Preclinical evaluation of [11C]NE40, a type 2 cannabinoid receptor PET tracer

Evens, Nele; Vandeputte, Caroline; Coolen, Charlotte; Janssen, Peter; Sciot, Raf; Baekelandt, Veerle; Verbruggen, Alfons; Debyser, Zeger; Laere, Koen Van; Bormans, Guy

doi:10.1016/j.nucmedbio.2011.09.005

Cited by 61 publications

(59 citation statements)

References 27 publications

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“…Recent findings have indicated that nicotine attenuates Aβ-induced microglial activation by shifting microglial M1 to M2 state, and cannabinoid CB2R mediates the process, thereby suggesting the CB2R involved in microglia polarization shift [112]. Several CB2R selective ligands have been developed over the past years [113] and the preliminary clinical evaluation with 11 C-NE40 showed appropriate fast brain kinetics in the healthy human brain [114]. However, 11 C-NE40 has not succeeded in highlighting microglial activation in AD subjects as compared to healthy controls.…”

Section: Potential Alternative Molecular Targets For Activated Micmentioning

confidence: 99%

Molecular Targets for PET Imaging of Activated Microglia: The Current Situation and Future Expectations

Tronel

Largeau

Ribeiro

et al. 2017

IJMS

106

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Microglia, as cellular mediators of neuroinflammation, are implicated in the pathogenesis of a wide range of neurodegenerative diseases. Positron emission tomography (PET) imaging of microglia has matured over the last 20 years, through the development of radiopharmaceuticals targeting several molecular biomarkers of microglial activation and, among these, mainly the translocator protein-18 kDa (TSPO). Nevertheless, current limitations of TSPO as a PET microglial biomarker exist, such as low brain density, even in a neurodegenerative setting, expression by other cells than the microglia (astrocytes, peripheral macrophages in the case of blood brain barrier breakdown), genetic polymorphism, inducing a variation for most of TSPO PET radiopharmaceuticals’ binding affinity, or similar expression in activated microglia regardless of its polarization (pro- or anti-inflammatory state), and these limitations narrow its potential interest. We overview alternative molecular targets, for which dedicated radiopharmaceuticals have been proposed, including receptors (purinergic receptors P2X7, cannabinoid receptors, α7 and α4β2 nicotinic acetylcholine receptors, adenosine 2A receptor, folate receptor β) and enzymes (cyclooxygenase, nitric oxide synthase, matrix metalloproteinase, β-glucuronidase, and enzymes of the kynurenine pathway), with a particular focus on their respective contribution for the understanding of microglial involvement in neurodegenerative diseases. We discuss opportunities for these potential molecular targets for PET imaging regarding their selectivity for microglia expression and polarization, in relation to the mechanisms by which microglia actively participate in both toxic and neuroprotective actions in brain diseases, and then take into account current clinicians’ expectations.

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Section: Potential Alternative Molecular Targets For Activated Micmentioning

confidence: 99%

Molecular Targets for PET Imaging of Activated Microglia: The Current Situation and Future Expectations

Tronel

Largeau

Ribeiro

et al. 2017

IJMS

106

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“…Moreover, the administration of a selective CB2 agonist reduced infarct volume and improved motor function scores [16]. Recently, a PET tracer that binds specifically to CB2 was developed to illustrate CB2 availability in vivo [19]. Although it was reported that the binding of [ 11 C]NE40 24 h after ischemic injury using a photochemically induced thrombosis (PIT) technique failed to increase [20], six out of nine PET data were not corrected for the attenuation of radioactivity, and the correction is critical for the quantification of PET data.…”

Section: Introductionmentioning

confidence: 99%

In vivo TSPO and cannabinoid receptor type 2 availability early in post-stroke neuroinflammation in rats: a positron emission tomography study

