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

Abstract

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 P2X7specific PET ligand 18 F-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 18 F-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 (V T). 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 18 F-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 V T. Results: The average (mean ± SD) effective dose was 22.0 ± 1.0 μSv/MBq. The 2tissue compartment model was the most appropriate kinetic model, with LGA showing very similar results. Regional 2-tissue compartment model V T 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 V T variability was relatively high, with cortical V T 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 V T and 11.9% ± 2.2% for LGA V T. P2X7 occupancy approached saturation for single doses of JNJ-54175446 higher than 50 mg, and no reference region could be identified. Conclusion: 18 F-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.

Translational Model‐Informed Dose Selection for a Human Positron Emission Tomography Imaging Study of JNJ‐54175446, a P2X7 Receptor Antagonist

“…Eight healthy men underwent a baseline PET scan, and two postdose scans (separated at least 1 week apart; Table ). Data collected for the human exposure‐occupancy modeling analysis included blood samples for PK (~ 4, 4.75, and 6 hours postdose, corresponding to immediately before tracer injection, midway through, and immediately upon completion of the scan, respectively) and RO data from the [ 18 F]‐JNJ‐64413739 PET images …”

“…The study designs for the SAD (NCT02475148) 8 and MAD (NCT02515955) studies and the [ 18 F]-JNJ-64413739 PET study (NCT03088644) 9 have been described elsewhere and briefly summarized below and in Table S1. Protocols were approved by the investigational review board or ethics committee and all subjects provided written informed consent.…”

“…Data collected for the human exposure-occupancy modeling analysis included blood samples for PK (~ 4, 4.75, and 6 hours postdose, corresponding to immediately before tracer injection, midway through, and immediately upon completion of the scan, respectively) and RO data from the [ 18 F]-JNJ-64413739 PET images. 9 Monkey PET study design and sample collection The monkey PET study was performed at Molecular NeuroImaging (New Haven, CT) using protocols approved by the Institutional Animal Care and Use Committee. 12 One male (12.1 kg; received 3 single JNJ-54175446 doses) and one female (8.7 kg; received 2 single JNJ-54175446 doses) rhesus macaques (Macaca mulatta) received baseline, vehicle, or blockade scans prior to which JNJ-54175446 was administered intravenously (doses: 0.1, 0.4, 2.5, and 5.3 mg/kg), starting 10 minutes before [ 18 F]-JNJ-64413739 injection.…”

“…Results indicated an approximately full and continuous antagonism of IL‐1β stimulation at doses ≥ 50 mg/day. To confirm target engagement and define the exposure‐receptor occupancy (RO) relationship in the brain, a positron emission tomography (PET) study (NCT03088644l) was planned for JNJ‐54175446 with [ 18 F]‐JNJ‐64413739, a P2X7 receptor‐specific PET tracer. A measure of target engagement can be obtained by assessing the extent of competitive binding, or occupancy, by the drug .…”

The Role of Nuclear Medicine for COVID-19: Time to Act Now

“…There are wellestablished radiopharmaceuticals suitable as inflammatory biomarkers at an intracellular level, e.g. targeting the purinergic P2X7 receptor (6). While initially designed to quantify neuroinflammation, they can easily be repurposed for imaging the inflammosome and quantifying inflammation at a whole-body-level.…”