Effects of Long-Term Cocaine Self-Administration on Kappa Opioid Receptors in Socially Housed Cynomolgus Monkeys as Assessed with PET Imaging and Neuronally Derived Exosomes.

Background: The present study utilized PET imaging to examine how long-term cocaine self-administration (SA) and time-off from cocaine affected kappa opioid receptor (KOR) availability in the brain of previously cocaine-naïve monkeys. In addition, neuronally derived small extracellular vesicles (NDEs) were measured from plasma to identify peripheral measures of KORs.

Methods: Female (n=6) and male (n=7) cynomolgus monkeys, living in stable same-sex social groups, were trained to SA intravenous cocaine.

Degradable mesoporous organosilicon nanoparticles coated with chitosan-Cu complexes with dual stimulus-response for efficient prochloraz delivery.

Accurate pesticide application enhances efficiency, reduces usage and minimizes environmental risks. This study employed amino-functionalized degradable mesoporous organosilicon nanoparticles (DMON-N) as a carrier, with chitosan (CS) acting as a capping agent. Chemical cross-linking of CS with Cu through chelation promotes the formation of Cu-CS complexes.

Plasma Glial Fibrillary Acid Protein and Phosphorated Tau 181 Association with Presynaptic Density-Dependent Tau Pathology at F-SynVesT-1 Brain PET Imaging.

Background Synaptic loss is an important factor in Alzheimer disease (AD); however, blood assays that conveniently and rapidly reflect changes in synaptic density are lacking. Purpose To correlate multiple potential synaptic blood markers with synaptic density measured using F-SynVesT-1, a fluorine 18 (F)-labeled radiotracer, brain PET and to explore the independent associations between these markers and synaptic density. Materials and Methods This prospective study included 50 cognitively unimpaired (mean age, 65.

Noninvasive quantification of [F]SynVesT-1 binding using simplified reference tissue model 2.

Purpose: [F]SynVesT-1, a positron emission tomography (PET) radiotracer for the synaptic vesicle glycoprotein 2A (SV2A), demonstrates kinetics similar to [C]UCB-J, with high brain uptake, fast kinetics fitting well with the one-tissue compartment (1TC) model, and excellent test-retest reproducibility. Challenges arise due to the similarity between k and [Formula: see text] (efflux rate of the reference region), when applying the simplified reference tissue model (SRTM) and related methods in [C]UCB-J studies to accurately estimate [Formula: see text]. This study evaluated the suitability of these methods to estimate [F]SynVesT-1 binding using centrum semiovale (CS) or cerebellum (CER) as reference regions.

Discovery of 4-(isopentyloxy)-3-nitrobenzamide derivatives as xanthine oxidase inhibitors through a non-anthraquinone exploration.

In our previous study, we reported a series of N-(9,10-anthraquinone-2-carbonyl) amino acid derivatives as novel inhibitors of xanthine oxidase (XO). Recognizing the suboptimal drug-like properties associated with the anthraquinone moiety, we embarked on a nonanthraquinone medicinal chemistry exploration in the current investigation. Through systematic structure-activity relationship (SAR) studies, we identified a series of 4-(isopentyloxy)-3-nitrobenzamide derivatives exhibiting excellent in vitro potency against XO.

Presynaptic density determined by SV2A PET is closely associated with postsynaptic metabotropic glutamate receptor 5 availability and independent of amyloid pathology in early cognitive impairment.

Introduction: Metabotropic glutamate receptor 5 (mGluR5) is involved in regulating integrative brain function and synaptic transmission. Aberrant mGluR5 signaling and relevant synaptic failure play a key role in the pathophysiological mechanism of Alzheimer's disease (AD).

Methods: Ten cognitively impaired (CI) individuals and 10 healthy controls (HCs) underwent [F]SynVesT-1 and [F]PSS232 positron emission tomography (PET)/magnetic resonance to assess synaptic density and mGluR5 availability.

Imaging a putative marker of brain cortisol regulation in alcohol use disorder.

Background: Stress is a potent activator of the hypothalamic-pituitary-adrenal (HPA) axis, initiating the release of glucocorticoid hormones, such as cortisol. Alcohol consumption can lead to HPA axis dysfunction, including altered cortisol levels. Until recently, research has only been able to examine peripheral cortisol associated with alcohol use disorder (AUD) in humans.

The associations between synaptic density and "A/T/N" biomarkers in Alzheimer's disease: An F-SynVesT-1 PET/MR study.

