/60/5/683.abstract AB The P2X7 receptor (P2X7R) is an adenosine triphosphate–gated ion channel that is predominantly expressed on microglial cells in the central nervous system. We report the clinical qualification of P2X7-specific PET ligand 18F-JNJ-64413739 in healthy volunteers, including dosimetry, kinetic modeling, test-retest variability, and blocking by the P2X7 antagonist JNJ-54175446. Methods: Whole-body dosimetry was performed in 3 healthy male subjects by consecutive whole-body PET/CT scanning, estimation of the normalized cumulated activity, and calculation of the effective dose using OLINDA (v1.1). Next, 5 healthy male subjects underwent a 120-min dynamic 18F-JNJ-64413739 PET/MRI scan with arterial blood sampling to determine the appropriate kinetic model. For this purpose, 1- and 2-tissue compartment models and Logan graphic analysis (LGA) were evaluated for estimating regional volumes of distribution (VT). PET/MRI scanning was repeated in 4 of these subjects to evaluate medium-term test-retest variability (interscan interval, 26–97 d). For the single-dose occupancy study, 8 healthy male subjects underwent baseline and postdose 18F-JNJ-64413739 PET/MRI scans 4–6 h after the administration of a single oral dose of JNJ-54175446 (dose range, 5–300 mg). P2X7 occupancies were estimated using a Lassen plot and regional baseline and postdose VT. Results: The average (mean ± SD) effective dose was 22.0 ± 1.0 μSv/MBq. The 2-tissue compartment model was the most appropriate kinetic model, with LGA showing very similar results. Regional 2-tissue compartment model VT values were about 3 and were rather homogeneous across all brain regions, with slightly higher estimates for the thalamus, striatum, and brain stem. Between-subject VT variability was relatively high, with cortical VT showing an approximate 3-fold range across subjects. As for time stability, the acquisition time could be reduced to 90 min. The average regional test-retest variability values were 10.7% ± 2.2% for 2-tissue compartment model VT and 11.9% ± 2.2% for LGA VT. P2X7 occupancy approached saturation for single doses of JNJ-54175446 higher than 50 mg, and no reference region could be identified. Conclusion: 18F-JNJ-64413739 is a suitable PET ligand for the quantification of P2X7R expression in the human brain. It can be used to provide insight into P2X7R expression in health and disease, to evaluate target engagement by P2X7 antagonists, and to guide dose selection.