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Cyclooxygenase-2 (COX-2) is a target for inflammation and colorectal cancer (CRC). This study evaluated the COX-2 neuro-PET radiopharmaceutical, [11C]MC1, in CRC xenograft mice. [11C]MC1 was evaluated in ICRscid mice with HT-29 and HCT-116 CRC xenografts, with high and low COX-2 expression, respectively, by immunohistochemistry, cellular uptake, dynamic PET/MR imaging, ex vivo biodistribution, and radiometabolite analysis. HT-29 xenografts were well visualized with [11C]MC1 using PET/MR. Time-activity curves revealed steady tumor radioactivity accumulation in HT-29 xenografts that plateaued from 40 to 60 min (3.07 ± 0.65 %ID/g) and was significantly reduced by pre-treatment with MC1 or celecoxib (1.62 ± 0.29 and 1.18 ± 0.21 %ID/g, respectively, p = 0.045 and p = 0.005). Radiometabolite analysis showed that [11C]MC1 accounted for >90 % of tumor radioactivity, with

Mutations in the gene encoding activin receptor-like kinase 2 (ALK2) are implicated in the pathophysiology of a pediatric brainstem cancer, diffuse intrinsic pontine glioma (DIPG). Inhibitors of ALK2 that cross the blood-brain barrier have been proposed as a method of treatment for DIPG. As part of an open science approach to radiopharmaceutical and drug discovery, we developed 11C-labeled radiotracers from potent and selective lead ALK2 inhibitors to investigate their brain permeability through positron emission tomography (PET) neuroimaging. Four radiotracers were synthesized by 11C-methylation and assessed by dynamic PET imaging in healthy Sprague-Dawley rats. One of the compounds, [ 11 C]M4K2127, showed high initial brain uptake (SUV ∼ 2), including in the region of interest (pons). This data supports the use of this chemotype as a brain penetrant ALK2 inhibitor that permeates evenly into the pons with potential application for the treatment of DIPG.

CBD-2115 was selected from a library of 148 compounds based on a pyridinyl-indole scaffold as a first-in-class 4R-tau radiotracer. In vitro binding assays showed [3H]CBD-2115 had a KD value of 6.9 nM and a nominal Bmax of 500 nM in 4R-tau expressing P301L transgenic mouse tissue. In binding assays with human brain tissue homogenates, [3H]CBD-2115 has a higher affinity (4.9 nM) for progressive supranuclear palsy specific 4R-tau deposits than [3H]flortaucipir (45 nM) or [3H]MK-6240 (>50 nM). [18F]CBD-2115 was reliably synthesized (3-11% radiochemical yield with molar activity of 27-111 GBq/μmol and >97% radiochemical purity). Dynamic PET imaging was conducted in mice, rats, and nonhuman primates, and all species showed initial brain uptake of 0.5-0.65 standardized uptake value with fast clearance from normal tissues. [3H]CBD-2115 could be a useful lead radioligand for further research in 4R-tauopathies, and PET radiotracer development will focus on improving brain uptake and binding affinity.

Serum amyloid P component (SAP) is a universal constituent of human amyloid deposits including those in Alzheimer's disease. SAP has been observed to be elevated in patients with depression, and higher SAP levels are associated with better response to the antidepressant escitalopram. The mechanisms underlying these clinical observations remain unclear. We examined the effect of SAP on serotonin transporter (SERT) expression and localization using Western blot, confocal microscopy, and positron emission tomography with the radioligand [