A newly developed SV2A radiotracer, F-SynVesT-1, was used in this study to investigate synaptic density and its association with Alzheimer's disease (AD) "A/T/N" biomarkers. The study included a cohort of 97 subjects, consisting of 64 patients with cognitive impairment (CI) and 33 individuals with normal cognition (CU). All subjects underwent F-SynVesT-1 PET/MR and F-florbetapir PET/CT scans.

Evaluation of a First PET Tracer Suitable for Imaging the Sigma-2 Receptor in the Brain of Nonhuman Primates.

The sigma-2 receptor (σ2R), recently identified as transmembrane protein 97, is expressed in many cell types and mediates important functions in both the peripheral and central nervous systems. Over the years, σ2R has emerged as a potential therapeutic target for cancer and neurological disorders such as Alzheimer's disease (AD). The currently available σ2R radiotracers have been developed primarily for cancer imaging with limited brain uptake.

First-in-Human PET Imaging of [F]SDM-4MP3: A Cautionary Tale.

[F]SynVesT-1 is a PET radiopharmaceutical that binds to the synaptic vesicle protein 2A (SV2A) and serves as a biomarker of synaptic density with widespread clinical research applications in psychiatry and neurodegeneration. The initial goal of this study was to concurrently conduct PET imaging studies with [F]SynVesT-1 at our laboratories. However, the data in the first two human PET studies had anomalous biodistribution despite the injected product meeting all specifications during the prerelease quality control protocols.

Low-Dose Augmentation With Buprenorphine for Treatment-Resistant Depression: A Multisite Randomized Controlled Trial With Multimodal Assessment of Target Engagement.

Background: The experimental therapeutics approach that combines a placebo-controlled clinical trial with translational neuroscience methods can provide a better understanding of both the clinical and physiological effects of pharmacotherapy. We aimed to test the efficacy and tolerability of low-dose augmentation with buprenorphine (BPN) for treatment-resistant depression, combined with multimodal assessment of target engagement.

Methods: In this multisite randomized clinical trial, 85 participants ≥50 years of age with a major depressive episode that had not responded to venlafaxine extended release were randomized to augmentation with BPN or placebo for 8 weeks.

Reversal of synapse loss in Alzheimer mouse models by targeting mGluR5 to prevent synaptic tagging by C1Q.

Microglia-mediated synaptic loss contributes to the development of cognitive impairments in Alzheimer's disease (AD). However, the basis for this immune-mediated attack on synapses remains to be elucidated. Treatment with the metabotropic glutamate receptor 5 (mGluR5) silent allosteric modulator (SAM), BMS-984923, prevents β-amyloid oligomer-induced aberrant synaptic signaling while preserving physiological glutamate response.

Imaging the fetal nonhuman primate brain with SV2A positron emission tomography (PET).

Purpose: Exploring synaptic density changes during brain growth is crucial to understanding brain development. Previous studies in nonhuman primates report a rapid increase in synapse number between the late gestational period and the early neonatal period, such that synaptic density approaches adult levels by birth. Prenatal synaptic development may have an enduring impact on postnatal brain development, but precisely how synaptic density changes in utero are unknown because current methods to quantify synaptic density are invasive and require post-mortem brain tissue.

Validation of SV2A-Targeted PET Imaging for Noninvasive Assessment of Neuroendocrine Differentiation in Prostate Cancer.

Neuroendocrine prostate cancer (NEPC) is an aggressive and lethal variant of prostate cancer (PCa), and it remains a diagnostic challenge. Herein we report our findings of using synaptic vesicle glycoprotein 2 isoform A (SV2A) as a promising marker for positron emission tomography (PET) imaging of neuroendocrine differentiation (NED). The bioinformatic analyses revealed an amplified SV2A gene expression in clinical samples of NEPC versus castration-resistant PCa with adenocarcinoma characteristics (CRPC-Adeno).

Further Investigation of Synaptic Vesicle Protein 2A (SV2A) Ligands Designed for Positron Emission Tomography and Single-Photon Emission Computed Tomography Imaging: Synthesis and Structure-Activity Relationship of Substituted Pyridinylmethyl-4-(3,5-difluorophenyl)pyrrolidin-2-ones.

A series of synaptic vesicle protein 2A (SV2A) ligands were synthesized to explore the structure-activity relationship and to help further investigate a hydrogen bonding pharmacophore hypothesis. Racemic SynVesT-1 was used as a lead compound to explore the replacement of the 3-methyl group on the pyridinyl moiety with halogens and hydrocarbons. Pyridinyl isomers of racemic SynVesT-1 were also investigated.

