Imidazoline-I2 PET Tracers in Neuroimaging.

Targeting neuroinflammation, and in particular, microglial activation and astrocytosis, is a current area of the focus of new treatment interventions for a number of neurodegenerative disorders. Probing the roles of microglia and astrocytes in human disease requires the development of useful tools, such as PET imaging tools that are specific for the cell type(s) of interest. This review concentrates on the recent advances in the development of Imidazoline binding site (IBS) PET tracers, which are purported to target astrocytes, and hence could represent key clinical imaging tools for targeting astrocytes in neurodegenerative disease.

Functional Alternatives to Alcohol.

The consumption of alcohol is associated with well-known health harms and many governments worldwide are actively engaged in devising approaches to reduce them. To this end, a common proposed strategy aims at reducing alcohol consumption. This approach has led to the development of non-alcoholic drinks, which have been especially welcome by younger, wealthier, health-conscious consumers, who have been turning away from alcohol to look toward alternatives.

Astrogliosis in aging and Parkinson's disease dementia: a new clinical study with C-BU99008 PET.

The role of astrogliosis in the pathology of brain aging and neurodegenerative diseases has recently drawn great attention. Imidazoline-2 binding sites represent a possible target to map the distribution of reactive astrocytes. In this study, we use C-BU99008, an imidazoline-2 binding sites-specific PET radioligand, to image reactive astrocytes in healthy controls and patients with established Parkinson's disease dementia.

Relationship between astrocyte reactivity, using novel C-BU99008 PET, and glucose metabolism, grey matter volume and amyloid load in cognitively impaired individuals.

Post mortem neuropathology suggests that astrocyte reactivity may play a significant role in neurodegeneration in Alzheimer's disease. We explored this in vivo using multimodal PET and MRI imaging. Twenty subjects (11 older, cognitively impaired patients and 9 age-matched healthy controls) underwent brain scanning using the novel reactive astrocyte PET tracer C-BU99008, F-FDG and F-florbetaben PET, and T1-weighted MRI.

Impact of COVID-19 restrictions on alcohol consumption behaviours.

Background: We aimed to evaluate how coronavirus (COVID-19) restrictions had altered individual's drinking behaviours, including consumption, hangover experiences, and motivations to drink, and changing levels of depression and anxiety.

Method: We conducted an online cross-sectional self-report survey. Whole group analysis compared pre- versus post-COVID restrictions.

Astrocyte reactivity with late-onset cognitive impairment assessed in vivo using C-BU99008 PET and its relationship with amyloid load.

C-BU99008 is a novel positron emission tomography (PET) tracer that enables selective imaging of astrocyte reactivity in vivo. To explore astrocyte reactivity associated with Alzheimer's disease, 11 older, cognitively impaired (CI) subjects and 9 age-matched healthy controls (HC) underwent 3T magnetic resonance imaging (MRI), F-florbetaben and C-BU99008 PET. The 8 amyloid (Aβ)-positive CI subjects had higher C-BU99008 uptake relative to HC across the whole brain, but particularly in frontal, temporal, medial temporal and occipital lobes.

Acute effects of MDMA on trust, cooperative behaviour and empathy: A double-blind, placebo-controlled experiment.

Background: 3,4-Methylenedioxymethamphetamine (MDMA) is being actively researched as an adjunct to psychotherapy. It may be beneficial to trust, empathy and cooperative behaviour due to its acute prosocial effects.

Aim: To test (a) the acute effects of MDMA on measures of empathy, trust and cooperative behaviour, and (b) subacute changes in mood three days after MDMA administration.

Imidazoline 2 binding sites reflecting astroglia pathology in Parkinson's disease: an in vivo11C-BU99008 PET study.

Astroglia are multifunctional cells that regulate neuroinflammation and maintain homeostasis within the brain. Astroglial α-synuclein-positive cytoplasmic accumulations have been shown post-mortem in patients with Parkinson's disease and therefore astroglia may play an important role in the initiation and progression of Parkinson's disease. Imidazoline 2 binding sites are expressed on activated astroglia in the cortex, hippocampus, basal ganglia and brainstem; therefore, by measuring imidazoline 2 binding site levels we can indirectly evaluate astrogliosis in patients with Parkinson's disease.

First evaluation of PET-based human biodistribution and radiation dosimetry of C-BU99008, a tracer for imaging the imidazoline binding site.

