Exploring occupancy of the histamine H<sub>3</sub> receptor by pitolisant in humans using PET

Rusjan, Pablo; Sabioni, Pamela; Ciano, Patricia Di; Mansouri, Esmaeil; Boileau, Isabelle; Laveillé, Alexia; Capet, Marc; Duvauchelle, Thierry; Schwartz, Jean‐Charles; Robert, Philippe; Foll, Bernard Le

doi:10.1111/bph.15067

Cited by 15 publications

(5 citation statements)

References 30 publications

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“…Seventh, in this study we did not measure [ 18 F]FEPPA fp. It has been difficult to obtain reliable f p measurements [80] and it is known that V T /f p for [ 11 C]PBR28 increase its variability (e.g., [81]); thus, consistent with previous studies with [ 18 F]FEPPA, V T /f p was not used as outcome measure in this study Contrary to the hypothesis of elevated levels of TSPO in ASD, we conclude that participants with ASD present either no significant difference in TSPO concentration when compared to matched controls, or significantly lower levels of TSPO when excluding concurrent MDE.…”

Section: Discussionmentioning

confidence: 99%

In vivo imaging translocator protein (TSPO) in autism spectrum disorder

Simpson

Gharehgazlou

Silva

et al. 2022

Neuropsychopharmacol.

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Converging evidence points to the significant involvement of the immune system in autism spectrum disorders (ASD). Positron emission tomography (PET) can quantify translocator protein 18 kDa (TSPO), a marker with increased expression mainly in microglia and, to some extent astroglia during neuropsychiatric diseases with inflammation. This preliminary analysis explored, for the first time, whether TSPO binding was altered in male and female participants with ASD in vivo using full kinetic quantification. Thirteen individuals with ASD (IQ > 70 [n = 12], IQ = 62 [n = 1]), 5 F, 25 ± 5 years) were scanned with [ 18 F]FEPPA PET. Data from 13 typically developing control participants with matching age and TSPO rs6971 polymorphism (9 F, age 24 ± 5 years) were chosen from previous studies for comparison. The two tissue compartment model (2TCM) was used to determine the total volume of distribution ([ 18 F]FEPPA V T ) in four previously identified regions of interest (ROI): prefrontal, temporal, cerebellar, and anterior cingulate cortices. We observe no significant difference in [ 18 F]FEPPA V T relative to controls (F (1,26) = 1.74, p = 0.20). However, 2 ASD participants with higher V T had concurrent major depressive episodes (MDE), which has been consistently reported during MDE. After excluding those 2 ASD participants, in a post-hoc analysis, our results show lower [ 18 F]FEPPA V T in ASD participants compared to controls (F (1,24) = 6.62, p = 0.02). This preliminary analysis provides evidence suggesting an atypical neuroimmune state in ASD.

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Section: Discussionmentioning

confidence: 99%

In vivo imaging translocator protein (TSPO) in autism spectrum disorder

Simpson

Gharehgazlou

Silva

et al. 2022

Neuropsychopharmacol.

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“… 66 Another explanation could be the existence of species differences in receptor expression, affinity, or other physiological parameters between monkeys and rats. 67 In a clinical PET study with [ 11 C]GSK-189254, a therapeutic dose (40 mg daily) of pitolisant (inverse agonist/antagonist) was associated with an H 3 receptor occupancy of 84%, 68 which suggests that the occupancy of AG-0029 observed in our study may be too low for therapeutic efficacy. Since our [ 11 C]GSK-189254 data indicated moderate H 3 receptor occupancy even at the 10 mg/kg dose, higher drug doses (30 or 50 mg/kg) or multiple doses of AG-0029 seem to be required to achieve therapeutic effects of H3 receptor blockade.…”

Section: Discussionmentioning

confidence: 75%

Binding of the Dual-Action Anti-Parkinsonian Drug AG-0029 to Dopamine D₂ and Histamine H₃ Receptors: A PET Study in Healthy Rats

