GM-1020: a novel, orally bioavailable NMDA receptor antagonist with rapid and robust antidepressant-like effects at well-tolerated doses in rodents.

The NMDA receptor (NMDAR) antagonist ketamine has shown great potential as a rapid-acting antidepressant; however, its use is limited by poor oral bioavailability and a side effect profile that necessitates in-clinic dosing. GM-1020 is a novel NMDAR antagonist that was developed to address these limitations of ketamine as a treatment for depression. Here, we present the preclinical characterization of GM-1020 alongside ketamine, for comparison. In vitro, we profiled GM-1020 for binding to NMDAR and functional inhibition using patch-clamp electrophysiology. In vivo, GM-1020 was assessed for antidepressant-like efficacy using the Forced Swim Test (FST) and Chronic Mild Stress (CMS), while motor side effects were assessed in spontaneous locomotor activity and on the rotarod. The pharmacokinetic properties of GM-1020 were profiled across multiple preclinical species. Electroencephalography (EEG) was performed to determine indirect target engagement and provide a potentially translational biomarker. These results demonstrate that GM-1020 is an orally bioavailable NMDAR antagonist with antidepressant-like efficacy at exposures that do not produce unwanted motor effects.

Understanding the evolution of trust in a participatory health research partnership: A qualitative study.

INTRODUCTION: Advancements in evaluating the impact of participatory health research (PHR) have been made through comprehensive models like the community-based participatory research (CBPR) conceptual model, which provides a useful framework for exploring how context and partnership processes can influence health research design and interventions. However, challenges in operationalising aspects of the model limit our understanding and evaluation of the PHR process. Trust is frequently identified as an important component of the CBPR model, which supports the development of key partnership outcomes, such as partnership synergy. However, trust continues to be limited to a binary view (as present or absent), which is problematic given its inherently dynamic and temporal nature. STUDY AIM: The aim of this qualitative study is to understand the evolution of trust in the national public and patient involvement (PPI) network in Ireland. SETTING AND PARTICIPANTS: Participants from the PPI network (n = 15/21) completed a semistructured interview discussing the evolution of trust by reviewing four social network maps derived from a previous longitudinal study. ANALYSIS: Following Braun and Clarke, we used reflexive thematic analysis, to iteratively develop, analyse and interpret our mediated reflection of the data. RESULTS: Participants described the evolution of trust as a function of three contextual factors: (1) the set-up and organisation of the network, (2) how people work together and (3) reflection on the process and outcomes. Their descriptions across these themes seemed to vary depending on partnership type with National Partners and Site Leads having more opportunities to demonstrate trust (e.g., via leadership roles or more resources), compared to Local. Thus, visibility and the opportunity to be visible, depending on the set-up and organisation of the network and how people work together, seemingly play an important role in the evolution of trust over time. Based on these findings, we provide important questions for reflection across themes that could be considered for future PHR partnerships. DISCUSSION: Given that the opportunity and visibility to build and maintain trust over time may not be equally available to all partners, it is important to find ways to invest in and commit to equitable relationships as the key to the success (i.e., longevity) of partnerships. We reflect on/offer important implications for those engaging in PHR partnerships and those who fund such research. PATIENT OR PUBLIC CONTRIBUTION: A Research Advisory Group comprising four research partners (representing academic, service and community organisations) from the PPI Ignite Network provided input and approval for the research objectives of this study as well as previously published work informing this study. Informal consultation occurred with members of this group to discuss findings from this study, assisting with the way findings are presented and described, to be accessible for diverse audiences. Two Research Advisory Group members were involved in the interpretation of the results, and one is a co-author of this manuscript (Zoe Hughes).

Long-term sea level rise modeling of a basin-tidal inlet system reveals sediment sinks.

