n-(2-methoxybenzyl)-n-(4-phenoxypyridin-3-yl)acetamide and Schizophrenia

Patients with schizophrenia show whole brain and cortical gray matter (GM) volume reductions which are progressive early in their illness. Microglia, the resident immune cells in the CNS, phagocytose neurons and synapses. Some post mortem and in vivo studies in schizophrenia show evidence for elevated microglial activation compared to matched controls. However, it is currently unclear how these results relate to changes in cortical structure.. Fourteen patients with schizophrenia and 14 ultra high risk for psychosis (UHR) subjects alongside two groups of age and genotype matched healthy controls received [. These findings suggest that microglial activity is related to the altered cortical volume seen in schizophrenia. Longitudinal investigations are required to determine whether microglial activation leads to cortical gray matter loss.

Topics: Acetamides; Adolescent; Adult; Brain; Carbon Radioisotopes; Female; Gray Matter; Humans; Magnetic Resonance Imaging; Male; Positron-Emission Tomography; Psychotic Disorders; Pyridines; Receptors, GABA; Schizophrenia; Young Adult

Several lines of evidence are indicative of a role for immune activation in the pathophysiology of schizophrenia. Nevertheless, studies using positron emission tomography (PET) and radioligands for the translocator protein (TSPO), a marker for glial activation, have yielded inconsistent results. Whereas early studies using a radioligand with low signal-to-noise in small samples showed increases in patients, more recent studies with improved methodology have shown no differences or trend-level decreases. Importantly, all patients investigated thus far have been on antipsychotic medication, and as these compounds may dampen immune cell activity, this factor limits the conclusions that can be drawn. Here, we examined 16 drug-naive, first-episode psychosis patients and 16 healthy controls using PET and the TSPO radioligand [

Topics: Acetamides; Adult; Biomarkers; Brain; Carbon Radioisotopes; Case-Control Studies; Female; Gray Matter; Humans; Male; Microglia; Neuroglia; Positron-Emission Tomography; Psychotic Disorders; Pyridines; Radioligand Assay; Radiopharmaceuticals; Receptors, GABA; Schizophrenia

Schnurri-2 (Shn-2) knockout (KO) mice have been proposed as a preclinical neuroinflammatory schizophrenia model. We used behavioral studies and imaging markers that can be readily translated to human populations to explore brain effects of inflammation. Shn-2 KO mice and their littermate control mice were imaged with two novel PET ligands; an inflammation marker [(11)C]PBR28 and the mGluR5 ligand [(18)F]FPEB. Locomotor activity was measured using open field exploration with saline, methamphetamine or amphetamine challenge. A significantly increased accumulation of [(11)C]PBR28 was found in the cortex, striatum, hippocampus and olfactory bulb of Shn-2 KO mice. Increased mGluR5 binding was also observed in the cortex and hippocampus of the Shn-2 KO mice. Open field locomotor testing revealed a large increase in novelty-induced hyperlocomotion in Shn-2 KO mice with abnormal (decreased) responses to either methamphetamine or amphetamine. These data provide additional support to demonstrate that the Shn-2 KO mouse model exhibits several behavioral and pathological markers resembling human schizophrenia making it an attractive translational model for the disease.

Topics: Acetamides; Amphetamine; Animals; Brain; Carbon Radioisotopes; Central Nervous System Stimulants; Cerebral Cortex; Disease Models, Animal; DNA-Binding Proteins; Exploratory Behavior; Fluorine Radioisotopes; Hippocampus; Inflammation; Methamphetamine; Mice, Knockout; Motor Activity; Nitriles; Positron-Emission Tomography; Pyridines; Radiopharmaceuticals; Receptor, Metabotropic Glutamate 5; Schizophrenia

Second-generation radioligands for translocator protein (TSPO), an inflammation marker, are confounded by the codominant rs6971 polymorphism that affects binding affinity. The resulting three groups are homozygous for high-affinity state (HH), homozygous for low-affinity state (LL), or heterozygous (HL). We tested if in vitro binding to leukocytes distinguished TSPO genotypes and if genotype could affect clinical studies using the TSPO radioligand [(11)C]PBR28. In vitro binding to leukocytes and [(11)C]PBR28 brain imaging were performed in 27 human subjects with known TSPO genotype. Specific [(3)H]PBR28 binding was measured in prefrontal cortex of 45 schizophrenia patients and 47 controls. Leukocyte binding to PBR28 predicted genotype in all subjects. Brain uptake was ∼40% higher in HH than HL subjects. Specific [(3)H]PBR28 binding in LL controls was negligible, while HH controls had ∼80% higher binding than HL controls. After excluding LL subjects, specific binding was 16% greater in schizophrenia patients than controls. This difference was insignificant by itself (P=0.085), but was significant after correcting for TSPO genotype (P=0.011). Our results show that TSPO genotype influences PBR28 binding in vitro and in vivo. Correcting for this genotype increased statistical power in our postmortem study and is recommended for in vivo positron emission tomography studies.

Topics: Acetamides; Alzheimer Disease; Biomarkers; Brain; Carbon Radioisotopes; Case-Control Studies; Heterozygote; Homozygote; Humans; In Vitro Techniques; Leukocytes; Polymorphism, Single Nucleotide; Positron-Emission Tomography; Protein Binding; Pyridines; Radioligand Assay; Radiopharmaceuticals; Receptors, GABA; Schizophrenia; Tritium