AI-based identification of therapeutic agents targeting GPCRs: introducing ligand type classifiers and systems biology.

Identifying ligands targeting G protein coupled receptors (GPCRs) with novel chemotypes other than the physiological ligands is a challenge for screening campaigns. Here we present an approach that identifies novel chemotype ligands by combining structural data with a random forest agonist/antagonist classifier and a signal-transduction kinetic model. As a test case, we apply this approach to identify novel antagonists of the human adenosine transmembrane receptor type 2A, an attractive target against Parkinson's disease and cancer.

Reversal of Tau-Dependent Cognitive Decay by Blocking Adenosine A1 Receptors: Comparison of Transgenic Mouse Models with Different Levels of Tauopathy.

The accumulation of tau is a hallmark of several neurodegenerative diseases and is associated with neuronal hypoactivity and presynaptic dysfunction. Oral administration of the adenosine A receptor antagonist rolofylline (KW-3902) has previously been shown to reverse spatial memory deficits and to normalize the basic synaptic transmission in a mouse line expressing full-length pro-aggregant tau (Tau) at low levels, with late onset of disease. However, the efficacy of treatment remained to be explored for cases of more aggressive tauopathy.

Mutated Isocitrate Dehydrogenase (mIDH) as Target for PET Imaging in Gliomas.

Gliomas are the most common primary brain tumors in adults. A diffuse infiltrative growth pattern and high resistance to therapy make them largely incurable, but there are significant differences in the prognosis of patients with different subtypes of glioma. Mutations in isocitrate dehydrogenase (IDH) have been recognized as an important biomarker for glioma classification and a potential therapeutic target.

Cannabidiol enhances cerebral glucose utilization and ameliorates psychopathology and cognition: A case report in a clinically high-risk mental state.

Adolescent individuals often present with subtle, sub-threshold psychiatric syndromes that fluctuate or persist for years. These symptoms have been classified as Clinically High-Risk mental states (CHR), negatively affecting these individuals' psychosocial development and integration by reducing performance and affecting interpersonal relations. The pathophysiological underpinnings have not been studied in detail, contributing to the current lack of appropriate intervention strategies.

Evaluation of the F-labeled analog of the therapeutic all-D-enantiomeric peptide RD2 for amyloid β imaging.

Positron emission tomography (PET) imaging with radiotracers that bind to fibrillary amyloid β (Aβ) deposits is an important tool for the diagnosis of Alzheimer's disease (AD) and for the recruitment of patients into clinical trials. However, it has been suggested that rather than the fibrillary Aβ deposits, it is smaller, soluble Aβ aggregates that exert a neurotoxic effect and trigger AD pathogenesis. The aim of the current study is to develop a PET probe that is capable of detecting small aggregates and soluble Aβ oligomers for improved diagnosis and therapy monitoring.

Elevated concentrations of macrophage migration inhibitory factor in serum and cerebral microdialysate are associated with delayed cerebral ischemia after aneurysmal subarachnoid hemorrhage.

Objective: Inflammation is increasingly recognized to be involved in the pathophysiology of aneurysmal subarachnoid hemorrhage (aSAH) and may increase the susceptibility to delayed cerebral ischemia (DCI). Macrophage migration inhibitory factor (MIF) has been shown to be elevated in serum and cerebrospinal fluid (CSF) after aSAH. Here, we determined MIF levels in serum, CSF and cerebral microdialysate (MD) at different time-points after aSAH and evaluated their clinical implications.

Next Generation Copper Mediators for the Efficient Production of F-Labeled Aromatics.

Cu-mediated radiofluorination is a versatile tool for the preparation of F-labeled (hetero)aromatics. In this work, we systematically evaluated a series of complexes and identified several generally applicable mediators for highly efficient radiofluorination of aryl boronic and stannyl substrates. Utilization of these mediators in nBuOH/DMI or DMI significantly improved F-labeling yields despite use of lower precursor amounts.

Transcranial-Direct-Current-Stimulation Accelerates Motor Recovery After Cortical Infarction in Mice: The Interplay of Structural Cellular Responses and Functional Recovery.

Background: Transcranial direct current stimulation (tDCS) promotes recovery after stroke in humans. The underlying mechanisms, however, remain to be elucidated. Animal models suggest tDCS effects on neuroinflammation, stem cell proliferation, neurogenesis, and neural plasticity.

Two Decades of Brain Tumour Imaging with O-(2-[F]fluoroethyl)-L-tyrosine PET: The Forschungszentrum Jülich Experience.

O-(2-[F]fluoroethyl)-L-tyrosine (FET) is a widely used amino acid tracer for positron emission tomography (PET) imaging of brain tumours. This retrospective study and survey aimed to analyse our extensive database regarding the development of FET PET investigations, indications, and the referring physicians' rating concerning the role of FET PET in the clinical decision-making process. Between 2006 and 2019, we performed 6534 FET PET scans on 3928 different patients against a backdrop of growing demand for FET PET.