Cyclooxygenase-1 (COX-1), a biomarker for neuroinflammation, is implicated in the progression and prognosis of ovarian cancer (OvCa). This study considered the repurposing of 11C-labeled 1,5-bis(4-methoxyphenyl)-3-(2,2,2-trifluoroethoxy)-1H-1,2,4-triazole (11C-PS13), a COX-1 PET neuroimaging radiopharmaceutical, in OvCa xenograft mouse models. Methods:11C-PS13 was evaluated in ICRscid mice with subcutaneous or intraperitoneal human OVCAR-3 OvCa xenografts by dynamic PET/MRI, ex vivo biodistribution, and radiometabolite analysis of plasma and tumor. Results: OVCAR-3 xenografts were well visualized with 11C-PS13 in xenograft mouse models. Time–activity curves revealed a steady accumulation of tumor radioactivity that plateaued from 40 to 60 min and was significantly reduced by pretreatment with ketoprofen (3.56 ± 0.81 and 1.30 ± 0.18 percentage injected dose/g without and with pretreatment, respectively, P = 0.01). Radiometabolite analysis showed that intact 11C-PS13 accounted for more than 80% of radioactivity in the tumor, with less than 20% in plasma, at 40 min after injection. Conclusion:11C-PS13 shows promise for PET imaging of COX-1 in OvCa, and rapid translation for clinical cancer research should be considered.

The endocannabinoid enzyme, fatty acid amide hydrolase (FAAH), has been proposed as a therapeutic target for alcohol use disorder (AUD) and co-morbid psychiatric illnesses. Investigating this target in the living human brain and its relationship to clinical outcome is a critical step of informed drug development. Our objective was to establish whether brain FAAH levels are low in individuals with AUD and related to drinking behavior. In this pilot study, treatment-seeking patients with AUD completed two PET scans with the FAAH radiotracer [C-11]CURB after 3–7 days (n = 14) and 2–4 weeks (n = 9) of monitored abstinence. Healthy controls (n = 25) completed one scan. FAAH genetic polymorphism (rs324420) and blood concentrations of anandamide and other N-acylethanolamines metabolized by FAAH were determined and AUD symptoms assessed. In AUD, brain FAAH levels were globally lower than controls during early abstinence (F(1,36) = 5.447; p = 0.025)) and FAAH substrates (anandamide, oleoylethanolamide, and N-docosahexaenoylethanolamide) were significantly elevated (30–67%). No significant differences in FAAH or FAAH substrates were noted after 2–4 weeks abstinence. FAAH levels negatively correlated with drinks per week (r = −0.57, p = 0.032) and plasma concentrations of the three FAAH substrates (r > 0.57; p

Ibrutinib is a first-generation Bruton's tyrosine kinase (BTK) inhibitor that has shown efficacy in autoimmune diseases and has consequently been developed as a positron emission tomography (PET) radiotracer. Herein, we report the automated radiosynthesis of [11C]ibrutinib through 11C-carbonylation of the acrylamide functional group, by reaction of the secondary amine precursor with [11C]CO, iodoethylene, and palladium–NiXantphos. [11C]Ibrutinib was reliably formulated in radiochemical yields of 5.4% ± 2.5% (non-decay corrected; n = 9, relative to starting [11C]CO2), radiochemical purity >99%, and molar activity of 58.8 ± 30.8 GBq/μmol (1.55 ± 0.83 Ci/μmol). Preliminary PET/magnetic resonance imaging with [11C]ibrutinib in experimental autoimmune encephalomyelitis (EAE) mice showed a 49% higher radioactivity accumulation in the spinal cord of mice with EAE scores of 2.5 vs. sham mice.

PURPOSE: Cyclooxygenase-2 (COX-2) is a target for inflammation and colorectal cancer (CRC). This study evaluated the COX-2 neuro-PET radiopharmaceutical, [(11)C]MC1, in CRC xenograft mice. PROCEDURES: [(11)C]MC1 was evaluated in ICRscid mice with HT-29 and HCT-116 CRC xenografts, with high and low COX-2 expression, respectively, by immunohistochemistry, cellular uptake, dynamic PET/MR imaging, ex vivo biodistribution, and radiometabolite analysis. RESULTS: HT-29 xenografts were well visualized with [(11)C]MC1 using PET/MR. Time-activity curves revealed steady tumor radioactivity accumulation in HT-29 xenografts that plateaued from 40 to 60 min (3.07 ± 0.65 %ID/g) and was significantly reduced by pre-treatment with MC1 or celecoxib (1.62 ± 0.29 and 1.18 ± 0.21 %ID/g, respectively, p = 0.045 and p = 0.005). Radiometabolite analysis showed that [(11)C]MC1 accounted for >90 % of tumor radioactivity, with

The growing number of surveillance cameras imposes great demand on high efficiency video coding. Although modern video coding standards have significantly improved the video coding efficiency, they...

