Identification and In Vitro and In Vivo Characterization of KAC-50.1 as a Potential α-Synuclein PET Radioligand.

The accumulation of aggregated α-synuclein (α-syn) is a pathological hallmark of Parkinson's disease (PD) and other synucleinopathies. Here within, we report the in vitro characterization targeting site 2 of α-syn fibrils and in vivo evaluation of NHPs of KAC-50.1 as a potential α-syn positron emission tomography (PET) radioligand.

Ligand bias and inverse agonism on 5-HT receptor-mediated modulation of G protein activity in post-mortem human brain.

Background And Purpose: Whereas biased agonism on the 5-HT receptor has been ascribed to hallucinogenic properties of psychedelics, no information about biased inverse agonism on this receptor is available. In schizophrenia, increased 5-HT receptor constitutive activity has been suggested, highlighting the therapeutic relevance of inverse agonism. This study characterized the modulation of G protein activity promoted by different drugs, commonly considered as 5-HT receptor antagonists, in post-mortem human brain cortex.

Effect of antipsychotic drugs on group II metabotropic glutamate receptor expression and epigenetic control in postmortem brains of schizophrenia subjects.

Antipsychotic-induced low availability of group II metabotropic glutamate receptors (including mGluR and mGluR) in brains of schizophrenia patients may explain the limited efficacy of mGluR ligands in clinical trials. Studies evaluating mGluR levels in well-designed, large postmortem brain cohorts are needed to address this issue. Postmortem samples from the dorsolateral prefrontal cortex of 96 schizophrenia subjects and matched controls were collected.

The α-synuclein PET tracer [18F] ACI-12589 distinguishes multiple system atrophy from other neurodegenerative diseases.

A positron emission tomography (PET) tracer detecting α-synuclein pathology will improve the diagnosis, and ultimately the treatment of α-synuclein-related diseases. Here we show that the PET ligand, [F]ACI-12589, displays good in vitro affinity and specificity for pathological α-synuclein in tissues from patients with different α-synuclein-related disorders including Parkinson's disease (PD) and Multiple-System Atrophy (MSA) using autoradiography and radiobinding techniques. In the initial clinical evaluation we include 23 participants with α-synuclein related disorders, 11 with other neurodegenerative disorders and eight controls.

Electroactive Materials Surface Charge Impacts Neuron Viability and Maturation in 2D Cultures.

Since neurons were first cultured outside a living organism more than a century ago, a number of experimental techniques for their maintenance have been developed. These methods have been further adapted and refined to study specific neurobiological processes under controlled experimental conditions. Despite their limitations, the simplicity and visual accessibility of 2D cultures have enabled the study of the effects of trophic factors, adhesion molecules, and biophysical stimuli on neuron function and morphology.

Synthesis and Preclinical Evaluation of [C]AZ11895530 for PET Imaging of the Serotonin 1A Receptor.

The serotonin 1A (5-HT) receptor is a G-protein-coupled receptor implicated in the pathophysiology of several neuropsychiatric and neurodegenerative disorders. We here report the preparation of two candidate 5-HT radioligands, [C]AZ11132132 ([C]) and [C]AZ11895530 ([C]), and their subsequent evaluation using autoradiography and using positron emission tomography (PET). Compounds and were radiolabeled at high radiochemical purity (>99%) and high molar activity (>38 GBq/μmol) by heteroatom methylation with [C]methyl iodide.

A Novel Dynamic Human In Vitro Model for Studying the Blood-Brain Barrier.

Constructing a reliable in vitro blood-brain barrier (BBB) model using human primary cells has been considered a major challenge during the past decades. These systems could provide valuable information regarding the effect of therapeutic compounds on different BBB cell types (endothelial cells, astrocytes, pericytes) and their ability to cross the barrier in order to reach the brain. Several attempts have been made to develop in vitro BBB models, but these studies mainly used rat, bovine, and porcine cells rather than human primary cells.

Development of C-Labeled ASEM Analogues for the Detection of Neuronal Nicotinic Acetylcholine Receptors (α7-nAChR).

The homo-pentameric alpha 7 receptor is one of the major types of neuronal nicotinic acetylcholine receptors (α7-nAChRs) related to cognition, memory formation, and attention processing. The mapping of α7-nAChRs by PET pulls a lot of attention to realize the mechanism and development of CNS diseases such as AD, PD, and schizophrenia. Several PET radioligands have been explored for the detection of the α7-nAChR.

Differential brain ADRA2A and ADRA2C gene expression and epigenetic regulation in schizophrenia. Effect of antipsychotic drug treatment.

Postsynaptic α-adrenoceptor density is enhanced in the dorsolateral prefrontal cortex (DLPFC) of antipsychotic-treated schizophrenia subjects. This alteration might be due to transcriptional activation, and could be regulated by epigenetic mechanisms such as histone posttranslational modifications (PTMs). The aim of this study was to evaluate ADRA2A and ADRA2C gene expression (codifying for α-adrenoceptor subtypes), and permissive and repressive histone PTMs at gene promoter regions in the DLPFC of subjects with schizophrenia and matched controls (n = 24 pairs).

Functional approaches to the study of G-protein-coupled receptors in postmortem brain tissue: [S]GTPγS binding assays combined with immunoprecipitation.

G-protein-coupled receptors (GPCRs) have an enormous biochemical importance as they bind to diverse extracellular ligands and regulate a variety of physiological and pathological responses. G-protein activation measures the functional consequence of receptor occupancy at one of the earliest receptor-mediated events. Receptor coupling to G-proteins promotes the GDP/GTP exchange on Gα subunits.

Di-aryl guanidinium derivatives: Towards improved α2-Adrenergic affinity and antagonist activity.