Simultaneous Assessment of Serum Levels and Pharmacologic Effects of Cannabinoids on Endocannabinoids and -Acylethanolamines by Liquid Chromatography-Tandem Mass Spectrometry.

The primary compounds of , delta-9-tetrahydrocannabinol (Δ-THC) and cannabidiol (CBD), inflict a direct influence on the endocannabinoid system-a complex lipid signaling network with a central role in neurotransmission and control of inhibitory and excitatory synapses. These phytocannabinoids often interact with endogenously produced endocannabinoids (eCBs), as well as their structurally related -acylethanolamines (NAEs), to drive neurobiological, nociceptive, and inflammatory responses. Identifying and quantifying changes in these lipid neuromodulators can be challenging owing to their low abundance in complex matrices.

Convenient PET-tracer production via SuFEx F-fluorination of nanomolar precursor amounts.

Recently, a protocol for radiolabeling of aryl fluorosulfates ("SuFEx click radiolabeling") using ultrafast F/F isotopic exchange has been reported. Although promising, the original procedure turned out to be rather inefficient. However, systematic optimization of the reaction parameters allowed for development of a robust method for SuFEx radiolabeling which obviates the need for azeotropic drying, base addition and HPLC purification.

Assessment of the In Vivo Relationship Between Cerebral Hypometabolism, Tau Deposition, TSPO Expression, and Synaptic Density in a Tauopathy Mouse Model: a Multi-tracer PET Study.

Cerebral glucose hypometabolism is a typical hallmark of Alzheimer's disease (AD), usually associated with ongoing neurodegeneration and neuronal dysfunction. However, underlying pathological processes are not fully understood and reproducibility in animal models is not well established. The aim of the present study was to investigate the regional interrelation of glucose hypometabolism measured by [F]FDG positron emission tomography (PET) with various molecular targets of AD pathophysiology using the PET tracers [F]PI-2620 for tau deposition, [F]DPA-714 for TSPO expression associated with neuroinflammation, and [F]UCB-H for synaptic density in a transgenic tauopathy mouse model.

Imaging of cerebral tryptophan metabolism using 7-[F]FTrp-PET in a unilateral Parkinsonian rat model.

Degradation products of the essential amino acid tryptophan (Trp) are important signaling molecules in the mammalian brain. Trp is metabolized either through the kynurenine pathway or enters serotonin and melatonin syntheses. The aim of the present work was to examine the potential of the novel PET tracer 7-[F]fluorotryptophan ([F]FTrp) to visualize all three pathways in a unilateral 6-OHDA rat model.

Evaluation of 3-l- and 3-d-[F]Fluorophenylalanines as PET Tracers for Tumor Imaging.

Purpose: The preclinical evaluation of 3-l- and 3-d-[F]FPhe in comparison to [F]FET, an established tracer for tumor imaging.

Methods: In vitro studies were conducted with MCF-7, PC-3, and U87 MG human tumor cell lines. In vivo µPET studies were conducted in healthy rats with/without the inhibition of peripheral aromatic l-amino acid decarboxylase by benserazide pretreatment ( = 3 each), in mice bearing subcutaneous MCF-7 or PC-3 tumor xenografts ( = 10), and in rats bearing orthotopic U87 MG tumor xenografts ( = 14).

Psilocybin targets a common molecular mechanism for cognitive impairment and increased craving in alcoholism.

Alcohol-dependent patients commonly show impairments in executive functions that facilitate craving and can lead to relapse. However, the molecular mechanisms leading to executive dysfunction in alcoholism are poorly understood, and new effective pharmacological treatments are desired. Here, using a bidirectional neuromodulation approach, we demonstrate a causal link between reduced prefrontal mGluR2 function and both impaired executive control and alcohol craving.

Drug Penetration into the Central Nervous System: Pharmacokinetic Concepts and In Vitro Model Systems.

Delivery of most drugs into the central nervous system (CNS) is restricted by the blood-brain barrier (BBB), which remains a significant bottleneck for development of novel CNS-targeted therapeutics or molecular tracers for neuroimaging. Consistent failure to reliably predict drug efficiency based on single measures for the rate or extent of brain penetration has led to the emergence of a more holistic framework that integrates data from various in vivo, in situ and in vitro assays to obtain a comprehensive description of drug delivery to and distribution within the brain. Coupled with ongoing development of suitable in vitro BBB models, this integrated approach promises to reduce the incidence of costly late-stage failures in CNS drug development, and could help to overcome some of the technical, economic and ethical issues associated with in vivo studies in animal models.