Background: We measured whole body distribution of C-BU99008, a new PET biomarker for non-invasive identification of the imidazoline binding site. The purpose of this phase I study was to evaluate the biodistribution and radiation dosimetry of C-BU99008 in healthy human subjects.

Methods: A single bolus injection of C-BU99008 (296 ± 10.

Evaluation of C-BU99008, a PET Ligand for the Imidazoline Binding Site in Human Brain.

The imidazoline binding site (IBS) is thought to be expressed in glia and implicated in the regulation of glial fibrillary acidic protein. A PET ligand for this target would be important for the investigation of neurodegenerative and neuroinflammatory diseases. C-BU99008 has previously been identified as a putative PET radioligand.

In vivo imaging of microglial activation by positron emission tomography with [(11)C]PBR28 in the 5XFAD model of Alzheimer's disease.

Microglial activation has been linked with deficits in neuronal function and synaptic plasticity in Alzheimer's disease (AD). The mitochondrial translocator protein (TSPO) is known to be upregulated in reactive microglia. Accurate visualization and quantification of microglial density by PET imaging using the TSPO tracer [(11)C]-R-PK11195 has been challenging due to the limitations of the ligand.

Optimising PET approaches to measuring 5-HT release in human brain.

A major goal in neuroscience is the measurement of neurotransmitters in living human brain. To date this has only been done reliably with dopamine using certain PET and SPECT radiotracers. The use of this technique has greatly advanced our understanding of dopamine and the dopaminergic system in normal and abnormal brain function.

Imaging endogenous opioid peptide release with [11C]carfentanil and [3H]diprenorphine: influence of agonist-induced internalization.

Understanding the cellular processes underpinning the changes in binding observed during positron emission tomography neurotransmitter release studies may aid translation of these methodologies to other neurotransmitter systems. We compared the sensitivities of opioid receptor radioligands, carfentanil, and diprenorphine, to amphetamine-induced endogenous opioid peptide (EOP) release and methadone administration in the rat. We also investigated whether agonist-induced internalization was involved in reductions in observed binding using subcellular fractionation and confocal microscopy.

The influence of different cellular environments on PET radioligand binding: an application to D2/3-dopamine receptor imaging.

Various D2/3 receptor PET radioligands are sensitive to endogenous dopamine release in vivo. The Occupancy Model is generally used to interpret changes in binding observed in in vivo competition binding studies; an Internalisation Hypothesis may also contribute to these changes in signal. Extension of in vivo competition imaging to other receptor systems has been relatively unsuccessful.

Evaluation of 11C-BU99008, a PET ligand for the imidazoline2 binding sites in rhesus brain.

Unlabelled: The development of a PET radioligand selective for I2-imidazoline binding sites (I2BS) would enable, for the first time, specific, measurable in vivo imaging of this target protein, along with assessment of alterations in expression patterns of this protein in disease pathophysiology.

Methods: BU99008 was identified as the most promising I2BS radioligand candidate and radiolabeled with (11)C via methylation. The in vivo binding properties of (11)C-BU99008 were assessed in rhesus monkeys to determine brain penetration, brain distribution, binding specificity and selectivity (via the use of the unlabeled blockers), and the most appropriate kinetic model for analyzing data generated with this PET radioligand.

Imaging imidazoline-I2 binding sites in porcine brain using 11C-BU99008.

Unlabelled: Changes in the density of imidazoline-I(2) binding sites have been observed in a range of neurologic disorders including Alzheimer's disease, Huntington's chorea, and glial tumor; however, the precise function of these sites remains unclear. A PET probe for I(2) binding sites would further our understanding of the target and may find application as a biomarker for early disease diagnosis. Compound BU99008 has previously been identified as a promising I(2) ligand from autoradiography studies, displaying high affinity and good selectivity toward the target.

Neural correlates of the psychedelic state as determined by fMRI studies with psilocybin.

Psychedelic drugs have a long history of use in healing ceremonies, but despite renewed interest in their therapeutic potential, we continue to know very little about how they work in the brain. Here we used psilocybin, a classic psychedelic found in magic mushrooms, and a task-free functional MRI (fMRI) protocol designed to capture the transition from normal waking consciousness to the psychedelic state. Arterial spin labeling perfusion and blood-oxygen level-dependent (BOLD) fMRI were used to map cerebral blood flow and changes in venous oxygenation before and after intravenous infusions of placebo and psilocybin.

Evaluation and initial in vitro and ex vivo characterization of the potential positron emission tomography ligand, BU99008 (2-(4,5-dihydro-1H-imidazol-2-yl)-1- methyl-1H-indole), for the imidazoline₂ binding site.

