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Rationale: The Diagnostic and Statistical Manual of Mental Disorders (Fifth Edition) classifies attention deficit hyperactivity disorder (ADHD) as a neurodevelopmental disorder that interferes with human functioning and development. As the clinical presentation of ADHD involves a deficiency in executive function, neurocognitive deficits involving distinctive neuropathological changes must be present for clinical diagnosis., Objectives: The vesicular monoamine transporter (VMAT), specifically VMAT-2, plays a role in ADHD pathogenesis. In addition, experimental data show that the stimulants (amphetamines and methylphenidate) are first-line treatments for the condition because of their extensive interaction with VMAT-2. The interactions of peptides, bupropion, and nutritional supplements with VMAT-2 receptors have been researched, but more evidence is needed to elucidate their pharmacodynamic properties. Therefore, this literature review evaluated the current pharmacological treatment modalities, peptides, and nutritional supplements for ADHD that target the VMAT-2 system., Methods, Results, and Conclusions: We obtained relevant studies from several platforms, including the National Center for Biotechnology, Clinical Key, Access Medicine, and PubMed. From the results of these studies, we observed that stimulants interact highly with the VMAT-2 transporter, with omega-3 fatty acids, peptides, and bupropion exerting some modulatory activity on VMAT-2. These agents should be considered for the future treatment of ADHD, although clinical-level research involving human participants is necessary., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a chronic debilitating condition with no cure that shares commonality with long-COVID. This review examines current understanding of long-COVID symptoms, characteristics of the affected population, the connection with ME/CFS, and the potential for salubrinal, an agent known for its influence on cellular stress pathways, to mitigate these disorders It also describes the historical development and mechanism of action of salubrinal, to mitigate endoplasmic reticulum (ER)/cellular stress responses, that could potentially contribute to symptom improvement in both ME/CFS and long-COVID patients. Further research and clinical trials are warranted to advance our understanding of the potential role of salubrinal in improving the quality of life for individuals with long-COVID-related ME/CFS symptoms as well as ME/CFS patients., Competing Interests: Declaration of interests The authors report no conflicts of interest that could affect the objectivity of the information presented in this review., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

The possibility of impaired cognitive function during deep space flight missions or while living on a Martian colony is a critical point of concern and pleads for further research. In addition, a fundamental gap exists both in our understanding and application of countermeasures for the consequences of long duration space travel and/or living in an extreme environment such as on the Moon or Mars. Previous studies, while heavily analyzing pre- and post-flight conditions, mostly fail to appreciate the cognitive stressors associated with space radiation, microgravity, confinement, hostile or closed environments, and the long distances from earth. A specific understanding of factors that affect cognition as well as structural and/or physiological changes in the brains of those on a space mission in addition to new countermeasures should result in improved health of our astronauts and reduce risks. At the core of cognitive changes are mechanisms we typically associate with aging, such as inflammatory responses, changes in brain metabolism, depression, and memory impairments. In fact, space flight appears to accelerate aging. In this review, we will discuss the importance of monitoring inflammatory and immune system mediators such as nuclear factor kappa B (NF-κB), and mitochondrial changes related to brain metabolism. We conclude with our recommended countermeasures that include pharmacological, metabolic, and nutritional considerations for the risks on cognition during space missions., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The author(s) declared that they were an editorial board member of Frontiers, at the time of submission. This had no impact on the peer review process and the final decision., (Copyright © 2024 Tocci, Ducai, Stoute, Hopkins, Sabbir, Beheshti and Albensi.)

Background/Objectives: Small molecules that interfere with the interaction between acetylated protein tails and the tandem bromodomains of BET (bromodomain and extra-terminal) family proteins are pivotal in modulating immune/inflammatory and neoplastic diseases. This study aimed to develop a novel PET imaging tracer, [ 11 C]GSK023, that targets the N-terminal bromodomain (BD1) of BET family proteins with high selectivity and potency, thereby enriching the chemical probe toolbox for epigenetic imaging. Methods: [ 11 C]GSK023, a radio-chemical probe, was designed and synthesized to specifically target the BET BD1. In vivo PET imaging evaluations were conducted on rodents, focusing on the tracer's distribution and binding specificity in various tissues. Blocking studies were performed to confirm the probe's selectivity and specificity. Results: The evaluations revealed that [ 11 C]GSK023 demonstrated good uptake in peripheral organs with limited brain penetration. Further blocking studies confirmed the probe's high binding specificity and selectivity for the BET BD1 protein, underscoring its potential utility in epigenetic imaging. Conclusions: The findings suggest that [ 11 C]GSK023 is a promising PET probe for imaging the BET BD1 protein, offering the potential to deepen our understanding of the roles of BET bro-modomains in disease and their application in clinical settings to monitor disease progression and therapeutic responses.

