Deep‐red to near‐infrared (NIR) OLEDs, which yield emission peak wavelengths beyond λ=660 nm, are applicable as unique light sources in plant growth or health monitoring systems. Compared with other ...visible‐spectrum OLEDs, however, research in the field of deep‐red OLEDs is not as advanced. In this work, three new types of dibenzofuran‐based host materials are developed as n‐type exciplex host partners. Combining these with the deep‐red iridium complex bis(2,3‐diphenylquinoxaline)iridium(dipivaloylmethane) ((DPQ)2Ir(dpm)) and N,N′‐di(naphalene‐1‐yl)‐N,N′‐diphenylbenzidine (α‐NPD) as a p‐type exciplex host partner, a highly efficient deep‐red OLED can be realized with a maximum external quantum efficiency (ηext,max) of over 16 % with Comission Internationale de l′Éclairge (CIE) coordinates of (0.71, 0.28). In addition, the effect of the doping concentration and the p/n ratio of the exciplex host on the efficiency and the lifetime of the OLEDs are investigated. Consequently, the optimized device exhibits a ηext,max of over 15 % and a six‐time longer lifetime operating at high brightness of 100 cd m−2 compared with other state‐of‐the‐art deep‐red OLEDs.
Deep red: A series of dibenzofuran‐based n‐type exciplex host partners is successfully developed for high‐efficiency and stable deep‐red phosphorescent organic light‐emitting devices (OLEDs) with an emission peak wavelength of λ=675 nm (see figure). The optimized device exhibits an external quantum efficiency of over 15 % and a six‐time longer lifetime compared with other state‐of‐the‐art OLEDs.
The chemogenetic technology referred to as designer receptors exclusively activated by designer drugs (DREADDs) offers reversible means to control neuronal activity for investigating its functional ...correlation with behavioral action. Deschloroclozapine (DCZ), a recently developed highly potent and selective DREADD actuator, displays a capacity to expand the utility of DREADDs for chronic manipulation without side effects in nonhuman primates, which has not yet been validated. Here we investigated the pharmacokinetics and behavioral effects of orally administered DCZ in female and male macaque monkeys. Pharmacokinetic analysis and PET occupancy examination demonstrated that oral administration of DCZ yielded slower and prolonged kinetics, and that its bioavailability was 10%-20% of that in the case of systemic injection. Oral DCZ (300-1000 μg/kg) induced significant working memory impairments for at least 4 h in monkeys with hM4Di expressed in the dorsolateral prefrontal cortex (Brodmann's area 46). Repeated daily oral doses of DCZ consistently caused similar impairments over two weeks without discernible desensitization. Our results indicate that orally delivered DCZ affords a less invasive strategy for chronic but reversible chemogenetic manipulation of neuronal activity in nonhuman primates, and this has potential for clinical application.
The use of designer receptors exclusively activated by designer drugs (DREADDs) for chronic manipulation of neuronal activity for days to weeks may be feasible for investigating brain functions and behavior on a long time-scale, and thereby for developing therapeutics for brain disorders, such as epilepsy. Here we performed pharmacokinetics and
occupancy study of orally administered deschloroclozapine to determine a dose range suitable for DREADDs studies. In monkeys expressing hM4Di in the prefrontal cortex, single and repeated daily doses significantly induced working-memory impairments for hours and over two weeks, respectively, without discernible desensitization. These results indicate that orally delivered deschloroclozapine produces long-term stable chemogenetic effects, and holds great promise for the translational use of DREADDs technology.
The term 'temporal discounting' describes both choice preferences and motivation for delayed rewards. Here we show that neuronal activity in the dorsal part of the primate caudate head (dCDh) signals ...the temporally discounted value needed to compute the motivation for delayed rewards. Macaque monkeys performed an instrumental task, in which visual cues indicated the forthcoming size and delay duration before reward. Single dCDh neurons represented the temporally discounted value without reflecting changes in the animal's physiological state. Bilateral pharmacological or chemogenetic inactivation of dCDh markedly distorted the normal task performance based on the integration of reward size and delay, but did not affect the task performance for different reward sizes without delay. These results suggest that dCDh is involved in encoding the integrated multi-dimensional information critical for motivation.
It has been widely accepted that dopamine (DA) plays a major role in motivation, yet the specific contribution of DA signaling at D
1
-like receptor (D
1
R) and D
2
-like receptor (D
2
R) to ...cost–benefit trade-off remains unclear. Here, by combining pharmacological manipulation of DA receptors (DARs) and positron emission tomography (PET) imaging, we assessed the relationship between the degree of D
1
R/D
2
R blockade and changes in benefit- and cost-based motivation for goal-directed behavior of macaque monkeys. We found that the degree of blockade of either D
1
R or D
2
R was associated with a reduction of the positive impact of reward amount and increasing delay discounting. Workload discounting was selectively increased by D
2
R antagonism. In addition, blocking both D
1
R and D
2
R had a synergistic effect on delay discounting but an antagonist effect on workload discounting. These results provide fundamental insight into the distinct mechanisms of DA action in the regulation of the benefit- and cost-based motivation, which have important implications for motivational alterations in both neurological and psychiatric disorders.
