Increased uptake of the P2X7 receptor radiotracer ¹⁸F‐JNJ‐64413739 in the brain and peripheral organs according to the severity of status epilepticus in male mice

Abstract

Objective: The P2X7 receptor (P2X7R) is an important contributor to neuroinflammation, responding to extracellularly released adenosine triphosphate. Expression of the P2X7R is increased in the brain in experimental and human epilepsy, and genetic or pharmacologic targeting of the receptor can reduce seizure frequency and severity in preclinical models. Experimentally induced seizures also increase levels of the P2X7R in blood. Here, we tested 18 F-JNJ-64413739, a positron emission tomography (PET) P2X7R antagonist, as a potential noninvasive biomarker of seizure-damage and epileptogenesis.Methods: Status epilepticus was induced via an intra-amygdala microinjection of kainic acid. Static PET studies (30 min duration, initiated 30 min after tracer administration) were conducted 48 h after status epilepticus via an intravenous injection of 18 F-JNJ-64413739. PET images were coregistered with a brain magnetic

Anti-seizure effects of JNJ-54175446 in the intra-amygdala kainic acid model of drug-resistant temporal lobe epilepsy in mice

“…Non-glial-based mechanisms are also possible for the effects of JNJ-54175446 in the present study. While the function of neuron-based P2X7 receptor activity is uncertain ( Armstrong et al, 2002 ; Sperlagh et al, 2002 ; Papp et al, 2004 ), studies have reported that the P2X7 receptor is over-expressed in neurons within a seizure focus ( Rappold et al, 2006 ; Jimenez-Pacheco et al, 2016 ; Wei et al, 2016 ; Mikkelsen et al, 2023 ; Morgan et al, 2023 ). The delayed and net outcome of P2X7 receptor antagonism may therefore be a combination of effects of blocking the receptor on different cell types and longer-term changes secondary to resolving gliosis.…”

“…Visualisation of P2X7 receptor binding in the brain was performed by autoradiography. 18 F-JNJ-64413739 synthesis was performed using a TRACERlab FX FN synthesis module (GE Healthcare) following a previously described method with minor modifications ( Morgan et al, 2023 ). In brief, [ 18 F]F − was generated in a Cyclone 18/9 cyclotron (IBA) by proton irradiation of 18 O-enriched water via the 18 O (p,n) 18 F nuclear reaction, and trapped on a preconditioned Sep-Pak Accell Plus QMA Light cartridge (Waters).…”

The P2X7 Receptor as a Mechanistic Biomarker for Epilepsy

“…Further exploring the diagnostic potential of P2X7R-PET imaging for epilepsy, we recently published a study using the P2X7R radiotracer [ 18 F]JNJ-64413739 [ 126 ]. Here, P2X7R radiotracer uptake was measured 48 h post-intra-amygdala KA-induced status epilepticus in mice, a timepoint that represents the seizure-free latent period in this model [ 135 ].…”

Increased Cerebral Level of P2X7R in a Tauopathy Mouse Model by PET Using [18F]GSK1482160

“…Several positron emission tomography (PET) tracers for P2X7R have been developed, 12 ]SMW139 showed a 6 times lower affinity for the rodent P2X7R than the human P2X7R and was rapidly metabolized in mice, with 30+% unmetabolized plasma fraction. 15,21 Increased [ 18 F]JNJ-64413739 uptake was reported in the brain and peripheral organs of animal models of epilepsy 22 and lipopolysaccharide (LPS)-injected mice. 23 Increased uptake of [ 11 C]GSK1482160 has also been reported in the cortex and hippocampus of LPS-treated mice in a blockable manner.…”

“…Several positron emission tomography (PET) tracers for P2X7R have been developed, including [ 18 F]­JNJ-64413739 ( K d = 1.0 nM), [ 18 F]­GSK1482160 ( K d = 4.3 nM), [ 11 C]­SWM139 ( K d = 4.6 nM), [ 18 F]­IUR-1601 ( K i = 4.3 nM) [ 11 C]­A-740003 ( K i = 0.1 nM), [ 123 I]­TZ6019 ( K i = 6.3 nM), [ 18 F]­PTTP ( K d = 12.4 nM), and [ 18 F]­FTTM ( K d = 25.4 nM) (the affinities are measured on hP2X7R). Earlier study showed that [ 11 C]­SMW139 showed a 6 times lower affinity for the rodent P2X7R than the human P2X7R and was rapidly metabolized in mice, with 30+% unmetabolized plasma fraction. , Increased [ 18 F]­JNJ-64413739 uptake was reported in the brain and peripheral organs of animal models of epilepsy and lipopolysaccharide (LPS)-injected mice . Increased uptake of [ 11 C]­GSK1482160 has also been reported in the cortex and hippocampus of LPS-treated mice in a blockable manner .…”