Posttraumatic stress disorder (PTSD) is a debilitating mental health condition that results from exposure to traumatic event(s). Decreased astrocyte-related proteins (e.g., glial fibrillary acidic protein, GFAP) and atrophic astrocytes in corticolimbic brain areas implicated in PTSD have been reported in experimental models suggesting that astrocyte pathology may be a feature of this disorder. We used positron emission tomography (PET) of the monoamine oxidase (MAO)-B probe [

[Image: see text] Glycogen synthase kinase-3 (GSK-3) is a positron emission tomography (PET) imaging target with implications in the pathogenesis of Alzheimer’s disease (AD). This preliminary study evaluates human AD and transgenic P301L mouse brain tissues using the GSK-3-targeting radiotracers [(3)H]PF-367 and [(3)H]OCM-44 in radioligand binding assays. A saturation analysis showed decreased GSK-3 density in female human AD compared to a normal healthy brain. Equivalence in density (B(max)), affinity (K(d)), and apparent affinity (K(i)) of both radiotracers was demonstrated to enable their interchangeability for in vitro evaluations of GSK-3 expression. An evaluation of P301L mouse brain by [(3)H]/[(11)C]OCM-44 delineated differences in the B(max) of GSK-3 between the control and transgenic mice within male subjects. PET imaging showed similar trends to those observed in vitro. Sex differences are revealed as a potential parameter to consider in the development of GSK-3-targeted diagnostics and therapeutics and could guide recruitment for clinical studies.

Objective To establish in an exploratory neuroimaging study whether γ-hydroxybutyrate (sodium oxybate [SO]), a sedative, anti-narcoleptic drug with abuse potential, transiently inhibits striatal dopamine release in the human. Methods Ten healthy participants (30 years; 6M, 4F) and one participant with narcolepsy received a baseline positron emission tomography scan of [C-11]raclopride, a D2/3 dopamine receptor radioligand sensitive to dopamine occupancy, followed approximately one week later by an oral sedative 3g dose of SO and two [C-11]raclopride scans (1 h, 7 h post SO). Plasma SO levels and drowsiness duration were assessed. Results No significant changes were detected in [C-11]raclopride binding in striatum overall 1 or 7 h after SO, but a small non-significant increase in [C-11]raclopride binding, implying decreased dopamine occupancy, was noted in limbic striatal subdivision at one hour (+6.5%; p uncorrected = 0.045; +13.2%, narcolepsy participant), returning to baseline at 7 h. A positive correlation was observed between drowsiness duration and percent change in [C-11]raclopride binding in limbic striatum (r = 0.73; p = 0.017). Conclusions We did not find evidence in this sample of human subjects of a robust striatal dopamine change, as was reported in non-human primates. Our preliminary data, requiring extension, suggest that a 3g sedative SO dose might cause slight transient inhibition of dopamine release in limbic striatum.

Background: Upregulation of the endocannabinoid enzyme fatty acid amide hydrolase (FAAH) has been linked to abnormal activity in frontoamygdalar circuits, a hallmark of posttraumatic stress disorder. We tested the hypothesis that FAAH levels in the amygdala were negatively correlated with functional connectivity between the amygdala and prefrontal cortex, subserving stress and affect control. Methods: Thirty-one healthy participants completed positron emission tomography (PET) imaging with the FAAH probe [C-11]CURB, and resting-state functional MRI scans. Participants were genotyped for the FAAH polymorphism rs324420, and trait neuroticism was assessed. We calculated amygdala functional connectivity using predetermined regions of interest (including the subgenual ventromedial prefrontal cortex [sgvmPFC] and the dorsal anterior cingulate cortex [dACC]) and a seed-to-voxel approach. We conducted correlation analyses on functional connectivity, with amygdala [C-11]CURB binding as a variable of interest. Results: The strength of amygdala functional connectivity with the sgvmPFC and dACC was negatively correlated with [C-11]CURB binding in the amygdala (sgvmPFC: r = −0.38, q = 0.04; dACC: r = –0.44; q = 0.03). Findings were partly replicated using the seed-to-voxel approach, which showed a cluster in the ventromedial prefrontal cortex, including voxels in the dACC but not the sgvmPFC (cluster-level, family-wise error rate corrected p < 0.05). Limitations: We did not replicate earlier findings of a relationship between an FAAH polymorphism (rs324420) and amygdala functional connectivity. Conclusion: Our data provide preliminary evidence that lower levels of FAAH in the amygdala relate to increased frontoamygdalar functional coupling. Our findings were consistent with the role of FAAH in regulating brain circuits that underlie fear and emotion processing in humans.

