PET Imaging of the P2X7 Ion Channel with a Novel Tracer [18F]JNJ-64413739 in a Rat Model of Neuroinflammation

Abstract

Purpose: The P2X7 receptor, an adenosine triphosphate (ATP)-gated purinoreceptor, has emerged as one of the key players in neuroinflammatory processes. Therefore, developing a positron emission tomography (PET) tracer for imaging of P2X7 receptors in vivo presents a promising approach to diagnose, monitor, and study neuroinflammation in a variety of brain disorders. To fulfill the goal of developing a P2X7 PET ligand as a biomarker of neuroinflammation, [ 18 F]JNJ-64413739 has been recently disclosed. Procedures: We evaluated [ 18 F]JNJ-64413739 in a rat model of neuroinflammation induced by an intracerebral injection of lipopolysaccharide (LPS). In vivo brain uptake was determined by PET imaging. Upregulation of neuroinflammatory biomarkers was determined by quantitative polymerase chain reaction (qPCR). Distribution of the tracer in the brain was determined by ex vivo autoradiography (ARG). The specificity of [ 18 F]JNJ-64413739 was confirmed by performing blocking experiments with the P2X7 antagonist JNJ-54175446. Results: Brain regions of rats injected with LPS had a significantly increased uptake (34 % ± 3 % s.e.m., p = 0.036, t test, standardized uptake value measured over the entire scanning period) of [ 18 F]JNJ-64413739 relative to the corresponding brain regions of control animals injected with phosphate-buffered saline (PBS). The uptake in the contralateral regions and cerebellum was not significantly different between the groups of animals. The increase in uptake of [ 18 F]JNJ-64413739 at the LPS-injected site observed by PET imaging was concordant with ex vivo ARG, upregulation of neuroinflammatory biomarkers, and elevated P2X7 expression levels. Conclusions: While further work is needed to study [ 18 F]JNJ-64413739 in other types of neuroinflammation, the current results favorably characterize [ 18 F]JNJ-64413739 as a potential PET tracer of central neuroinflammation.

PET imaging of P2X7R in the experimental autoimmune encephalomyelitis model of multiple sclerosis using [11C]SMW139

“…Han et al attempted to evaluate [ 11 C]GSK1482160 in vivo in the EAE model but did not succeed due to the low affinity of the tracer for rat P2X 7 R [31]. Systemic and intracerebral LPS models have been used to evaluate the currently available P2X 7 R tracers [17,30,32]; however, these artificial models are not ideal and P2X 7 R overexpression may not reflect the real pathological expression levels in neuroinflammation. We used the acute EAE model in Lewis rats which is characterized by microglia activation and macrophage infiltration mainly in the spinal cord and to a lesser extent in the brain stem and cerebellum [33,34].…”

“…Few PET tracers targeting P2X 7 R have recently been reported that display good affinity and blood brain barrier (BBB) permeability. For instance, Berdyyeva et al evaluated a fluor-18 labeled P2X 7 R antagonist, [ 18 F]JNJ-64413739, in a neuro-inflammatory model using intracerebral lipopolysaccharide (LPS) injection and found an increase of tracer uptake in the LPSinjected part of the brain compared to the contralateral side [17]. The same tracer was also evaluated in nonhuman primates (NHP) and showed target engagement and dose-dependent occupancy in the brain [18].…”

Positron Emission Tomography in the Inflamed Cerebellum: Addressing Novel Targets among G Protein-Coupled Receptors and Immune Receptors

“…Recently, the cerebellum was regarded as a preferable reference region of neuroradiological imaging [ 128 , 144 , 145 ]. However, new anatomical [ 26 , 146 ], cell biological and physiological approaches have moved it to a role in multiple functions for the organism and as an emancipated part of the brain.…”

“…Meanwhile, a collection of further potential PET tracers occurred. The results of a phase 1 study were presented recently by Koole et al [ 125 ] for the triazole derivative [ 18 F] JNJ64413739 ( Figure 11 : [ 48 ]) developed at the Janssen laboratories [ 125 , 126 , 127 , 128 ]. The compound with appropriate log P of 2.05 and selectivity for the target receptor is regarded as a promising structure for further evaluation as a PET tracer.…”

“…The tetrazole P2X7 receptor antagonist A438079 ( Figure 11 : [ 51 ]) released already 2006 in the Abbott laboratories shares with A-740003 ( Figure 10 : [ 45 ]) some nociceptive abilities which have been described to be due to its anti-inflammatory properties, especially in chronic processes like arthritis [ 126 , 127 , 128 ]. The compounds were selected from a series of tetrazole derivatives [ 131 , 132 , 133 ], and cyanoguanidines [ 131 ] presented properties of competitive inhibition at the original binding site of endogenous ligands.…”