Differential regulation of G protein-coupled receptor-associated proteins in the caudate and the putamen of cynomolgus macaques following chronic ethanol drinking.

The dorsal striatum is composed of the caudate nucleus and the putamen in human and non-human primates. These two regions receive different cortical projections and are functionally distinct. The caudate is involved in the control of goal-directed behaviors, while the putamen is implicated in habit learning and formation.

Preclinical Evaluation of Azabenzimidazole-Based PET Radioligands for γ-8 Dependent Transmembrane AMPA Receptor Regulatory Protein Imaging.

AMPA glutamate receptors (AMPARs) play a pivotal role in excitatory neurotransmission, particularly in the hippocampus where the TARP γ-8 subunit is enriched and serves as a target for emerging anti-epileptic drugs. To enable in vivo visualization of TARP γ-8 distribution and expression by positron emission tomography (PET), this study focuses on the development of novel F-labeled TARP γ-8 inhibitors and their corresponding precursors, stemming from the azabenzimidazole scaffold. The resulting radioligands [ F]TARP-2204 and [ F]TARP-2205 were successfully synthesized with acceptable radiochemical yield, high molar activity, and excellent radiochemical purity.

Synthesis and Biological Evaluation of Enantiomerically Pure () and ()[18F]OF-NB1 for Imaging the GluN2B Subunit-Containing NMDA Receptors.

GluN2B subunit-containing methyl-d-aspartate (NMDA) receptors have been implicated in various neurological disorders. Nonetheless, a validated fluorine-18 labeled positron emission tomography (PET) ligand for GluN2B imaging in the living human brain is currently lacking. The aim of this study was to develop a novel synthetic approach that allows an enantiomerically pure radiosynthesis of the previously reported PET radioligands ()[F]OF-NB1 and ()[F]OF-NB1 as well as to assess their and performance characteristics for imaging the GluN2B subunit-containing NMDA receptor in rodents.

Evaluation of [F]RoSMA-18-d as a CB2 PET Radioligand in Nonhuman Primates.

The cannabinoid type 2 receptor (CB2) has been implicated in a variety of central and peripheral inflammatory diseases, prompting significant interest in the development of CB2-targeted diagnostic and therapeutic agents. A validated positron emission tomography (PET) radioligand for imaging CB2 in the living human brain as well as in peripheral tissues is currently lacking. As part of our research program, we have recently identified the trisubstituted pyridine, [F]RoSMA-18-d, which proved to be highly suitable for and mapping of CB2 in rodents.

Influence of social rank on the development of long-term ethanol drinking trajectories in cynomolgus monkeys.

Background: Chronic stress contribute to the development of alcohol use disorder (AUD). However, characterizing the role of chronic social stressors in the development of problematic drinking trajectories in humans is complicated by practical and ethical constraints. Group-housed nonhuman primates develop social dominance hierarchies that represent a continuum of social experiences from enrichment in higher-ranked (dominant) monkeys to chronic social stress in lower-ranked (subordinate) individuals.

Structure-activity relationship of pyrazol-4-yl-pyridine derivatives and identification of a radiofluorinated probe for imaging the muscarinic acetylcholine receptor M.

There is an accumulating body of evidence implicating the muscarinic acetylcholine receptor 4 (M) in schizophrenia and dementia with Lewy bodies, however, a clinically validated M positron emission tomography (PET) radioligand is currently lacking. As such, the aim of this study was to develop a suitable M PET ligand that allows the non-invasive visualization of M in the brain. Structure-activity relationship studies of pyrazol-4-yl-pyridine derivates led to the discovery of target compound a subtype-selective positive allosteric modulator (PAM).

Synthesis and Biological Evaluation of Enantiomerically Pure ()- and ()-[F]OF-NB1 for Imaging the GluN2B Subunit-Containing NMDA receptors.

GluN2B subunit-containing -methyl-d-aspartate (NMDA) receptors have been implicated in various neurological disorders. Nonetheless, a validated fluorine-18 labeled positron emission tomography (PET) ligand for GluN2B imaging in the living human brain is currently lacking. As part of our PET ligand development program, we have recently reported on the preclinical evaluation of [F]OF-NB1 - a GluN2B PET ligand with promising attributes for potential clinical translation.

Imaging Leucine-Rich Repeat Kinase 2 In Vivo with F-Labeled Positron Emission Tomography Ligand.