Compounds with excellent receptor engagement displaying α-AR antagonist activity are useful not only for therapeutic purposes (e.g. antidepressants), but also to help in the crystallization of this particular GPCR.

Identification and in vitro characterization of C05-01, a PBB3 derivative with improved affinity for alpha-synuclein.

The neuropathological hallmark of Parkinsońs disease, multiple system atrophy and dementia with Lewy bodies is the accumulation of α-synuclein. The development of an imaging biomarker for α-synuclein is an unmet need. To date, no selective α-synuclein imaging agent has been identified, though initial studies suggest that the tau tracer [C]PBB3 displays some degree of binding to α-synuclein.

Imaging Mutant Huntingtin Aggregates: Development of a Potential PET Ligand.

Mutant huntingtin (mHTT) protein carrying the elongated N-terminal polyglutamine (polyQ) tract misfolds and forms protein aggregates characteristic of Huntington's disease (HD) pathology. A high-affinity ligand specific for mHTT aggregates could serve as a positron emission tomography (PET) imaging biomarker for HD therapeutic development and disease progression. To identify such compounds with binding affinity for polyQ aggregates, we embarked on systematic structural activity studies; lead optimization of aggregate-binding affinity, unbound fractions in brain, permeability, and low efflux culminated in the discovery of compound , which exhibited target engagement in autoradiography (ARG) studies in brain slices from HD mouse models and postmortem human HD samples.

Serotonin 5-HT receptor expression and functionality in postmortem frontal cortex of subjects with schizophrenia: Selective biased agonism via G-proteins.

Serotonin 5-HT receptors (5-HTRs) have been implicated in schizophrenia. However, postmortem studies on 5-HTRs expression and functionality in schizophrenia are scarce. The 5-HTR mRNA and immunoreactive protein expression were evaluated in postmortem tissue from dorsolateral prefrontal cortex (DLPFC) of antipsychotic-free (n = 18) and antipsychotic-treated (n = 9) subjects with schizophrenia, and matched controls (n = 27).

Synthesis, H-labelling and in vitro evaluation of a substituted dipiperidine alcohol as a potential ligand for chemokine receptor 2.

The immune system is implicated in the pathology of neurodegenerative disorders. The C-C chemokine receptor 2 (CCR2) is one of the key targets involved in the activation of the immune system. A suitable ligand for CCR2 could be a useful tool to study immune activation in central nervous system (CNS) disorders.

A novel dynamic multicellular co-culture system for studying individual blood-brain barrier cell types in brain diseases and cytotoxicity testing.

Blood brain barrier (BBB) cells play key roles in the physiology and pathology of the central nervous system (CNS). BBB dysfunction is implicated in many neurodegenerative diseases, including Alzheimer's disease (AD). The BBB consists of capillary endothelial cells, pericytes encircling the endothelium and surrounding astrocytes extending their processes towards it.

Substituted conformationally restricted guanidine derivatives: Probing the α2-adrenoceptors' binding pocket.

In this paper we report the design, synthesis and pharmacological evaluation of new N-substituted 2-amino-1,4-dihydroquinazolines, 2-amino-1,4-dihydropyridopyrimidines and 2-amino-4,5-dihydro-1,3-benzodiazepines as α2-adrenoceptors ligands. Computational studies show that the proposed substitutions and guanidine-containing ring size will probe an extensive area of the active site. Preparation of these molecules involved novel routes than those previously utilised in our laboratory for the preparation of the acyclic aryl-guanidine counterparts.

Allosteric signaling through an mGlu2 and 5-HT2A heteromeric receptor complex and its potential contribution to schizophrenia.

Heterotrimeric guanine nucleotide-binding protein (G protein)-coupled receptors (GPCRs) can form multiprotein complexes (heteromers), which can alter the pharmacology and functions of the constituent receptors. Previous findings demonstrated that the Gq/11-coupled serotonin 5-HT2A receptor and the Gi/o-coupled metabotropic glutamate 2 (mGlu2) receptor-GPCRs that are involved in signaling alterations associated with psychosis-assemble into a heteromeric complex in the mammalian brain. In single-cell experiments with various mutant versions of the mGlu2 receptor, we showed that stimulation of cells expressing mGlu2-5-HT2A heteromers with an mGlu2 agonist led to activation of Gq/11 proteins by the 5-HT2A receptors.

Evaluation of 5-HT2A and mGlu2/3 receptors in postmortem prefrontal cortex of subjects with major depressive disorder: effect of antidepressant treatment.

Several studies have demonstrated alterations in serotonin 5-HT2A (5-HT2AR) and glutamate metabotropic mGlu2 (mGlu2R) receptors in depression, but never in the same sample population. Recently it has been shown that both receptors form a functional receptor heterocomplex that is altered in schizophrenia. The present study evaluates the gene expression and protein density of 5-HT2AR and mGlu2/3R in the postmortem prefrontal cortex of subjects with major depressive disorder (n = 14) compared with control subjects (n = 14) in a paired design.

Plasma antioxidant capacity is reduced in Asperger syndrome.

Recent evidence suggests that children with autism have impaired detoxification capacity and may suffer from chronic oxidative stress. To our knowledge, there has been no study focusing on oxidative metabolism specifically in Asperger syndrome (a milder form of autism) or comparing this metabolism with other psychiatric disorders. In this study, total antioxidant status (TAOS), non-enzymatic (glutathione and homocysteine) and enzymatic (catalase, superoxide dismutase, and glutathione peroxidase) antioxidants, and lipid peroxidation were measured in plasma or erythrocyte lysates in a group of adolescent patients with Asperger syndrome, a group of adolescents with a first episode of psychosis, and a group of healthy controls at baseline and at 8-12 weeks.