et al. 2022

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Introduction : Parkinson’s disease (PD) is a neurodegenerative disorder characterized by motor dysfunction and a diverse range of nonmotor symptoms. Functional relationships between the dopaminergic and histaminergic systems suggest that dual-action pharmaceuticals like AG-0029 (D 2 /D 3 agonist/H 3 antagonist) could ameliorate both the motor and cognitive symptoms of PD. The current study aimed to demonstrate the interaction of AG-0029 with its intended targets in the mammalian brain using positron emission tomography (PET). Methods : Healthy male Wistar rats were scanned with a small-animal PET camera, using either the dopamine D 2 /D 3 receptor ligand [ 11 C]raclopride or the histamine H 3 receptor ligand [ 11 C]GSK-189254, before and after treatment with an intravenous, acute, single dose of AG-0029. Dynamic [ 11 C]raclopride PET data (60 min duration) were analyzed using the simplified reference tissue model 2 (SRTM2) with cerebellum as reference tissue and the nondisplaceable binding potential as the outcome parameter. Data from dynamic [ 11 C]GSK-189254 scans (60 min duration) with arterial blood sampling were analyzed using Logan graphical analysis with the volume of distribution ( V T ) as the outcome parameter. Receptor occupancy was estimated using a Lassen plot. Results : Dopamine D 2/3 receptor occupancies in the striatum were 22.6 ± 18.0 and 84.0 ± 3.5% (mean ± SD) after administration of 0.1 and 1 mg/kg AG-0029, respectively. In several brain regions, the V T values of [ 11 C]GSK-189254 were significantly reduced after pretreatment of rats with 1 or 10 mg/kg AG-0029. The H 3 receptor occupancies were 11.9 ± 8.5 and 40.3 ± 11.3% for the 1 and 10 mg/kg doses of AG-0029, respectively. Conclusions : Target engagement of AG-0029 as an agonist at dopamine D 2 /D 3 receptors and an antagonist at histamine H 3 receptors could be demonstrated in the rat brain with [ 11 C]raclopride and [ 11 C]GSK-189254 PET, respectively. The measured occupancy values reflect the previously reported high (subnanomolar) affinity of AG-0029 to D 2 /D 3 and moderate (submicromolar) affinity to H 3 receptors.

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“…It has high affinity and selectivity for the H 3 receptor. Specifically, the administration of a dose of 40 mg of pitolisant has been shown to lead to H 3 receptor occupancy of 84 ± 7% at the time of peak plasma concentration (Rusjan et al, 2020). Pitolisant induces central histaminergic and noradrenergic transmission in animal models that increase wakefulness and decrease REM sleep.…”

Section: H 3 Receptor Antagonistsmentioning

confidence: 99%

Histamine, Neuroinflammation and Neurodevelopment: A Review

Carthy

Ellender

2021

Front. Neurosci.

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The biogenic amine, histamine, has been shown to critically modulate inflammatory processes as well as the properties of neurons and synapses in the brain, and is also implicated in the emergence of neurodevelopmental disorders. Indeed, a reduction in the synthesis of this neuromodulator has been associated with the disorders Tourette’s syndrome and obsessive-compulsive disorder, with evidence that this may be through the disruption of the corticostriatal circuitry during development. Furthermore, neuroinflammation has been associated with alterations in brain development, e.g., impacting synaptic plasticity and synaptogenesis, and there are suggestions that histamine deficiency may leave the developing brain more vulnerable to proinflammatory insults. While most studies have focused on neuronal sources of histamine it remains unclear to what extent other (non-neuronal) sources of histamine, e.g., from mast cells and other sources, can impact brain development. The few studies that have started exploring this in vitro, and more limited in vivo, would indicate that non-neuronal released histamine and other preformed mediators can influence microglial-mediated neuroinflammation which can impact brain development. In this Review we will summarize the state of the field with regard to non-neuronal sources of histamine and its impact on both neuroinflammation and brain development in key neural circuits that underpin neurodevelopmental disorders. We will also discuss whether histamine receptor modulators have been efficacious in the treatment of neurodevelopmental disorders in both preclinical and clinical studies. This could represent an important area of future research as early modulation of histamine from neuronal as well as non-neuronal sources may provide novel therapeutic targets in these disorders.

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Exploring occupancy of the histamine H₃ receptor by pitolisant in humans using PET

Cited by 15 publications

References 30 publications

In vivo imaging translocator protein (TSPO) in autism spectrum disorder

In vivo imaging translocator protein (TSPO) in autism spectrum disorder

Binding of the Dual-Action Anti-Parkinsonian Drug AG-0029 to Dopamine D₂ and Histamine H₃ Receptors: A PET Study in Healthy Rats

Histamine, Neuroinflammation and Neurodevelopment: A Review

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Exploring occupancy of the histamine H3 receptor by pitolisant in humans using PET

Cited by 15 publications

References 30 publications

In vivo imaging translocator protein (TSPO) in autism spectrum disorder

In vivo imaging translocator protein (TSPO) in autism spectrum disorder

Binding of the Dual-Action Anti-Parkinsonian Drug AG-0029 to Dopamine D2 and Histamine H3 Receptors: A PET Study in Healthy Rats

Histamine, Neuroinflammation and Neurodevelopment: A Review

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Product

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Exploring occupancy of the histamine H₃ receptor by pitolisant in humans using PET

Binding of the Dual-Action Anti-Parkinsonian Drug AG-0029 to Dopamine D₂ and Histamine H₃ Receptors: A PET Study in Healthy Rats