Previous work found that 11Cdeschloroclozapine (11CDCZ) is superior to 11Cclozapine (11CCLZ) for imaging Designer Receptors Exclusively Activated by Designer Drugs (DREADDs). This study used PET to ...quantitatively and separately measure the signal from transfected receptors, endogenous receptors/targets, and non-displaceable binding in other brain regions to better understand this superiority. A genetically-modified muscarinic type-4 human receptor (hM4Di) was injected into the right amygdala of a male rhesus macaque. 11CDCZ and 11CCLZ PET scans were conducted 2–24 months later. Uptake was quantified relative to the concentration of parent radioligand in arterial plasma at baseline (n = 3 scans/radioligand) and after receptor blockade (n = 3 scans/radioligand). Both radioligands had greater uptake in the transfected region and displaceable uptake in other brain regions. Displaceable uptake was not uniformly distributed, perhaps representing off-target binding to endogenous receptor(s). After correction, 11CDCZ signal was 19% of that for 11CCLZ, and background uptake was 10% of that for 11CCLZ. Despite stronger 11CCLZ binding, the signal-to-background ratio for 11CDCZ was almost two-fold greater than for 11CCLZ. Both radioligands had comparable DREADD selectivity. All reference tissue models underestimated signal-to-background ratio in the transfected region by 40%–50% for both radioligands. Thus, the greater signal-to-background ratio of 11CDCZ was due to its lower background uptake.
The ability to infer others’ mental states is essential to social interactions. This ability, critically evaluated by testing whether one attributes false beliefs (FBs) to others, has been considered ...to be uniquely hominid and to accompany the activation of a distributed brain network. We challenge the taxon specificity of this ability and identify the causal brain locus by introducing an anticipatory-looking FB paradigm combined with chemogenetic neuronal manipulation in macaque monkeys. We find spontaneous gaze bias of macaques implicitly anticipating others’ FB-driven actions. Silencing of the medial prefrontal neuronal activity with inhibitory designer receptor exclusively activated by designer drugs (DREADDs) specifically eliminates the implicit gaze bias while leaving the animals’ visually guided and memory-guided tracking abilities intact. Thus, neuronal activity in the medial prefrontal cortex could have a causal role in FB-attribution-like behaviors in the primate lineage, emphasizing the importance of probing the neuronal mechanisms underlying theory of mind with relevant macaque animal models.
Display omitted
•Macaques exhibit implicit gaze bias anticipating others’ false-belief-driven actions•Inhibitory DREADDs silencing medial prefrontal neurons abolish the gaze bias•Macaques and humans share brain networks for false-belief attribution-like behaviors•Among the network, the medial prefrontal cortex is causally linked to mental attribution
Hayashi et al. ask whether only hominids possess theory of mind. They show macaques’ implicit gaze bias anticipating others’ false-belief-guided actions, which is abolished by chemogenetic silencing of the medial prefrontal cortex. Thus, false-belief attribution-like behaviors of non-human primates are underpinned by shared neuronal mechanisms with humans.
Although aberrations in the number and function of glutamate AMPA (α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid) receptors are thought to underlie neuropsychiatric disorders, no methods are ...currently available for visualizing AMPA receptors in the living human brain. Here we developed a positron emission tomography (PET) tracer for AMPA receptors. A derivative of 4-2-(phenylsulfonylamino)ethylthio-2,6-difluoro-phenoxyacetamide radiolabeled with
C (
CK-2) showed specific binding to AMPA receptors. Our clinical trial with healthy human participants confirmed reversible binding of
CK-2 in the brain according to Logan graphical analysis (UMIN000020975; study design: non-randomized, single arm; primary outcome: dynamics and distribution volumes of
CK-2 in the brain; secondary outcome: adverse events of
CK-2 during the 4-10 d following dosing; this trial met prespecified endpoints). In an exploratory clinical study including patients with epilepsy, we detected increased
CK-2 uptake in the epileptogenic focus of patients with mesial temporal lobe epilepsy, which was closely correlated with the local AMPA receptor protein distribution in surgical specimens from the same individuals (UMIN000025090; study design: non-randomized, single arm; primary outcome: correlation between
CK-2 uptake measured with PET before surgery and AMPA receptor protein density examined by biochemical study after surgery; secondary outcome: adverse events during the 7 d following PET scan; this trial met prespecified endpoints). Thus,
CK-2 is a potent PET tracer for AMPA receptors, potentially providing a tool to examine the involvement of AMPA receptors in neuropsychiatric disorders.