Much of the world's population lives close to coastlines and this proximity is becoming increasingly impactful because of sea-level rise (SLR). Barrier islands and backbarrier saltmarshes, which comprise >10% of these coasts, are particularly susceptible. To better understand this risk, we model backbarrier morphologic and hydrodynamic evolution over a 200-year period of SLR, incorporating an erodible bed and a range of grain sizes. Here, we show that reduction in intertidal area creates negative feedback, shifting transport of coarse sediment (silt and sand) through the inlet from net export to net import. Imposing a modest marsh vertical accretion rate decreases the period of silt and sand import to 40 years (years 90 to 130) before being exported again. Clay is continuously exported thereby decreasing inorganic deposition on marshes and threatening their sustainability. Simulated marsh loss increases tidal prism and the volume of sand contained in ebb deltas, depleting coastal sand resources.

A meta-analytical review of the impact of mindfulness on creativity: Framing current lines of research and defining moderator variables.

Findings relating to the impact of mindfulness interventions on creative performance remain inconsistent, perhaps because of discrepancies between study designs, including variability in the length of mindfulness interventions, the absence of control groups or the tendencies to explore creativity as one unitary construct. To derive a clearer understanding of the impact that mindfulness interventions may exert on creative performance, two meta-analytical reviews were conducted, drawing respectively on studies using a control group design (n = 20) and studies using a pretest-posttest design (n = 17). A positive effect was identified between mindfulness and creativity, both for control group designs (d = 0.42, 95% CIs [0.29, 0.54]) and pretest-posttest designs (d = 0.59, 95% CIs [0.38, 0.81]). Subgroup analysis revealed that intervention length, creativity task (i.e., divergent vs. convergent thinking tasks) and control group type, were significant moderators for control group studies, whereas only intervention length was a significant moderator for pretest-posttest studies. Overall, the findings support the use of mindfulness as a tool to enhance creative performance, with more advantageous outcomes for convergent as opposed to divergent thinking tasks. We discuss the implications of study design and intervention length as key factors of relevance to future research aimed at advancing theoretical accounts of the relationship between mindfulness and creativity.

With equity in mind: Evaluating an interactive hybrid global surgery course for cross-site interdisciplinary learners.

There is limited understanding of the role of transcultural, cross-site educational partnerships for global surgery training between high- and low- or middle-income country (LMIC) institutions. We describe the development, delivery, and appraisal of a hybrid, synchronous, semester-long Global Surgical Care course by global health collaborators from widely different contexts, and evaluate the equity of the collaboration. The course was collaboratively modified by surgical educators and public health professionals with emphasis on collaboration ethics. Faculty from high-income and LMICs were paired to deliver lectures. To collaborate internationally, students and faculty participated either onsite or online. Perceptions and knowledge gained were quantitatively evaluated through participant and faculty cross-sectional surveys, using Likert scales, prioritization rankings, and free text responses analysed qualitatively. Equity was assessed using the Fair Trade Learning rubric and additional probes. Thirty-five learners from six institutions participated. Teams produced mock National, Surgical, Obstetric, and Anaesthesia Plans (NSOAPs) for selected LMICs, and reported a 9% to 65% increase in self-reported global health competencies following the course. Online learners had favourable perceptions of learning, but experienced connectivity challenges. Barriers to effective group work included time differences and logistics of communication for dispersed team members. Individuals taking the course for academic credit scored significantly higher than other learners in peer assessments of participation (8.56±1.53 versus 5.03±3.14; p<0.001). Using the Fair Trade Rubric, 60% of equity indicators were ideal, and no respondents perceived neo-colonialism in the partnership. Blended, synchronous, interdisciplinary global surgery courses based on "North-South" partnerships with a focus on equity in design and delivery are feasible but require careful and deliberate planning to minimize epistemic injustice. Such programs should address surgical systems strengthening, and not create dependency. Equity in such engagements should be evaluated and monitored in an ongoing fashion to stimulate discussion and continuous improvement.

The public and patient involvement imperative in Ireland: Building on policy drivers.

