Author: Veronese, Mattia ; Lythgoe, David J ; Howes, Oliver D ; Jauhar, Sameer ; Arumuham, Atheeshaan ; Rabiner, Eugenii A ; Onwordi, Ellis Chika ; Nour, Matthew M ; Beck, Katherine

AbstractBackgroundThe histamine-3 receptor (H3R) may have a role in cognitive processes through its action as a presynaptic heteroreceptor inhibiting the release of glutamate in the brain. To explore this, we examined anterior cingulate cortex (ACC) and striatum H3R availability in patients with schizophrenia and characterized their relationships with glutamate levels in corresponding brain regions.MethodsWe employed a cross-sectional study, recruiting 12 patients with schizophrenia and 12 healthy volunteers. Participants underwent positron emission tomography using the H3R-specific radio ligand [11C]MK-8278, followed by proton magnetic resonance spectroscopy to measure glutamate levels, recorded as Glu and Glx. Based on existing literature, the ACC and striatum were selected as regions of interest.ResultsWe found significant inverse relationships between tracer uptake and Glu (r = −0.66, P = .02) and Glx (r = −0.62, P = .04) levels in the ACC of patients, which were absent in healthy volunteers (Glu: r = −0.19, P = .56, Glx: r = 0.10, P = .75). We also found a significant difference in striatal (F1,20 = 6.00, P = .02) and ACC (F1,19 = 4.75, P = .04) Glx levels between groups.ConclusionsThese results provide evidence of a regionally specific relationship between H3Rs and glutamate levels, which builds on existing preclinical literature. Our findings add to a growing literature indicating H3Rs may be a promising treatment target in schizophrenia, particularly for cognitive impairment, which has been associated with altered glutamate signaling.

01 Oct 2023·Journal of Psychopharmacology

The histamine system and cognitive function: An in vivo H3 receptor PET imaging study in healthy volunteers and patients with schizophrenia

Article

Author: Veronese, Mattia ; Onwordi, Ellis Chika ; Arumuham, Atheeshaan ; Rabiner, Eugenii A ; Howes, Oliver D ; Nour, Matthew M

Background: The histamine-3 receptor (H3R) is an auto- and heteroreceptor that inhibits the release of histamine and other neurotransmitters. Post-mortem evidence has found altered H3R expression in patients with psychotic disorders, which may underlie cognitive impairment associated with schizophrenia (CIAS). Aims: We used positron emission tomography (PET) imaging to compare brain uptake of an H3R selective tracer between patients with schizophrenia and matched controls (healthy individuals). Regions of interest included the dorsolateral prefrontal cortex (DLPFC) and striatum. We explored correlations between tracer uptake and symptoms, including cognitive domains. Methods: A total of 12 patients and 12 matched controls were recruited to the study and were assessed with psychiatric and cognitive rating scales. They received a PET scan using the H3R-specific radioligand [11C]MK-8278 to determine H3R availability. Results: There was no statistically significant difference in tracer uptake between patients and controls in the DLPFC ( t19 = 0.79, p = 0.44) or striatum (t21 = 1.18, p = 0.25). An exploratory analysis found evidence for lower volume of distribution in the left cuneus (pFWE-corrected = 0.01). DLPFC tracer uptake was strongly correlated with cognition in controls (trail making test (TMT) A: r = 0.77, p = 0.006; TMT B: rho = 0.74, p = 0.01), but not in patients (TMT A: r = −0.18, p = 0.62; TMT B: rho = −0.06, p = 0.81). Conclusions: These findings indicate H3R in the DLPFC might play a role in executive function and this is disrupted in schizophrenia in the absence of major alterations in H3R availability as assessed using a selective radiotracer for H3R. This provides further evidence for the role of H3R in CIAS.

01 Jan 2014·Journal of Nuclear MedicineQ1 · MEDICINE

¹¹C-MK-8278 PET as a Tool for Pharmacodynamic Brain Occupancy of Histamine 3 Receptor Inverse Agonists

Q1 · MEDICINE

Article

Author: de Hoon, Jan ; Han, Lingling ; Iannone, Robert ; Van Laere, Koenraad J. ; Koole, Michel ; Mozley, David P. ; Cerchio, Kristine ; Bormans, Guy ; Van Hecken, Anne ; Plalcza, John ; Renger, John ; Hamill, Terence G. ; Burns, Donald H. ; Hargreaves, Richard J. ; Sanabria-Bohrquez, Sandra M. ; Depre, Marleen ; De Lepeleire, Inge

The histamine 3 (H3) receptor is a presynaptic autoreceptor in the central nervous system that regulates the synthesis and release of histamine and modulates the release of other major neurotransmitters. H3 receptor inverse agonists (IAs) may be efficacious in the treatment of various central nervous system disorders, including excessive daytime sleepiness, attention deficit hyperactivity disorder, Alzheimer disease, ethanol addiction, and obesity.METHODSUsing PET and a novel high-affinity and selective radioligand (11)C-MK-8278, we studied the tracer biodistribution, quantification, and brain H3 receptor occupancy (RO) of MK-0249 and MK-3134, 2 potential IA drugs targeting cerebral H3 receptors, in 6 healthy male subjects (age, 19-40 y). The relationship among H3 IA dose, time on target, and peripheral pharmacokinetics was further investigated in 15 healthy male volunteers (age, 18-40 y) with up to 3 PET scans and 3 subjects per dose level.RESULTSThe mean effective dose for (11)C-MK-8278 was 5.4 ± 1.1 μSv/MBq. Human brain kinetics showed rapid high uptake and fast washout. Binding potential values can be assessed using the pons as a reference region, with a test-retest repeatability of 7%. Drug RO data showed low interindividual variability per dose (mean RO SD, 2.1%), and a targeted 90% RO can be reached for both IAs at clinically feasible doses.CONCLUSION(11)C-MK-8278 is a useful novel PET radioligand for determination of human cerebral H3 receptor binding and allows highly reproducible in vivo brain occupancy of H3-targeting drugs, hereby enabling the evaluation of novel compounds in early development to select doses and schedules.

100 Deals associated with [11C]MK-8278

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Indication	Highest Phase	Country/Location	Organization	Date
Schizophrenia	Phase 1	United Kingdom	Imperial College London	19 Feb 2024
Schizophrenia	Phase 1	United Kingdom	Lundbeck Pharmaceuticals Ltd.	19 Feb 2024
Schizophrenia	Phase 1	United Kingdom	King's College London	19 Feb 2024
Nervous System Diseases	Preclinical	Belgium	UZ Leuven	01 Jan 2014

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