Leucine-rich repeat kinase 2 (LRRK2) has been demonstrated to be closely involved in the pathogenesis of Parkinson's disease (PD), and pharmacological blockade of LRRK2 represents a new opportunity for therapeutical treatment of PD and other related neurodegenerative conditions. The development of an LRRK2-specific positron emission tomography (PET) ligand would enable a target occupancy study in vivo and greatly facilitate LRRK2 drug discovery and clinical translation as well as provide a molecular imaging tool for studying physiopathological changes in neurodegenerative diseases. In this work, we present the design and development of compound (PF-06455943) as a promising PET radioligand through a PET-specific structure-activity relationship optimization, followed by comprehensive pharmacology and ADME/neuroPK characterization.

Assessment of cholesterol homeostasis in the living human brain.

Alterations in brain cholesterol homeostasis have been broadly implicated in neurological disorders. Notwithstanding the complexity by which cholesterol biology is governed in the mammalian brain, excess neuronal cholesterol is primarily eliminated by metabolic clearance via cytochrome P450 46A1 (CYP46A1). No methods are currently available for visualizing cholesterol metabolism in the living human brain; therefore, a noninvasive technology that quantitatively measures the extent of brain cholesterol metabolism via CYP46A1 could broadly affect disease diagnosis and treatment options using targeted therapies.

Punishment of ethanol choice in rhesus monkeys.

A defining characteristic of individuals diagnosed with alcohol use disorder (AUD) is that negative outcomes related to drinking do not lead them to reduce their alcohol use. In rodent models of AUD, this characteristic has been studied by adding the bitter tastant quinine to an ethanol solution. In this study, we extended this approach to a nonhuman primate model in which the ability of quinine to decrease the choice of a 4% ethanol solution vs.

Rich Club Characteristics of Alcohol-Naïve Functional Brain Networks Predict Future Drinking Phenotypes in Rhesus Macaques.

: A fundamental question for Alcohol use disorder (AUD) is how and when naïve brain networks are reorganized in response to alcohol consumption. The current study aimed to determine the progression of alcohol's effect on functional brain networks during transition from the naïve state to chronic consumption. : Resting-state brain networks of six female rhesus macaque ( monkeys were acquired using magnetoencephalography (MEG) prior to alcohol exposure and after free-access to alcohol using a well-established model of chronic heavy alcohol consumption.

Effect of chronic binge-like ethanol consumption on subsequent cocaine reinforcement in rhesus monkeys.

Background: Although most individuals with cocaine use disorder also abuse alcohol, little is known about the behavioral and pharmacological mechanisms that promote co-abuse. For example, it is unclear whether prior experience with alcohol renders individuals more sensitive to cocaine when it is subsequently experienced.

Methods: This study examined the effects of chronic ethanol consumption on subsequent cocaine reinforcement in rhesus monkeys.

PET Imaging of [C]MPC-6827, a Microtubule-Based Radiotracer in Non-Human Primate Brains.

Dysregulation of microtubules is commonly associated with several psychiatric and neurological disorders, including addiction and Alzheimer's disease. Imaging of microtubules in vivo using positron emission tomography (PET) could provide valuable information on their role in the development of disease pathogenesis and aid in improving therapeutic regimens. We developed [C]MPC-6827, the first brain-penetrating PET radiotracer to image microtubules in vivo in the mouse brain.

Synthesis and Preliminary Evaluation of [ C]GNE-1023 as a Potent PET Probe for Imaging Leucine-Rich Repeat Kinase 2 (LRRK2) in Parkinson's Disease.

Leucine-rich repeat kinase 2 (LRRK2) is a large protein involved in the pathogenesis of Parkinson's disease (PD). It has been demonstrated that PD is mainly conferred by LRRK2 mutations that bring about increased kinase activity. As a consequence, selective inhibition of LRRK2 may help to recover the normal functions of LRRK2, thereby serving as a promising alternative therapeutic target for PD treatment.

Effects of stimulation of mu opioid and nociceptin/orphanin FQ peptide (NOP) receptors on alcohol drinking in rhesus monkeys.

Alcohol use disorder (AUD) persists as a devastating public health problem; widely effective pharmacological treatments are needed. Evidence from rodent models suggests that stimulating brain receptors for the neuropeptide nociceptin/orphanin FQ (NOP) can decrease ethanol drinking. We characterized the effects of the mu opioid peptide (MOP) receptor agonist buprenorphine and the buprenorphine analog (2S)-2-[(5R,6R,7R,14S)-N-cyclopropylmethyl-4,5-epoxy-6,14-ethano-3-hydroxy-6 methoxymorphinan-7-yl]-3,3-dimethylpentan-2-ol (BU08028), which stimulates MOP and NOP receptors, in a translational nonhuman primate model of AUD.