What can we learn from the history of Public and Patient Involvement (PPI) in healthcare and research across global jurisdictions? Depending on region and context, the terminology and heritage of involvement in research vary. In this paper, we draw on global traditions to explore dominant themes and key considerations and critiques pertaining to PPI in order to inform a PPI culture shift in Ireland. We then describe the heritage of PPI in Ireland and present the case for combining methodological imperatives with policy drivers to support and encourage meaningful involvement. Specifically, we propose that PPI can be enriched by the theory and processes of participatory health research (PHR); and that implementation requires concurrent capacity building. We conclude with a call for Irish researchers (authors of this paper included) to consider the conceptual complexities and nuances of a participatory approach to build on the policy imperatives driving PPI and to contribute to the international evidence base and research culture. Specifically, we call for Irish health researchers and funders to consider and reflect on: (1) the rich literature of PHR as a resource for enacting meaningful PPI; (2) the roots and origins of varying participatory health research methods; (3) how community/patient groups can lead health research; and (4) co-learning and partnership synergy to create space for both academic and community expertise; and (5) the importance of using standardized reporting tools.

First-in-Human Evaluation of 18F-PF-06445974, a PET Radioligand That Preferentially Labels Phosphodiesterase-4B.

Phosphodiesterase-4 (PDE4), which metabolizes the second messenger cyclic adenosine monophosphate (cAMP), has 4 isozymes: PDE4A, PDE4B, PDE4C, and PDE4D. PDE4B and PDE4D have the highest expression in the brain and may play a role in the pathophysiology and treatment of depression and dementia. This study evaluated the properties of the newly developed PDE4B-selective radioligand 18F-PF-06445974 in the brains of rodents, monkeys, and humans. Methods: Three monkeys and 5 healthy human volunteers underwent PET scans after intravenous injection of 18F-PF-06445974. Brain uptake was quantified as total distribution volume (V T) using the standard 2-tissue-compartment model and serial concentrations of parent radioligand in arterial plasma. Results: 18F-PF-06445974 readily distributed throughout monkey and human brain and had the highest binding in the thalamus. The value of V T was well identified by a 2-tissue-compartment model but increased by 10% during the terminal portions (40 and 60 min) of the monkey and human scans, respectively, consistent with radiometabolite accumulation in the brain. The average human V T values for the whole brain were 9.5 ± 2.4 mL ⋅ cm-3 Radiochromatographic analyses in knockout mice showed that 2 efflux transporters-permeability glycoprotein (P-gp) and breast cancer resistance protein (BCRP)-completely cleared the problematic radiometabolite but also partially cleared the parent radioligand from the brain. In vitro studies with the human transporters suggest that the parent radioligand was a partial substrate for BCRP and, to a lesser extent, for P-gp. Conclusion: 18F-PF-06445974 quantified PDE4B in the human brain with reasonable, but not complete, success. The gold standard compartmental method of analyzing brain and plasma data successfully identified the regional densities of PDE4B, which were widespread and highest in the thalamus, as expected. Because the radiometabolite-induced error was only about 10%, the radioligand is, in the opinion of the authors, suitable to extend to clinical studies.

Translational Pharmacology of PRAX-944, a Novel T-Type Calcium Channel Blocker in Development for the Treatment of Essential Tremor.

BACKGROUND: Essential tremor is the most common movement disorder with clear unmet need. Mounting evidence indicates tremor is caused by increased neuronal burst firing and oscillations in cerebello-thalamo-cortical circuitry and may be dependent on T-type calcium channel activity. T-type calcium channels regulate sigma band electroencephalogram (EEG) power during non-rapid eye movement sleep, representing a potential biomarker of channel activity. PRAX-944 is a novel T-type calcium channel blocker in development for essential tremor. OBJECTIVES: Using a rat tremor model and sigma-band EEG power, we assessed pharmacodynamically-active doses of PRAX-944 and their translation into clinically tolerated doses in healthy participants, informing dose selection for future efficacy trials. METHODS: Harmaline-induced tremor and spontaneous locomotor activity were used to assess PRAX-944 efficacy and tolerability, respectively, in rats. Sigma-power was used as a translational biomarker of T-type calcium channel blockade in rats and, subsequently, in a phase 1 trial assessing pharmacologic activity and tolerability in healthy participants. RESULTS: In rats, PRAX-944 dose-dependently reduced tremor by 50% and 72% at 1 and 3 mg/kg doses, respectively, without locomotor side effects. These doses also reduced sigma-power by ~30% to 50% in rats. In healthy participants, sigma-power was similarly reduced by 34% to 50% at 10 to 100 mg, with no further reduction at 120 mg. All doses were well tolerated. CONCLUSIONS: In rats, PRAX-944 reduced sigma-power at concentrations that reduced tremor without locomotor side effects. In healthy participants, comparable reductions in sigma-power indicate that robust T-type calcium channel blockade was achieved at well-tolerated doses that may hold promise for reducing tremor in patients with essential tremor. © 2022 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