Discovery of novel PET radiotracers targeting neuroinflammation (microglia and astrocytes) is actively pursued. Employing a lipopolysaccharide (LPS) rat model, this longitudinal study evaluated the translocator protein 18-kDa radiotracer [18F]FEPPA (primarily microglia) and monoamine oxidase B radiotracers [11C]L-deprenyl and [11C]SL25.1188 (astrocytes preferred). Increased [18F]FEPPA binding peaked at 1 week in LPS-injected striatum whereas increased lazabemide-sensitive [11C]L-deprenyl binding developed later. No increase in radiotracer uptake was observed for [11C]SL25.1188. The unilateral intrastriatal LPS rat model may serve as a useful tool for benchmarking PET tracers targeted toward distinct phases of neuroinflammatory reactions involving both microglia and astrocytes.

Mutations in the gene encoding activin receptor-like kinase 2 (ALK2) are implicated in the pathophysiology of a pediatric brainstem cancer, diffuse intrinsic pontine glioma (DIPG). Inhibitors of ALK2 that cross the blood–brain barrier have been proposed as a method of treatment for DIPG. As part of an open science approach to radiopharmaceutical and drug discovery, we developed 11C-labeled radiotracers from potent and selective lead ALK2 inhibitors to investigate their brain permeability through positron emission tomography (PET) neuroimaging. Four radiotracers were synthesized by 11C-methylation and assessed by dynamic PET imaging in healthy Sprague–Dawley rats. One of the compounds, [11C]M4K2127, showed high initial brain uptake (SUV ∼ 2), including in the region of interest (pons). This data supports the use of this chemotype as a brain penetrant ALK2 inhibitor that permeates evenly into the pons with potential application for the treatment of DIPG.

CBD-2115 was selected from a library of 148 compounds based on a pyridinyl-indole scaffold as a first-in-class 4R-tau radiotracer. In vitro binding assays showed [(3)H]CBD-2115 had a K(D) value of 6.9 nM and a nominal B(max) of 500 nM in 4R-tau expressing P301L transgenic mouse tissue. In binding assays with human brain tissue homogenates, [(3)H]CBD-2115 has a higher affinity (4.9 nM) for progressive supranuclear palsy specific 4R-tau deposits than [(3)H]Flortaucipir (45 nM) or [(3)H]MK-6240 (>50 nM). [(18)F]CBD-2115 was reliably synthesized (3–11% radiochemical yield with molar activity of 27 – 111 GBq/μmol and >97% radiochemical purity). Dynamic PET imaging was conducted in mice, rats and non-human primate and all species showed initial brain uptake of 0.5–0.65 standardized uptake value with fast clearance from normal tissues. [(3)H]CBD-2115 could be a useful lead radioligand for further research in 4R-tauopathies, and PET radiotracer development will focus on improving brain uptake and binding affinity.