Synthesis and Preliminary Evaluations of a Triazole-Cored Antagonist as a PET Imaging Probe ([F]N2B-0518) for GluN2B Subunit in the Brain.

GluN2B is the most studied subunit of N-methyl-d-aspartate receptors (NMDARs) and implicated in the pathologies of various central nervous system disorders and neurodegenerative diseases. As pan NMDAR antagonists often produce debilitating side effects, new approaches in drug discovery have shifted to subtype-selective NMDAR modulators, especially GluN2B-selective antagonists. While positron emission tomography (PET) studies of GluN2B-selective NMDARs in the living brain would enable target engagement in drug development and improve our understanding in the NMDAR signaling pathways between normal and disease conditions, a suitable PET ligand is yet to be identified.

Changes in nonhuman primate brain function following chronic alcohol consumption in previously naïve animals.

Introduction: Chronic alcohol abuse is associated with neurophysiological changes in brain activity; however, these changes are not well localized in humans. Non-human primate models of alcohol abuse enable control over many potential confounding variables associated with human studies. The present study utilized high-resolution magnetoencephalography (MEG) to quantify the effects of chronic EtOH self-administration on resting state (RS) brain function in vervet monkeys.

Effects of alcohol on c-Myc protein in the brain.

Alcoholism is a disorder categorized by significant impairment that is directly related to persistent and extreme use of alcohol. The effects of alcoholism on c-Myc protein expression in the brain have been scarcely studied. This is the first study to investigate the role different characteristics of alcoholism have on c-Myc protein in the brain.

The effects of chronic alcohol self-administration in nonhuman primate brain networks.

Background: Long-term alcohol abuse is associated with change in behavior, brain structure, and brain function. However, the nature of these changes is not well understood. In this study, we used network science to analyze a nonhuman primate model of ethanol self-administration to evaluate functional differences between animals with chronic alcohol use and animals with no exposure to alcohol.

Monkey alcohol tissue research resource: banking tissues for alcohol research.

Background: An estimated 18 million adults in the United States meet the clinical criteria for diagnosis of alcohol abuse or alcoholism, a disorder ranked as the third leading cause of preventable death. In addition to brain pathology, heavy alcohol consumption is comorbid with damage to major organs including heart, lungs, liver, pancreas, and kidneys. Much of what is known about risk for and consequences of heavy consumption derive from rodent or retrospective human studies.

The effects of chronic ethanol self-administration on hippocampal 5-HT1A receptors in monkeys.

Background: Chronic alcohol consumption reduces brain serotonin and alters the synaptic mechanisms involved in memory formation. Hippocampal 5-HT1A receptors modulate these mechanisms, but the neuroadaptive response of 5HT1A receptors to chronic alcohol self-administration is not well understood.

Methods: Hippocampal tissue from monkeys that voluntarily self-administered ethanol for 12 months (n=9) and accompanying controls (n=8) were prepared for in vitro receptor autoradiography and laser capture microdissection.

Standardized method for the harvest of nonhuman primate tissue optimized for multiple modes of analyses.

Appropriate animal models are critical to conduct translational studies of human disorders without variables that can confound clinical studies. Such analytic methods as patch-clamp electrophysiological and voltammetric recordings of neurons in brain slices require living brain tissue. In order to obtain viable tissue from nonhuman primate brains, tissue collection methods must be designed to preserve cardiovascular and respiratory functions for as long as possible.

MRI-guided dissection of the nonhuman primate brain: a case study.

Numerous biochemical as well as electrophysiological techniques require tissue that must be retrieved very quickly following death in order to preserve the physiological integrity of the neuronal environment. Therefore, the ability to accurately predict the precise locations of brain regions of interest (ROI) and to retrieve those areas as quickly as possible following the brain harvest is critical for subsequent analyses. One way to achieve this objective is the utilization of high-resolution MRI to guide the subsequent dissections.

Long-acting depot formulation of luprolide acetate as a method of hypothalamic down regulation for controlled ovarian hyperstimulation and oocyte production in Macaca fascicularis.

Reproductive function in some nonhuman primate species parallels that of the human. As a result, studies addressing aspects of reproductive function primarily involve the use of nonhuman primate models. The objective of the present study was to assess the efficiency of two hypothalamic down-regulation techniques combined with a single controlled ovarian hyperstimulation protocol for mature oocyte production in the cynomolgus macaque (Macaca fascicularis).