The novel persistent sodium current inhibitor PRAX-562 has potent anticonvulsant activity with improved protective index relative to standard of care sodium channel blockers.

OBJECTIVE: This study investigates the effects of PRAX-562 on sodium current (INa ), intrinsic neuronal excitability, and protection from evoked seizures to determine whether a preferential persistent INa inhibitor would exhibit improved preclinical efficacy and tolerability compared to two standard voltage-gated sodium channel (NaV ) blockers. METHODS: Inhibition of INa  was characterized using patch clamp analysis. The effect on intrinsic excitability was measured using evoked action potentials recorded from hippocampal CA1 pyramidal neurons in mouse brain slices. Anticonvulsant activity was evaluated using the maximal electroshock seizure (MES) model, and tolerability was assessed by measuring spontaneous locomotor activity (sLMA). RESULTS: PRAX-562 potently and preferentially inhibited persistent INa induced by ATX-II or the SCN8A mutation N1768D (half-maximal inhibitory concentration [IC50 ] = 141 and 75 nmol·L-1 , respectively) relative to peak INa tonic/resting block (60× preference). PRAX-562 also exhibited potent use-dependent block (31× preference to tonic block). This profile is considerably different from standard NaV blockers, including carbamazepine (CBZ; persistent INa IC50 = 77 500 nmol·L-1 , preference ratios of 30× [tonic block], less use-dependent block observed at various frequencies). In contrast to CBZ, PRAX-562 reduced neuronal intrinsic excitability with only a minor reduction in action potential amplitude. PRAX-562 (10 mg/kg po) completely prevented evoked seizures without affecting sLMA (MES unbound brain half-maximal efficacious concentration = 4.3 nmol·L-1 , sLMA half-maximal tolerated concentration = 69.7 nmol·L-1 , protective index [PI] = 16×). In contrast, CBZ and lamotrigine (LTG) had PIs of approximately 5.5×, with significant overlap between doses that were anticonvulsant and that reduced locomotor activity. SIGNIFICANCE: PRAX-562 demonstrated robust preclinical anticonvulsant activity similar to CBZ but improved compared to LTG. PRAX-562 exhibited significantly improved preclinical tolerability compared with standard NaV blockers (CBZ and LTG), potentially due to the preference for persistent INa . Preferential targeting of persistent INa may represent a differentiated therapeutic option for diseases of hyperexcitability, where standard NaV blockers have demonstrated efficacy but poor tolerability.

Discovery of the First Orally Available, Selective KNa1.1 Inhibitor: In Vitro and In Vivo Activity of an Oxadiazole Series.

The gene KCNT1 encodes the sodium-activated potassium channel KNa1.1 (Slack, Slo2.2). Variants in the KCNT1 gene induce a gain-of-function (GoF) phenotype in ionic currents and cause a spectrum of intractable neurological disorders in infants and children, including epilepsy of infancy with migrating focal seizures (EIMFS) and autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE). Effective treatment options for KCNT1-related disease are absent, and novel therapies are urgently required. We describe the development of a novel class of oxadiazole KNa1.1 inhibitors, leading to the discovery of compound 31 that reduced seizures and interictal spikes in a mouse model of KCNT1 GoF.

Effects of mangrove cover on coastal erosion during a hurricane in Texas, USA.