Assessment of test-retest reproducibility of [F]SynVesT-1, a novel radiotracer for PET imaging of synaptic vesicle glycoprotein 2A.

Purpose: Synaptic abnormalities are associated with many brain disorders. Recently, we developed a novel synaptic vesicle glycoprotein 2A (SV2A) radiotracer [F]SynVesT-1 and demonstrated its excellent imaging and binding properties in nonhuman primates. The aim of this study was to perform dosimetry calculations in nonhuman primates and to evaluate this tracer in humans and assess its test-retest reliability in comparison with [C]UCB-J.

First-in-Human Evaluation of F-SynVesT-1, a Radioligand for PET Imaging of Synaptic Vesicle Glycoprotein 2A.

The use of synaptic vesicle glycoprotein 2A radiotracers with PET imaging could provide a way to measure synaptic density quantitatively in living humans. C-UCB-J (()-1-((3-(C-methyl-C)pyridin-4-yl)methyl)-4-(3,4,5-trifluorophenyl)pyrrolidin-2-one), previously developed and assessed in nonhuman primates and humans, showed excellent kinetic properties as a PET radioligand. However, it is labeled with the short half-life isotope C.

Positron Emission Tomography Imaging Evaluation of a Novel F-Labeled Sigma-1 Receptor Radioligand in Cynomolgus Monkeys.

We report a convenient radiosynthesis and the first positron emission tomography (PET) imaging evaluation of [F]FBFP as a potent sigma-1 (σ) receptor radioligand with advantageous characteristics. [F]FBFP was synthesized in one step from an iodonium ylide precursor. In cynomolgus monkeys, [F]FBFP displayed high brain uptake and suitable tissue kinetics for quantitative analysis.

Kinetic Modeling and Test-Retest Reproducibility of C-EKAP and C-FEKAP, Novel Agonist Radiotracers for PET Imaging of the κ-Opioid Receptor in Humans.

The κ-opioid receptor (KOR) is implicated in various neuropsychiatric disorders. We previously evaluated an agonist tracer, C-GR103545, for PET imaging of KOR in humans. Although C-GR103545 showed high brain uptake, good binding specificity, and selectivity for KOR, it displayed slow kinetics and relatively large test-retest variability of total distribution volume () estimates (15%).

Synthesis and Preclinical Evaluation of an F-Labeled Synaptic Vesicle Glycoprotein 2A PET Imaging Probe: [F]SynVesT-2.

Synaptic vesicle glycoprotein 2A (SV2A) is a 12-pass transmembrane glycoprotein ubiquitously expressed in presynaptic vesicles. imaging of SV2A using PET has potential applications in the diagnosis and prognosis of a variety of neuropsychiatric diseases, e.g.

Preclinical In Vitro and In Vivo Characterization of Synaptic Vesicle 2A-Targeting Compounds Amenable to F-18 Labeling as Potential PET Radioligands for Imaging of Synapse Integrity.

Purpose: Current synaptic vesicle 2A (SV2A) positron emission tomography (PET) imaging agents include the nanomolar affinity probes [C]UCB-J and [F]UCB-H derived from the anti-epileptic drug levitaracetam (Keppra®). An industry-utilized "de-risking" approach was used to carry out initial pharmacological characterization and to assess potential next-generation candidates amenable to F-18 radiolabeling for preliminary evaluation.

Procedures: Radioligand binding methods were employed in mammalian brain homogenates to determine the SV2A affinity (K) and maximal binding capacity (B) of [H]UCB-J.

Anti-edema and antioxidant combination therapy for ischemic stroke via glyburide-loaded betulinic acid nanoparticles.

Stroke is a deadly disease without effective pharmacotherapies, which is due to two major reasons. First, most therapeutics cannot efficiently penetrate the brain. Second, single agent pharmacotherapy may be insufficient and effective treatment of stroke requires targeting multiple complementary targets.

Synthesis and in vivo evaluation of [F]UCB-J for PET imaging of synaptic vesicle glycoprotein 2A (SV2A).

Purpose: Synaptic abnormalities have been implicated in a variety of neuropsychiatric disorders, including epilepsy, Alzheimer's disease, and schizophrenia. Hence, PET imaging of the synaptic vesicle glycoprotein 2A (SV2A) may be a valuable in vivo biomarker for neurologic and psychiatric diseases. We previously developed [C]UCB-J, a PET radiotracer with high affinity and selectivity toward SV2A; however, the short radioactive half-life (20 min for C) places some limitations on its broader application.