Hosoya

Fukumoto

Kakiuchi

et al. 2017

J Neuroinflammation

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BackgroundUpregulated levels of 18-kDa translocator proteins (TSPO) and type 2 endocannabinoid receptors (CB2) are considered to reflect different aspects of microglia-related neuroinflammatory responses in the brain. Relative to the increase in the TSPO expression that occurs slightly later during neuroinflammation in a proinflammatory fashion, CB2 activation is considered to relate to the neuroprotective responses that occurs predominantly at an early stage of brain disorders. These findings, however, were deduced from studies with different animal samples under different experimental settings. Here, we aimed to examined the differences in TSPO binding and CB2 availability at an early stage of stroke in the same animal using positron emission tomography (PET).MethodsWe used a total of eight Sprague-Dawley rats that underwent photothrombotic stroke surgery. The binding levels of a TSPO tracer [11C](R)PK11195 and a CB2 tracer [11C]NE40 were measured at 24 h after the surgery in the same animal using PET in combination with immunohistochemistry for CB2 and several other markers. A morphological inspection was also performed with X-ray computed tomography for small animals.ResultsThe levels of [11C]NE40 binding potential (BPND) were significantly higher in the cerebral cortical region on the lesion side than those on the non-lesion side, whereas no difference was found in the levels of [11C](R)PK11195 BPND between hemispheres. The tracer influx index (R1) data were all reduced on the lesion side irrespective of tracers. This increase in [11C]NE40 BPND was concomitant with an elevation in CB2 expression mainly within the microglia in the peri-infarct area, as shown by immunohistochemical examinations with Iba-1, CD11b/c+, and NG2+ staining.ConclusionsThe present results provide in vivo evidence of different responses of microglia occurring in the acute state of stroke. The use of the CB2 tracer [11C]NE40 allows us to evaluate the roles played by the neuroprotective aspect of microglia in acute neuroinflammatory processes.Electronic supplementary materialThe online version of this article (doi:10.1186/s12974-017-0851-4) contains supplementary material, which is available to authorized users.

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“…Researchers from KU Leuven University used animals that were stereotactically injected with viral vectors that drove expression of human CB2 receptors in the striatum [14–16]. In this condition, PET imaging revealed specific and reversible binding of CB2 radiotracers to overexpressed human CB2 receptors [14–16].…”

Section: Introductionmentioning

confidence: 99%

“…In this condition, PET imaging revealed specific and reversible binding of CB2 radiotracers to overexpressed human CB2 receptors [14–16]. The best radioligand of this series, [ 11 C]NE40, was studied in healthy human subjects [17], but [ 11 C]NE40 did not demonstrate an increase of CB2 binding in AD patients versus healthy controls [18].…”

Section: Introductionmentioning

confidence: 99%

Cannabinoid CB2 Receptors in a Mouse Model of Aβ Amyloidosis: Immunohistochemical Analysis and Suitability as a PET Biomarker of Neuroinflammation

et al. 2015

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In Alzheimer’s disease (AD), one of the early responses to Aβ amyloidosis is recruitment of microglia to areas of new plaque. Microglial receptors such as cannabinoid receptor 2 (CB2) might be a suitable target for development of PET radiotracers that could serve as imaging biomarkers of Aβ-induced neuroinflammation. Mouse models of amyloidosis (J20APPswe/ind and APPswe/PS1ΔE9) were used to investigate the cellular distribution of CB2 receptors. Specificity of CB2 antibody (H60) was confirmed using J20APPswe/ind mice lacking CB2 receptors. APPswe/PS1ΔE9 mice were used in small animal PET with a CB2-targeting radiotracer, [11C]A836339. These studies revealed increased binding of [11C]A836339 in amyloid-bearing mice. Specificity of the PET signal was confirmed in a blockade study with a specific CB2 antagonist, AM630. Confocal microscopy revealed that CB2-receptor immunoreactivity was associated with astroglial (GFAP) and, predominantly, microglial (CD68) markers. CB2 receptors were observed, in particular, in microglial processes forming engulfment synapses with Aβ plaques. In contrast to glial cells, neuron (NeuN)-derived CB2 signal was equal between amyloid-bearing and control mice. The pattern of neuronal CB2 staining in amyloid-bearing mice was similar to that in human cases of AD. The data collected in this study indicate that Aβ amyloidosis without concomitant tau pathology is sufficient to activate CB2 receptors that are suitable as an imaging biomarker of neuroinflammation. The main source of enhanced CB2 PET binding in amyloid-bearing mice is increased CB2 immunoreactivity in activated microglia. The presence of CB2 immunoreactivity in neurons does not likely contribute to the enhanced CB2 PET signal in amyloid-bearing mice due to a lack of significant neuronal loss in this model. However, significant loss of neurons as seen at late stages of AD might decrease the CB2 PET signal due to loss of neuronally-derived CB2. Thus this study in mouse models of AD indicates that a CB2-specific radiotracer can be used as a biomarker of neuroinflammation in the early preclinical stages of AD, when no significant neuronal loss has yet developed.

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Preclinical evaluation of [11C]NE40, a type 2 cannabinoid receptor PET tracer

Cited by 61 publications

References 27 publications

Molecular Targets for PET Imaging of Activated Microglia: The Current Situation and Future Expectations

Molecular Targets for PET Imaging of Activated Microglia: The Current Situation and Future Expectations

In vivo TSPO and cannabinoid receptor type 2 availability early in post-stroke neuroinflammation in rats: a positron emission tomography study

Cannabinoid CB2 Receptors in a Mouse Model of Aβ Amyloidosis: Immunohistochemical Analysis and Suitability as a PET Biomarker of Neuroinflammation

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