Production of 6-l-[F]Fluoro--tyrosine in an Automated Synthesis Module for C-Labeling.

6-l-[F]Fluoro--tyrosine (6-l-[F]FMT) represents a valuable alternative to 6-l-[F]FDOPA which is conventionally used for the diagnosis and staging of Parkinson's disease. However, clinical applications of 6-l-[F]FMT have been limited by the paucity of practical production methods for its automated production. Herein we describe the practical preparation of 6-l-[F]FMT using alcohol-enhanced Cu-mediated radiofluorination of Bpin-substituted chiral Ni(II) complex in the presence of non-basic BuONTf using a volatile PrOH/MeCN mixture as reaction solvent.

[F]ALX5406: A Brain-Penetrating Prodrug for GlyT1-Specific PET Imaging.

Selective inhibition of glycine transporter 1 (GlyT1) has emerged as a potential approach to alleviate -methyl-d-aspartate receptor (NMDAR) hypofunction in patients with schizophrenia and cognitive decline. ALX5407 is a potent and selective inhibitor of GlyT1 derived from the metabolic intermediate sarcosine (-methylglycine) that showed antipsychotic potential in a number of animal models. Whereas clinical application of ALX5407 is limited by adverse effects on motor performance and respiratory function, a suitably radiolabeled drug could represent a promising PET tracer for the visualization of GlyT1 in the brain.

Changes in endogenous daytime melatonin levels after aneurysmal subarachnoid hemorrhage - Preliminary findings from an observational cohort study.

Introduction: Aneurysmal subarachnoid hemorrhage (aSAH) is associated with early and delayed brain injury due to several underlying and interrelated processes, which include inflammation, oxidative stress, endothelial, and neuronal apoptosis. Treatment with melatonin, a cytoprotective neurohormone with anti-inflammatory, anti-oxidant and anti-apoptotic effects, has been shown to attenuate early brain injury (EBI) and to prevent delayed cerebral vasospasm in experimental aSAH models. Less is known about the role of endogenous melatonin for aSAH outcome and how its production is altered by the pathophysiological cascades initiated during EBI.

Translational Development of a Zr-89-Labeled Inhibitor of Prostate-specific Membrane Antigen for PET Imaging in Prostate Cancer.

Purpose: We present here a Zr-89-labeled inhibitor of prostate-specific membrane antigen (PSMA) as a complement to the already established F-18- or Ga-68-ligands.

Procedures: The precursor PSMA-DFO (ABX) was used for Zr-89-labeling. This is not an antibody, but a peptide analogue of the precursor for the production of [Lu]Lu-PSMA-617.

An Zr-Labeled PSMA Tracer for PET/CT Imaging of Prostate Cancer Patients.

The short half-life of existing prostate-specific membrane antigen (PSMA) tracers limits their time for internalization into tumor cells after injection, which is an essential prerequisite for robust detection of tumor lesions with low PSMA expression on PET/CT scans. Because of its longer half-life, the Zr-labeled ligand Zr-PSMA-DFO allows acquisition of PET scans up to 6 d after injection, thereby overcoming the above limitation. We investigated whether Zr-PSMA-DFO allowed more sensitive detection of weak PSMA-positive prostate cancer lesions.

Radiosynthesis and Biological Evaluation of [F]R91150, a Selective 5-HT Receptor Antagonist for PET-Imaging.

Serotonergic 5-HT receptors in cortical and forebrain regions are an important substrate for the neuromodulatory actions of serotonin in the brain. They have been implicated in the etiology of many neuropsychiatric disorders and serve as a target for antipsychotic, antidepressant, and anxiolytic drugs. Positron emission tomography imaging using suitable radioligands can be applied for quantification of receptor densities and receptor occupancy for therapy evaluation.

Feasibility of short imaging protocols for [F]PI-2620 tau-PET in progressive supranuclear palsy.

Purpose: Dynamic 60-min positron emission tomography (PET) imaging with the novel tau radiotracer [F]PI-2620 facilitated accurate discrimination between patients with progressive supranuclear palsy (PSP) and healthy controls (HCs). This study investigated if truncated acquisition and static time windows can be used for [F]PI-2620 tau-PET imaging of PSP.

Methods: Thirty-seven patients with PSP Richardson syndrome (PSP-RS) were evaluated together with ten HCs.

Retinal Vessel Responses to Flicker Stimulation Are Impaired in Ca 2.3-Deficient Mice-An Evaluation Using Retinal Vessel Analysis (RVA).

Metabolic demand increases with neuronal activity and adequate energy supply is ensured by neurovascular coupling (NVC). Impairments of NVC have been reported in the context of several diseases and may correlate with disease severity and outcome. Voltage-gated Ca-channels (VGCCs) are involved in the regulation of vasomotor tone.