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Preclinical evaluation of [ <sup>18</sup> F]MA3, a CB <sub/>2</sub> receptor agonist radiotracer for Positron Emission Tomography
摘要： Background and Purpose: Non-invasive in vivo imaging of CB2 receptors (CB2R) using positron emission tomography (PET) is pursued to study neuroinflammation. The purpose of this study is to evaluate the in vivo binding specificity of [18F]MA3, a CB2R agonist, in a rat model with local overexpression of human CB2R (hCB2R). Methods: [18F]MA3 was produced with good radiochemical yield and radiochemical purity. The radiotracer was evaluated in rats with local overexpression of hCB2R and in a healthy non-human primate using PET. Key results: Ex vivo autoradiography demonstrated CB2 specific binding of [18F]MA3 in rat hCB2R vector injected striatum. In a PET study, increased tracer binding in the hCB2R vector injected striatum compared to the contralateral control vector injected striatum was observed. Binding in hCB2R vector injected striatum was blocked with a structurally non related CB2R inverse agonist and a displacement study confirmed the reversibility of tracer binding. This study identified the utility of mutated inactive vector model for evaluation of CB2R agonist PET tracers. [18F]MA3 PET scans in the non-human primate showed good uptake and fast wash out from brain, but no CB2 specific binding was observed. Conclusion and Implications: Evaluation of [18F]MA3 in a rat model with local overexpression of hCB2R showed CB2 specific and reversible tracer binding. [18F]MA3 showed good brain uptake and subsequent wash out in a healthy non-human primate but no specific binding was observed. Further clinical evaluation of [18F]MA3 in patients with neuroinflammation is warranted.
关键词： CB2R,PET imaging,neuroinflammation,[18F]MA3,radiotracer
更新于2025-09-23 15:22:29
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PET Imaging of the P2X7 Ion Channel with a Novel Tracer [18F]JNJ-64413739 in a Rat Model of Neuroinflammation
摘要： 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, [18F]JNJ-64413739 has been recently disclosed. Procedures: We 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. 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 [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. Conclusions: While 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.
关键词： Lipopolysaccharide,Rats,Positron emission tomography (PET),PET imaging,P2X7 receptor,LPS,[18F]JNJ-64413739,Neuroinflammation
更新于2025-09-23 15:22:29
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Laser Moxibustion Alleviates Knee Osteoarthritis Pain by Inhibiting Spinal Microglial Activation-Mediated Neuroinflammation in Rats
摘要： Background: Central sensitization driven by glial activation-mediated neuroinflammation is recognized as a key mechanism in pain processing. Laser moxibustion using low-intensity laser irradiation of corresponding acupoints significantly relieves knee osteoarthritis (KOA) pain. However, the underlying mechanism of its effects on KOA pain is still not completely understood. Objective: In this study, we aimed to investigate whether laser moxibustion could alleviate KOA pain by inhibiting spinal glial activation and proinflammatory cytokines upregulation in monosodium iodoacetate (MIA)-induced KOA pain in rats. Materials and methods: Sprague-Dawley rats were divided randomly into three groups: Saline + Sham Laser, MIA + Laser, and MIA + Sham Laser. A 10.6 lm laser was used to irradiate ST35 (Dubi) for 10 min once every 2 days for a total of seven applications. The paw withdrawal mechanical threshold and weight-bearing distribution were performed to evaluate the nociceptive behaviors. Spinal expressions of microglial marker, ionized calcium binding adaptor molecule-1 (Iba-1); astrocyte marker, glial fibrillary acidic protein (GFAP); pro-inflammatory cytokines, tumor necrosis factor-a (TNF-a), interleukin-1b (IL-1b), and interleukin-6 (IL-6) were measured 14 days after MIA injection. Results: The results showed that laser moxibustion significantly reversed the MIA-induced mechanical hyperalgesia and weight-bearing difference up to 14 days compared with MIA + Sham Laser group ( p < 0.05 or p < 0.01). Moreover, both the protein level and immunofluorescence intensity of Iba-1 in the ipsilateral spinal cord dorsal horn were markedly decreased in the MIA + Laser group than those in the MIA + Sham Laser group ( p < 0.01). However, there was no significant difference in the expression of GFAP between groups ( p > 0.05). In addition, laser moxibustion decreased the upregulation of TNF-a, IL-1b, and IL-6 compared with the MIA + Sham Laser group ( p < 0.01). Conclusions: This study demonstrated that laser moxibustion at ST35 significantly alleviated MIA-induced KOA pain through inhibition of the microglial activation-mediated neuroinflammation, at least partially, by suppressing the production of proinflammatory cytokines, which may provide a potential analgesic target for KOA pain relief.
关键词： glial activation,knee osteoarthritis pain,laser moxibustion,neuroinflammation
更新于2025-09-16 10:30:52
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Molecular Imaging of Neuroinflammation in HIV
摘要： The development of combined antiretroviral therapy (cART) has increased the lifespan of persons living with HIV (PLWH), with most PLWH having a normal life expectancy. While significant progress has occurred, PLWH continue to have multiple health complications, including HIVassociated neurocognitive disorders (HAND). While the exact cause of HAND is not known, persistent neuroinflammation is hypothesized to be an important potential contributor. Molecular imaging using positron emission tomography (PET) can non-invasively evaluate neuroinflammation. PET radiotracers specific for increased expression of the translocator protein18kDa (TSPO) on activated microglia can detect the presence of neuroinflammation in PLWH. However, results from these studies have been inconsistent and inconclusive. Future studies are needed to address key limitations that continue to persist with these techniques before accurate conclusions can be drawn regarding the role of persistent neuroinflammation in PLWH.
关键词： Neuroinflammation,Human immunodeficiency virus (HIV),Positron emission tomography (PET),Translocator protein 18 kDa (TSPO),HIV-associated neurocognitive impairment (HAND)
更新于2025-09-09 09:28:46