RATIONALE. The long held speculation that the brain serotonin system mediates some behavioural effects of the psychostimulant cocaine is supported in part by the high affinity of cocaine for the serotonin transporter (SERT) and by reports that the serotonin transporter (SERT), estimated by SERT binding, is increased in brain of human chronic cocaine users. Excessive SERT activity and consequent synaptic serotonin deficiency might cause a behavioural (e.g., mood) abnormality in chronic users of the drug. OBJECTIVE AND METHODS. Previous studies focused on changes in SERT binding, which might not necessarily reflect changes in SERT protein. Therefore, we compared levels of SERT protein, using a quantitative Western blot procedure, in autopsied brain (striatum, cerebral cortices) of chronic human cocaine users (n=9), who all tested positive for the drug/metabolite in brain, to those in control subjects (n=15) and, as a separate drug of abuse group, in chronic heroin users (n=11). RESULTS. We found no significant difference in protein levels of SERT or the serotonin synthesizing enzyme tryptophan hydroxylase-2 amongst the control and drug abuse groups. In the cocaine users no significant correlations were observed between SERT and brain levels of cocaine plus metabolites, or with levels of serotonin or its metabolite 5-hydroxyindoleacetic acid. CONCLUSION. Our postmortem data suggest that a robust increase in striatal/cerebral cortical SERT protein is not a common characteristic of chronic, human cocaine users.

Cyclooxygenase-1 (COX-1), a biomarker for neuroinflammation, is implicated in the progression and prognosis of ovarian cancer (OvCa). This study considered the repurposing of (11)C-labeled 1,5-bis(4-methoxyphenyl)-3-(2,2,2-trifluoroethoxy)-1H-1,2,4-triazole ((11)C-PS13), a COX-1 PET neuroimaging radiopharmaceutical, in OvCa xenograft mouse models. Methods: (11)C-PS13 was evaluated in ICRscid mice with subcutaneous or intraperitoneal human OVCAR-3 OvCa xenografts by dynamic PET/MRI, ex vivo biodistribution, and radiometabolite analysis of plasma and tumor. Results: OVCAR-3 xenografts were well visualized with (11)C-PS13 in xenograft mouse models. Time–activity curves revealed a steady accumulation of tumor radioactivity that plateaued from 40 to 60 min and was significantly reduced by pretreatment with ketoprofen (3.56 ± 0.81 and 1.30 ± 0.18 percentage injected dose/g without and with pretreatment, respectively, P = 0.01). Radiometabolite analysis showed that intact (11)C-PS13 accounted for more than 80% of radioactivity in the tumor, with less than 20% in plasma, at 40 min after injection. Conclusion: (11)C-PS13 shows promise for PET imaging of COX-1 in OvCa, and rapid translation for clinical cancer research should be considered.

Additional file 1.

There has been considerable interest in the development of dopamine D3 receptor (DRD3) partial agonists and antagonists for the treatment of substance use disorders. Pre-clinical evidence overwhelmingly supports the use of these drugs, but translation to humans has remained elusive due to the lack of selective compounds that are suitable for use in humans. Although it has been established for full antagonists, little in vivo occupancy data are available with DRD3 partial agonists. Here we investigate for the first time in healthy controls, the in vivo occupancy of a novel D3 partial agonist (BP1.4979) at the DRD3 and DRD2. Participants received either a single dose (1, 3, 10 or 30 mg) or a subchronic regimen (5-7 days, q.d. or b.i.d) of BP1.4979, with the last dose given at 1, 12 or 24 h prior to scanning with [11C]-(+)-PHNO. Single and subchronic administration of BP1.4979 dose-dependently occupied the DRD3 and DRD2, and this occupancy was preferential for the DRD3, notably at longer time points after administration of BP1.4979. Also consistent with preference for the DRD3, prolactin levels were minimally increased, and no subjective effects of BP1.4979 were reported. Serum levels of BP1.4979 were higher than its active metabolite, BP1.6239, while no notable increases in the inactive metabolite, BP1.6197, were found. These findings indicate the range of doses that can be used to occupy selectively the DRD3 over the DRD2 with BP1.4979 and speak to the use of in vivo imaging approaches in dose finding studies.