Colony-stimulating factor 1 receptor (CSF1R) is a specific biomarker for microglia. In this study, we developed a novel PET radioligand for CSF1R, 11C-GW2580, and compared it to a reported CSF1R ...tracer, 11C-CPPC, in mouse models of acute and chronic neuroinflammation and a rhesus monkey. Dynamic 11C-GW2580- and 11C-CPPC-PET images were quantified by reference tissue-based models and standardized uptake value ratio. Both tracers exhibited increased uptake in the lesioned striata of lipopolysaccharide-injected mice and in the forebrains of AppNL-G-F/NL-G-F-knock-in mice, spatially in agreement with an increased 18-kDa translocator protein radioligand retention. Moreover, 11C-GW2580 captured changes in CSF1R availability more sensitively than 11C-CPPC, with a larger dynamic range and a smaller inter-individual variability, in these model animals. PET imaging of CSF1R in a rhesus monkey displayed moderate-to-high tracer retention in the brain at baseline. Homologous blocker (i. e. unlabeled tracer) treatment reduced the uptake of 11C-GW2580 by ∼30% in all examined brain regions except for centrum semi-ovale white matter, but did not affect the retention of 11C-CPPC. In summary, our results demonstrated that 11C-GW2580-PET captured inflammatory microgliosis in the mouse brain with higher sensitivity than a reported radioligand, and displayed saturable binding in the monkey brain, potentially providing an imaging-based quantitative biomarker for reactive microgliosis.
Positron emission tomography (PET) allows biomolecular tracking but PET monitoring of brain networks has been hampered by a lack of suitable reporters. Here, we take advantage of bacterial ...dihydrofolate reductase, ecDHFR, and its unique antagonist, TMP, to facilitate in vivo imaging in the brain. Peripheral administration of radiofluorinated and fluorescent TMP analogs enabled PET and intravital microscopy, respectively, of neuronal ecDHFR expression in mice. This technique can be used to the visualize neuronal circuit activity elicited by chemogenetic manipulation in the mouse hippocampus. Notably, ecDHFR‐PET allows mapping of neuronal projections in non‐human primate brains, demonstrating the applicability of ecDHFR‐based tracking technologies for network monitoring. Finally, we demonstrate the utility of TMP analogs for PET studies of turnover and self‐assembly of proteins tagged with ecDHFR mutants. These results establish opportunities for a broad spectrum of previously unattainable PET analyses of mammalian brain circuits at the molecular level.
SYNOPSIS
ecDHFR‐based reporter system can be utilized for bimodal fluorescence and Positron emission tomography (PET) imaging of expression and dynamics of its fused protein of interest in living animal brains, offering broad‐spectrum analyses of a mammalian deep brain circuit at molecular levels.
We established a genetically encoded ecDHFR‐based reporter system applicable for bimodal optical and PET imaging in living animal brains.
The reporter gene expression driven by an activity‐dependent promoter illuminates neuronal ensemble activities elicited by chemogenetic manipulation in the mouse hippocampal circuit.
ecDHFR/TMP systems enable visualization of neuronal tracts in deep brain regions of non‐human primates.
The utility of TMP analogs for PET monitoring of aggregation and turnover of proteins tagged with mutant forms of ecDHFR.
Application of bacterial dihydrofolate reductase ecDHFR and its unique antagonist TMP achieves a broad spectrum of previously unattainable in vivo PET analyses of mammalian brain circuits at the molecular level.
Purpose
Phosphodiesterase (PDE) 7 is a potential therapeutic target for neurological and inflammatory diseases, although in vivo visualization of PDE7 has not been successful. In this study, we aimed ...to develop
11
CMTP38 as a novel positron emission tomography (PET) ligand for PDE7.
Methods
11
CMTP38 was radiosynthesized by
11
C-cyanation of a bromo precursor with
11
CHCN. PET scans of rat and rhesus monkey brains and in vitro autoradiography of brain sections derived from these species were conducted with
11
CMTP38. In monkeys, dynamic PET data were analyzed with an arterial input function to calculate the total distribution volume (
V
T
). The non-displaceable binding potential (
BP
ND
) in the striatum was also determined by a reference tissue model with cerebellar reference. Finally, striatal occupancy of PDE7 by an inhibitor was calculated in monkeys according to changes in
BP
ND
.
Results
11
CMTP38 was synthesized with radiochemical purity ≥99.4% and molar activity of 38.6 ± 12.6 GBq/μmol. Autoradiography revealed high radioactivity in the striatum and its reduction by non-radiolabeled ligands, in contrast with unaltered autoradiographic signals in other regions. In vivo PET after radioligand injection to rats and monkeys demonstrated that radioactivity was rapidly distributed to the brain and intensely accumulated in the striatum relative to the cerebellum. Correspondingly, estimated
V
T
values in the monkey striatum and cerebellum were 3.59 and 2.69 mL/cm
3
, respectively. The cerebellar
V
T
value was unchanged by pretreatment with unlabeled MTP38. Striatal
BP
ND
was reduced in a dose-dependent manner after pretreatment with MTP-X, a PDE7 inhibitor. Relationships between PDE7 occupancy by MTP-X and plasma MTP-X concentration could be described by Hill’s sigmoidal function.
Conclusion
We have provided the first successful preclinical demonstration of in vivo PDE7 imaging with a specific PET radioligand.
11
CMTP38 is a feasible radioligand for evaluating PDE7 in the brain and is currently being applied to a first-in-human PET study.
PDF
![[11C]deschloroclozapine is ...](http://api.summon.serialssolutions.com/2.0.0/image/issn/XR4PS5YY4K/0271-678X/small "[11C]deschloroclozapine is an improved PET radioligand for quantifying a human muscarinic DREADD expressed in monkey brain")
