Whole-Body Biodistribution and Radiation Dosimetry of the Cannabinoid Type 2 Receptor Ligand [11C]-NE40 in Healthy Subjects

Ahmad, Rawaha; Koole, Michel; Evens, Nele; Serdons, Kim; Verbruggen, Alfons; Bormans, Guy; Laere, Koen Van

doi:10.1007/s11307-013-0626-y

Cited by 67 publications

(52 citation statements)

References 34 publications

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“…Interestingly, there was no difference in CRIP1a mRNA, which has been previously reported to show an opposite regulation pattern as the CB 1 receptor (42). In contrast to receptor mapping studies over lifespan in humans, which find no changes in CB 2 receptor binding distribution with age in healthy individuals (43), we report that dorsal medullary CB 2 mRNA is increased in aged relative to younger SD rats. Expression of CB 2 receptors on brain microglia is upregulated during neuroinflammation (44), which may be the source of elevated CB 2 receptor mRNA in dorsal medulla of older rats detected by our study.…”

Section: Discussioncontrasting

confidence: 99%

Alterations in the Medullary Endocannabinoid System Contribute to Age-related Impairment of Baroreflex Sensitivity

Schaich

Shaltout

Grabenauer

et al. 2015

Journal of Cardiovascular Pharmacology

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As they age, Sprague-Dawley (SD) rats develop elevated systolic blood pressure associated with impaired baroreflex sensitivity (BRS) for control of heart rate. We previously demonstrated in young hypertensive (mRen2)27 rats that impaired BRS is restored by CB1 cannabinoid receptor blockade in the solitary tract nucleus (NTS), consistent with elevated content of the endocannabinoid 2-arachidonoylglycerol (2-AG) in dorsal medulla relative to normotensive SD rats. There is no effect of CB1 receptor blockade in young SD rats. We now report in older SD rats that dorsal medullary 2-AG levels are two-fold higher at 70 versus 15 weeks of age (4.22 ± 0.61 vs. 1.93 ± 0.22 ng/mg tissue; P < 0.05). Furthermore, relative expression of CB1 receptor mRNA is significantly lower in aged rats, while CB2 receptor mRNA is significantly higher. In contrast to young adult SD rats, microinjection of the CB1 receptor antagonist SR141716A (36 pmol) into the NTS of older SD rats normalized BRS in animals exhibiting impaired baseline BRS (0.56 ± 0.06 baseline vs. 1.06 ± 0.05 ms/mmHg after 60 min; P < 0.05). Therefore, this study provides evidence for alterations in the endocannabinoid system within the NTS of older SD rats that contribute to age-related impairment of BRS.

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Section: Discussioncontrasting

confidence: 99%

Alterations in the Medullary Endocannabinoid System Contribute to Age-related Impairment of Baroreflex Sensitivity

Schaich

Shaltout

Grabenauer

et al. 2015

Journal of Cardiovascular Pharmacology

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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

115

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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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“…2 In this context, the in vivo imaging of cannabinoid type 2 receptors (CB2R) with positron emission tomography (PET) might be crucial to further understand the role of these receptors on inflammatory reactions underlying brain diseases. Several PET radiotracers for CB2 receptors have been synthesized and tested preclinically, such as [ 23 Among them, [ 11 C]A-836339 has been suggested as a promising radiotracer for the in vivo evaluation of a neuroinflammatory reaction in both a systemic lipopolysaccharide (LPS)-induced mouse model of neuroinflammation and a mouse model of Alzheimer's disease. 22 In contrast, [ 11 C]NE40 has not shown to be sensitive enough to visualize the CB2 receptor expression after cerebral ischemia in mice in part due to its low affinity for CB2 receptors.…”

Section: Introductionmentioning

confidence: 99%

PET imaging of cannabinoid type 2 receptors with [¹¹C]A-836339 did not evidence changes following neuroinflammation in rats

Pottier

Gómez‐Vallejo

Padró

et al. 2017

J Cereb Blood Flow Metab

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Cannabinoid type 2 receptors (CB2R) have emerged as promising targets for the diagnosis and therapy of brain pathologies. However, no suitable radiotracers for accurate CB2R mapping have been found to date, limiting the investigation of the CB2 receptor expression using positron emission tomography (PET) imaging. In this work, we report the evaluation of the in vivo expression of CB2R with [11 C]A-836339 PET after cerebral ischemia and in two rat models of neuroinflammation, first by intrastriatal LPS and then by AMPA injection. PET images and in vitro autoradiography showed a lack of specific [ 11 C]A-836339 uptake in these animal models demonstrating the limitation of this radiotracer to image CB2 receptor under neuroinflammatory conditions. Further, using immunohistochemistry, the CB2 receptor displayed a modest expression increase after cerebral ischemia, LPS and AMPA models. Finally, [18 F]DPA-714-PET and immunohistochemistry demonstrated decreased neuroinflammation by a selective CB2R agonist, JWH133. Taken together, these findings suggest that [11 C]A-836339 is not a suitable radiotracer to monitor in vivo CB2R expression by using PET imaging. Future studies will have to investigate alternative radiotracers that could provide an accurate binding to CB2 receptors following brain inflammation.

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Whole-Body Biodistribution and Radiation Dosimetry of the Cannabinoid Type 2 Receptor Ligand [11C]-NE40 in Healthy Subjects

Cited by 67 publications

References 34 publications

Alterations in the Medullary Endocannabinoid System Contribute to Age-related Impairment of Baroreflex Sensitivity

Alterations in the Medullary Endocannabinoid System Contribute to Age-related Impairment of Baroreflex Sensitivity

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

PET imaging of cannabinoid type 2 receptors with [¹¹C]A-836339 did not evidence changes following neuroinflammation in rats

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Whole-Body Biodistribution and Radiation Dosimetry of the Cannabinoid Type 2 Receptor Ligand [11C]-NE40 in Healthy Subjects

Cited by 67 publications

References 34 publications

Alterations in the Medullary Endocannabinoid System Contribute to Age-related Impairment of Baroreflex Sensitivity

Alterations in the Medullary Endocannabinoid System Contribute to Age-related Impairment of Baroreflex Sensitivity

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

PET imaging of cannabinoid type 2 receptors with [11C]A-836339 did not evidence changes following neuroinflammation in rats

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PET imaging of cannabinoid type 2 receptors with [¹¹C]A-836339 did not evidence changes following neuroinflammation in rats