We tested the hypothesis that mangroves provide better coastal protection than salt marsh vegetation using 10 1,008-m2 plots in which we manipulated mangrove cover from 0 to 100%. Hurricane Harvey passed over the plots in 2017. Data from erosion stakes indicated up to 26 cm of vertical and 970 cm of horizontal erosion over 70 months in the plot with 0% mangrove cover, but relatively little erosion in other plots. The hurricane did not increase erosion, and erosion decreased after the hurricane passed. Data from drone images indicated 196 m2 of erosion in the 0% mangrove plot, relatively little erosion in other plots, and little ongoing erosion after the hurricane. Transects through the plots indicated that the levee (near the front of the plot) and the bank (the front edge of the plot) retreated up to 9 m as a continuous function of decreasing mangrove cover. Soil strength was greater in areas vegetated with mangroves than in areas vegetated by marsh plants, or nonvegetated areas, and increased as a function of plot-level mangrove cover. Mangroves prevented erosion better than marsh plants did, but this service was nonlinear, with low mangrove cover providing most of the benefits.

Building Resources in Caregivers: Feasibility of a Brief Writing Intervention to Increase Benefit Finding in Caregivers.

The Building Resources in Caregivers (BRiC) is a pilot feasibility trial that compared the effects of a 2-week benefit finding writing expressive intervention to a control intervention, who wrote about the weather. Caregivers completed primary (benefit finding) and secondary (quality of life, depression and anxiety) outcome measures at pre (t1), immediately post-test (t2) and 1 month later (t3). They also completed measures relating to trial feasibility, difficulty, and acceptance. Using complete case analysis only, analysis revealed no effect of the intervention for primary or secondary outcomes. Despite this, there were no differences between the intervention and control groups on key feasibility measures. Caregivers in the control condition were less likely to recommend this to other caregivers. Moreover, qualitative commentary provided by caregivers suggested that not everyone enjoyed the writing, some found it stressful, offering up some explanation for our findings. Our pilot trial suggests that any future benefit-finding writing intervention would require several procedure modifications including tailoring to a specific cohort of caregivers, in particular those who like writing, before it has some utility as a psychosocial intervention.

Helping parents to help children overcome fear: The influence of a short video tutorial.

OBJECTIVES: Anxiety runs in families, and its transmission is largely environmental. However, studies rarely explore this process in clinically anxious parents or ask participants to face a genuine fear. We also do not know whether this process is modifiable. This study will explore these questions using a sample of clinically anxious parents. DESIGN: Experimental design comparing clinically anxious parents with non-anxious parents, and exploring the effects of a tutorial intervention versus a control group. METHODS: Parents with and without anxiety disorders and their children (5-9 years) participated (N = 72). Children chose two fearful animal stimuli. Parents helped the child approach the first in graded steps. The following parental behaviours were recorded: positive/negative verbal information; positive/negative modelling; encouragement/praising of approach/avoidance behaviours. Half the parents were then randomly assigned to a short video tutorial advising how to help children cope with fearful situations. The remainder watched a control video. The approach task was repeated with the second stimulus. RESULTS: Parenting behaviours fell into two categories: 'approach parenting' (encouraging/praising/modelling approach; positive verbal information) and 'avoidance parenting' (encouraging/praising/modelling avoidance; negative verbal information). The parenting tutorial increased 'approach parenting' and decreased 'avoidance parenting' and was associated with increased child approach towards fearful stimuli. This was not moderated by parent or child anxiety. CONCLUSIONS: Parenting, particularly 'avoidance parenting', is associated with children's approach and avoidance. A short video tutorial modified these parenting behaviours and reduced avoidance. These effects were apparent regardless of parent or child anxiety level. PRACTITIONER POINTS: Avoidance and approach parenting may influence children's response to fearful stimuli. Avoidance parenting may be more problematic than lack of approach parenting. Approach and avoidance parenting are amenable to manipulation by short video tutorial. Parenting improvement resulted in increased approach behaviour in children.

The location discrimination reversal task in mice is sensitive to deficits in performance caused by aging, pharmacological and other challenges.