The paired bromodomains (BD1 and BD2), located in the bromodomain and extra-terminal (BET) family proteins, perform specific functions in gene transcriptional control and expression. Targeting specific bromodomains with inhibitors holds promise for achieving therapeutic benefits with reduced side effects. However, the comprehension of this target related to the disease is still restricted. Positron emission tomography (PET) imaging is a powerful tool that provides a valuable avenue for exploring the BD2 bromodomain. This investigation introduces a novel radioligand, [ 11 C]I-58, for PET targeting the BET BD2 domain. The synthesis of compound I-58, along with its radiosynthetic process for C11 labeling, is detailed, and the suitability of [ 11 C]I-58 for PET imaging of the BD2 bromodomain is evaluated. Initial PET study findings in mice indicate that [ 11 C]I-58 exhibits suitable biodistribution in peripheral organs and tissues. Additionally, in vitro autoradiography studies and blocking experiments provide compelling evidence supporting the specific binding of [ 11 C]I-58 to the BD2 bromodomain. These results establish [ 11 C]I-58 as a promising instrument for the PET imaging of the BD2 bromodomain. This research not only holds the potential to pave the path for developing PET radioligands precisely targeting the BD2 bromodomain but also adds to a more profound comprehension of the biological mechanisms linked to the BD bromodomain., Competing Interests: The authors declare no competing financial interest., (© 2024 The Authors. Published by American Chemical Society.)

Alcohol use disorder (AUD) is a disorder of clinical and public health significance requiring novel and improved therapeutic solutions. Both environmental and genetic factors play a significant role in its pathophysiology. However, the underlying epigenetic molecular mechanisms that link the gene-environment interaction in AUD remain largely unknown. In this proof-of-concept study, we showed, for the first time, the neuroepigenetic biomarker capability of non-invasive imaging of class I histone deacetylase (HDAC) epigenetic enzymes in the in vivo brain for classifying AUD patients from healthy controls using a machine learning approach in the context of precision diagnosis. Eleven AUD patients and 16 age- and sex-matched healthy controls completed a simultaneous positron emission tomography-magnetic resonance (PET/MR) scan with the HDAC-binding radiotracer [ 11 C]Martinostat. Our results showed lower HDAC expression in the anterior cingulate region in AUD. Furthermore, by applying a genetic algorithm feature selection, we identified five particular brain regions whose combined [ 11 C]Martinostat relative standard uptake value (SUVR) features could reliably classify AUD vs. controls. We validate their promising classification reliability using a support vector machine classifier. These findings inform the potential of in vivo HDAC imaging biomarkers coupled with machine learning tools in the objective diagnosis and molecular translation of AUD that could complement the current diagnostic and statistical manual of mental disorders (DSM)-based intervention to propel precision medicine forward., Competing Interests: C.W. and J.M.H. are inventors of the [11C]Martinostat epigenetic PET radiotracer imaging probe used in this project., (© 2024 The Author(s).)

Accrued evidence has indicated that epigenetic mechanisms altered by alcohol have been implicated in the progression and development of alcoholic liver disease (ALD). SIRT1 plays an important role in ALD progression and has emerged as a promising therapeutic target for treating ALD. The purpose of this study is to investigate the efficacy of [ 11 C]WL-1 for quantitative imaging of SIRT1 in mouse models of early-stage ALD. Positron emission tomography/computerized tomography (PET/CT) imaging was carried out 60 min following the injection of [ 11 C]WL-1 in mouse models of early-stage ALD and normal control mice. The time-activity curves for ALD mouse livers showed remarkably decreased total uptake of [ 11 C]WL-1 relative to that for control mouse livers. Moreover, compared with the normal control mice, decreased uptake in the cortex, hippocampus, and cerebellum was also observed in early-stage ALD mice, while the uptake of [ 11 C]WL-1 in amygdala showed no significant changes. Western blot analysis confirmed that the protein levels of SIRT1 in the brains of early-stage ALD mice were decreased significantly when compared to the normal control mouse brains. Collectively, PET imaging with [ 11 C]WL-1 would facilitate future clinical studies, aiming to demonstrate the roles of SIRT1 in ALD.