The density of the Imidazoline₂ binding site (I₂BS) has been shown to change in psychiatric conditions such as depression and addiction, along with neurodegenerative disorders such as Alzheimer's disease and Huntington's chorea. The presence of I₂BS on glial cells and the possibility that they may in some way regulate glial fibrillary acidic protein has led to increased interest into the role of I₂BS and I₂BS ligands in conditions characterized by marked gliosis. In addition, it has been suggested that I₂BS may be a marker for human glioblastomas.

Measuring endogenous 5-HT release by emission tomography: promises and pitfalls.

Molecular in vivo neuroimaging techniques can be used to measure regional changes in endogenous neurotransmitters, evoked by challenges that alter synaptic neurotransmitter concentration. This technique has most successfully been applied to the study of endogenous dopamine release using positron emission tomography, but has not yet been adequately extended to other neurotransmitter systems. This review focuses on how the technique has been applied to the study of the 5-hydroxytryptamine (5-HT) system.

GABAB receptors in addiction and its treatment.

The GABA(B) receptor plays an important role in the control of neurotransmitter release, and experiments using preclinical models have shown that modulation of this receptor can have profound effects on the reward process. This ability to affect the reward process has led to clinical investigations into the possibility that this could be a viable target in the treatment of addiction. Presented here is an overview of a number of studies testing this hypothesis in different drug dependencies.

The administration of psilocybin to healthy, hallucinogen-experienced volunteers in a mock-functional magnetic resonance imaging environment: a preliminary investigation of tolerability.

This study sought to assess the tolerability of intravenously administered psilocybin in healthy, hallucinogen-experienced volunteers in a mock-magnetic resonance imaging environment as a preliminary stage to a controlled investigation using functional magnetic resonance imaging to explore the effects of psilocybin on cerebral blood flow and activity. The present pilot study demonstrated that up to 2 mg of psilocybin delivered as a slow intravenous injection produces short-lived but typical drug effects that are psychologically and physiologically well tolerated. With appropriate care, this study supports the viability of functional magnetic resonance imaging work with psilocybin.

Identification of an imidazoline binding protein: creatine kinase and an imidazoline-2 binding site.

Drugs that bind to imidazoline binding proteins have major physiological actions. To date, three subtypes of such proteins, I(1), I(2) and I(3), have been proposed, although characterisations of these binding proteins are lacking. I(2) binding sites are found throughout the brain, particularly dense in the arcuate nucleus of the hypothalamus.

In vitro and in vivo effect of BU99006 (5-isothiocyanato-2-benzofuranyl-2-imidazoline) on I2 binding in relation to MAO: evidence for two distinct I2 binding sites.

BU99006 is an irreversible I(2) ligand which selectively inactivates I(2) binding sites, making it an ideal tool with which to study I(2) site mechanism. We sought to determine the effects of BU99006 on I(2) binding in relation to monoamine oxidase (MAO), and the time course of these effects. In vitro, rat brain membranes that were pre-treated with 10 microM BU99006 showed no change in MAO activity, despite suffering a significant reduction in [(3)H]2BFI binding (52.

2-(4,5-Dihydroimidazol-2-yl)benzimidazoles as highly selective imidazoline I2/adrenergic alpha2 receptor ligands.

2-(4,5-Dihydroimidazol-2-yl)benzimidazoles have been identified as selective imidazoline I2/alpha2-adrenoceptor ligands. 4-Methyl (2) and 4-chloro (4) derivatives display I2 affinity at nanomolar concentration (Ki=4.4 and 17.

Preparation, structure and affinity for imidazoline I2 receptors and alpha2-adrenoceptors of 1-[(4,5-dihydroimidazolidin-2-yl)imino]indan-2-ols.

Two enantiomers IR, 2S-(+)-cis (3a) and IS, 2R-(-)-cis (3b) of 1-[(4,5-dihydroimidazolidin-2-yl)imino]indan-2-ol were prepared by reacting 2-chloro-4,5-dihydroimidazole (1) with corresponding 1-amino-indan-2-ols (2a-b). The compounds obtained are structural analogues of PMS 952 agent containing imino bridge in place of methylene group. Compound 3a exhibited moderate almost equal activity at both imidazoline I2 receptors and alpha2-adrenoceptors, while enantiomer 3b was found to be selective for alpha2-adrenoceptors (alpha2/I2 selectivity ratio = 10.