Deficits in hippocampal-mediated pattern separation are one aspect of cognitive function affected in schizophrenia (SZ) or Alzheimer's disease (AD). To develop novel therapies, it is beneficial to explore this specific aspect of cognition preclinically. The location discrimination reversal (LDR) task is a hippocampal-dependent operant paradigm that evaluates spatial learning and cognitive flexibility using touchscreens. Here we assessed baseline performance as well as multimodal disease-relevant manipulations in mice. Mice were trained to discriminate between the locations of two images where the degree of separation impacted performance. Administration of putative pro-cognitive agents was unable to improve performance at narrow separation. Furthermore, a range of disease-relevant manipulations were characterized to assess whether performance could be impaired and restored. Pertinent to the cholinergic loss in AD, scopolamine (0.1 mg/kg) produced a disruption in LDR, which was attenuated by donepezil (1 mg/kg). Consistent with NMDA hypofunction in cognitive impairment associated with SZ, MK-801 (0.1 mg/kg) also disrupted performance; however, this deficit was not modified by rolipram. Microdeletion of genes associated with SZ (22q11) resulted in impaired performance, which was restored by rolipram (0.032 mg/kg). Since aging and inflammation affect cognition and are risk factors for AD, these aspects were also evaluated. Aged mice were slower to acquire the task than young mice and did not reach the same level of performance. A systemic inflammatory challenge (lipopolysaccharide (LPS), 1 mg/kg) produced prolonged (7 days) deficits in the LDR task. These data suggest that LDR task is a valuable platform for evaluating disease-relevant deficits in pattern separation and offers potential for identifying novel therapies.

Preventing family transmission of anxiety: Feasibility RCT of a brief intervention for parents.

OBJECTIVES: Children of anxious parents are at high risk of anxiety disorders themselves. The evidence suggests that this is due to environmental rather than genetic factors. However, we currently do little to reduce this risk of transmission. There is evidence that supporting parenting in those with mental health difficulties can ameliorate this risk. Therefore, the objective of this study was to test the feasibility of a new one-session, group-based, preventive parenting intervention for parents with anxiety disorders. DESIGN: Feasibility Randomized Controlled Trial. METHODS: A total of 100 parents with anxiety disorders, recruited from adult mental health services in England (and child aged 3-9 years), were randomized to receive the new intervention (a 1-day, group workshop), or to treatment as usual. Children's anxiety disorder and anxiety symptoms were assessed to 12 months by outcome assessors who were blind to group allocation. Exploratory analyses were conducted on an intention to treat basis, as far as possible. RESULTS: A total of 51 participants were randomized to the intervention condition and 49 to the control condition (82% and 80% followed to 12 months, respectively). The attendance rate was 59%, and the intervention was highly acceptable to parents who received it. The RCT was feasible, and 12-month follow-up attrition rates were low. Children whose parents were in the control condition were 16.5% more likely to have an anxiety disorder at follow-up than those in the intervention group. No adverse events were reported. CONCLUSIONS: An inexpensive, light-touch, psycho-educational intervention may be useful in breaking the intergenerational cycle of transmission of anxiety disorders. A substantive trial is warranted. PRACTITIONER POINTS: Anxiety disorders run in families, but we currently do little to help anxious parents to raise confident children. A brief group workshop was highly acceptable to such parents and was very inexpensive to run. Children of parents who took part in the brief intervention were 16.5% less likely to have an anxiety disorder, 1 year later, than children whose parents were in the control group. This was a feasibility study, and while it showed that both the intervention and the research were feasible, the study needs replicating with a much larger sample. Many parents faced barriers to attending the workshop, and future efforts should focus on widening accessibility. We were unable to obtain sufficient self-report data from children, so the outcomes are based on parent report only.

Verbal working memory and functional large-scale networks in schizophrenia.