Although the epigenetic regulatory protein histone deacetylase 6 (HDAC6) has been recently implicated in the etiology of Alzheimer's disease (AD), little is known about the role of HDAC6 in the etiopathogenesis of AD and whether HDAC6 can be a potential therapeutic target for AD. Here, we performed positron emission tomography (PET) imaging in combination with histopathological analysis to better understand the underlying pathomechanisms of HDAC6 in AD. We first developed [ 18 F]PB118 which was demonstrated as a valid HDAC6 radioligand with excellent brain penetration and high specificity to HDAC6. PET studies of [ 18 F]PB118 in 5xFAD mice showed significantly increased radioactivity in the brain compared to WT animals, with more pronounced changes identified in the cortex and hippocampus. The translatability of this radiotracer for AD in a potential human use was supported by additional studies, including similar uptake profiles in non-human primates, an increase of HDAC6 in AD-related human postmortem hippocampal tissues by Western blotting protein analysis, and our ex vivo histopathological analysis of HDAC6 in postmortem brain tissues of our animals. Collectively, our findings show that HDAC6 may lead to AD by mechanisms that tend to affect brain regions particularly susceptible to AD through an association with amyloid pathology., (© 2022 Chinese Pharmaceutical Association and Institute of Materia Medica, Chinese Academy of Medical Sciences. Production and hosting by Elsevier B.V.)

To better understand the role of bromodomain and extra-terminal domain (BET) proteins in epigenetic mechanisms, we developed a series of thienodiazepine-based derivatives and identified two compounds, 3a and 6a , as potent BET inhibitors. Further in vivo pharmacokinetic studies and analysis of in vitro metabolic stability of 6a revealed excellent brain penetration and reasonable metabolic stability. Compounds 3a and 6a were radiolabeled with fluorine-18 in two steps and utilized in positron emission tomography (PET) imaging studies in mice. Preliminary PET imaging results demonstrated that [ 18 F] 3a and [ 18 F] 6a have good brain uptake (with maximum SUV = 1.7 and 2, respectively) and binding specificity in mice brains. These results show that [ 18 F] 6a is a potential PET radiotracer that could be applied to imaging BET proteins in the brain. Further optimization and improvement of the metabolic stability of [ 18 F] 6a are still needed in order to create optimal PET imaging probes of BET family members.

Two tandem bromodomains (BD1 and BD2) of bromodomain and extraterminal domain (BET) family proteins have shown distinct roles in mediating gene transcription and expression. Inhibitors that interact with a specific bromodomain may contribute to a specific therapeutic potential with fewer side effects. However, little is known about this disease-related target. Positron emission tomography (PET) imaging could allow us to achieve in-depth knowledge of the BD2 bromodomain. Herein we describe the radiosynthesis and evaluation of [ 11 C] 1 as a BRD4 BD2 bromodomain PET imaging radioligand. Our preliminary PET imaging results in rodents demonstrated that [ 11 C] 1 had suitable biodistribution in peripheral organs and tissues. Further blocking studies indicated that [ 11 C] 1 had good binding specificity toward the BD2 bromodomain. This study may pave the way for the development of a PET radioligand specifically targeting BD1/2 bromodomains as well as for the biological mechanism investigation of BD1/2 bromodomains.

We report herein the discovery of a positron emission tomography (PET) tracer for the (NOD)-like receptor protein 3 (NLRP3). Our recent medicinal chemistry campaign on developing sulfonamide-based NLRP3 inhibitors led to an analog, 1, with a methoxy substituent amenable to labeling with carbon-11. PET/CT imaging studies indicated that [ 11 C]1 exhibited rapid blood-brain barrier (BBB) penetration and moderate brain uptake, as well as blockable uptake in the brain. [ 11 C]1, thus suggesting the potential to serve as a useful tool for imaging NLRP3 inflammasome in living brains., (Copyright © 2021 Elsevier Ltd. All rights reserved.)