Abstract
PurposeThe 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, [18F]JNJ-64413739 has been recently disclosed.ProceduresWe evaluated [18F]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 [18F]JNJ-64413739 was confirmed by performing blocking experiments with the P2X7 antagonist JNJ-54175446.ResultsBrain 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 [18F]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 [18F]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.ConclusionsWhile further work is needed to study [18F]JNJ-64413739 in other types of neuroinflammation, the current results favorably characterize [18F]JNJ-64413739 as a potential PET tracer of central neuroinflammation.
Highlights
Neuroinflammation is thought to play a role in many neuropsychiatric and neurological conditions [1,2,3,4]; its exact contribution remains poorly understood [5,6,7]
Since P2X7 tracers have not been evaluated in a rat LPS local neuroinflammation model, we first conducted a pilot imaging study with [18F]JNJ-64413739 to select the optimal time points and LPS dose for subsequent imaging experiments
To confirm neuroinflammation induced by LPS in brain tissue, we used quantitative RT-PCR to measure messenger RNA levels of neuroinflammatory marker genes Tspo, Aif1, and P2rx7 in both LPS- and phosphate-buffered saline (PBS)-injected brains
Summary
Neuroinflammation is thought to play a role in many neuropsychiatric and neurological conditions [1,2,3,4]; its exact contribution remains poorly understood [5,6,7] This is partially due to limited diagnostic tools to measure inflammation in the central nervous system (CNS) [8]. Some failures were due to existing genetic polymorphisms affecting TSPO binding in humans [31,32,33] While this limitation can be corrected [34,35,36,37], the non-specific role of TSPO in neuroinflammation are more difficult to address [9, 38, 39], as TSPO is involved in many cellular functions not specific to central inflammation [40,41,42,43,44]
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