The aim of this study was to test whether bilinear and nonlinear effective connectivity (EC) measures of working memory fMRI data can differentiate between patients with schizophrenia (SZ) and healthy controls (HC). We applied bilinear and nonlinear Dynamic Causal Modeling (DCM) for the analysis of verbal working memory in 16 SZ and 21 HC. The connection strengths with nonlinear modulation between the dorsolateral prefrontal cortex (DLPFC) and the ventral tegmental area/substantia nigra (VTA/SN) were evaluated. We used Bayesian Model Selection at the group and family levels to compare the optimal bilinear and nonlinear models. Bayesian Model Averaging was used to assess the connection strengths with nonlinear modulation. The DCM analyses revealed that SZ and HC used different bilinear networks despite comparable behavioral performance. In addition, the connection strengths with nonlinear modulation between the DLPFC and the VTA/SN area showed differences between SZ and HC. The adoption of different functional networks in SZ and HC indicated neurobiological alterations underlying working memory performance, including different connection strengths with nonlinear modulation between the DLPFC and the VTA/SN area. These novel findings may increase our understanding of connectivity in working memory in schizophrenia.

The Discovery of a Novel Phosphodiesterase (PDE) 4B-Preferring Radioligand for Positron Emission Tomography (PET) Imaging.

As part of our effort in identifying phosphodiesterase (PDE) 4B-preferring inhibitors for the treatment of central nervous system (CNS) disorders, we sought to identify a positron emission tomography (PET) ligand to enable target occupancy measurement in vivo. Through a systematic and cost-effective PET discovery process, involving expression level (Bmax) and biodistribution determination, a PET-specific structure-activity relationship (SAR) effort, and specific binding assessment using a LC-MS/MS "cold tracer" method, we have identified 8 (PF-06445974) as a promising PET lead. Compound 8 has exquisite potency at PDE4B, good selectivity over PDE4D, excellent brain permeability, and a high level of specific binding in the "cold tracer" study. In subsequent non-human primate (NHP) PET imaging studies, [18F]8 showed rapid brain uptake and high target specificity, indicating that [18F]8 is a promising PDE4B-preferring radioligand for clinical PET imaging.

The isozyme selective phosphodiesterase-4 inhibitor, ABI-4, attenuates the effects of lipopolysaccharide in human cells and rodent models of peripheral and CNS inflammation.

Inhibitors of phosphodiesterase-4 (PDE4) have been approved for the treatment of inflammatory disorders, but are associated with dose-limiting nausea and vomiting. These side effects are hypothesized to be mediated by inhibition of the PDE4D isozyme. Here we demonstrate the anti-inflammatory effects of the novel brain penetrant PDE4D-sparing PDE4 inhibitor, ABI-4. ABI-4 was a potent (EC50∼14nM) inhibitor of lipopolysaccharide (LPS) induced TNF-α release from mouse microglia and human PBMCs. ABI-4 (0.32mg/kg) blocked LPS-induced release of pro-inflammatory cytokines (TNF-α, IL-1ß, IL-6) in blood and brain of mice. In a rat model of endotoxin induced uveitis, ABI-4 (0.03-0.3mg/kg) demonstrated steroid-like efficacy in preventing leucocyte infiltration of the aqueous humor when administered 4h after LPS. LPS (0.32mg/kg×5days) caused a 30% upregulation of translocator protein (TSPO) binding which was prevented by co-administration of ABI-4 (0.32mg/kg). In a paradigm to assess motivation, LPS (0.32mg/kg) reduced the number of rewards received, whereas the effect was significantly blunted in mice dosed with ABI-4 (P<0.05) or in PDE4B-/- mice. PDE4B was also shown to modulate brain and plasma levels of TNF-α and IL-1ß in aged mice. Aged mice dosed chronically with ABI-4 (0.32mg/kg) as well as aged PDE4B-/- mice, had significantly lower levels of TNF-α and IL-1ß in brain and plasma relative to vehicle treated or PDE4+/+ mice. Together these data demonstrate that the PDE4D sparing, PDE4 inhibitor, ABI-4 retains potency and efficacy in exerting anti-inflammatory effects. This mechanism warrants further investigation in human disorders involving neuroinflammation.

Defining the brain circuits involved in psychiatric disorders: IMI-NEWMEDS.

Despite the vast amount of research on schizophrenia and depression in the past two decades, there have been few innovative drugs to treat these disorders. Precompetitive research collaborations between companies and academic groups can help tackle this innovation deficit, as illustrated by the achievements of the IMI-NEWMEDS consortium.