Background A key component of alcohol dependence (AD), a severe form of alcohol use disorder, is the negative emotional state during withdrawal. Monoamine oxidase A (MAO-A) is an important enzyme that metabolizes monoamines and creates oxidative stress. Elevations in MAO-A level, especially in the prefrontal and anterior cingulate cortex (PFC and ACC), are associated with low mood states, including the dysphoria of early alcohol withdrawal in humans. The aim of the present study was to determine whether chronic alcohol vapor exposure causes an upregulation of MAO-A activity or level in the PFC and ACC of rodents during acute withdrawal. Methods Sprague-Dawley rats were exposed to ethanol vapor or control condition for 17 h per day for 8 weeks. MAO-A activity and protein levels were measured immediately after exposure, acute withdrawal (24 h), protracted withdrawal (4 day), and protracted abstinence (3 weeks) (n = 16/group; 8 alcohol exposed, 8 control). Results Chronic ethanol vapor exposure significantly elevated MAO-A activity and protein levels in the PFC and ACC at 24-h withdrawal (multivariate analysis of variance (MANOVA), activity: F2,13 = 3.82, p = .05, protein: F2,13 = 5.13, p = .02). There were no significant changes in MAO-A level or activity at other timepoints. Conclusions The results of this study suggest a causal relationship between acute alcohol withdrawal and elevated MAO-A levels and activity, clarifying the observation of greater MAO-A binding in human alcohol withdrawal. This has important implications for developing methods of targeting MAO-A and/or sequelae of its dysregulation in alcohol dependence.

Recent human brain imaging studies implicate dysregulation of monoamine oxidase-A (MAO-A), in particular in the prefrontal cortex (PFC) and anterior cingulate cortex (ACC), in the development of major depressive disorder (MDD). This study investigates the influence of four alterations underlying important pathologies of MDD, namely, chronic elevation of glucocorticoid levels, glutathione depletion, changes in female gonadal sex hormones and serotonin concentration fluctuation, on MAO-A and MAO-B activities in rats. Young adult rats exposed chronically to the synthetic glucocorticoid dexamethasone at 0, 0.05, 0.5, and 2.0mg/kg/day (osmotic minipumps) for eight days showed significant dose-dependent increases in activities of MAO-A in PFC (+17%, p

The endocannabinoid and dopaminergic systems have independently been implicated in substance use disorder and obesity. We investigated a potential interaction between genetically inherited variation in fatty acid amide hydrolase (FAAH, C385A), which metabolizes the cannabis-like endocannabinoid anandamide, and dopaminergic system, measured by dopamine receptor levels and mRNA. Binding of the dopamine D3 preferring probe [C-11]-(+)-PHNO was measured with positron emission tomography (PET) in 79 human subjects genotyped for the FAAH C385A polymorphism (36/79 AC + AA). Autoradiography with [H-3]-(+)-PHNO and in situ hybridization with a D3-specific S-35 riboprobe were carried out in 30 knock-in mice with the FAAH C385A polymorphism (20/30 AC + AA). We found that the FAAH genetic variant C385A was associated with significantly higher (+)-PHNO binding in both humans and in knock-in mice, and this effect was restricted to D3 selective brain regions (limbic striatum, globus pallidus, and ventral pallidum (9–14%; p

Convolution neural network (CNN) has shown its great success in video quality enhancement. Existing methods mainly conduct enhancement tasks in the spatial domain, exploring the pixel correlations within one frame. Taking advantage of the similarity across successive frames, this paper develops a learning-based multi-frame approach, with an aim to explore the greatest potential for video quality enhancement leveraging the temporal correlation. First, we apply a learning-based optical flow to compensate the temporal motion across neighboring frames. Afterwards, a deep CNN network, which is structured in an early-fusion manner, is designed to discover the joint spatial-temporal correlations within a video. To ensure the generality of our CNN model, we further propose a robust training strategy. One high-quality frame and one moderate-quality frame are paired to enhance the remaining low-quality frames in between, which considers a trade-off between frame distances and various frame quality. Experimental results demonstrate that our method outperforms state-of-the-art work in objective quality. The code and model of our approach are published in Github (https://github.com/IVC-Projects/LMVE).

Positron emission tomography (PET) imaging of the translocator protein (TSPO) is widely used as a biomarker of microglial activation. However, TSPO protein concentration in human brain has not been optimally quantified nor has its regional distribution been compared to TSPO binding. We determined TSPO protein concentration, change with age, and regional distribution by quantitative immunoblotting in autopsied human brain. Brain TSPO protein concentration (>0.1 ng/µg protein) was higher than those reported by in vitro binding assays by at least 2 to 70 fold. TSPO protein distributed widely in both gray and white matter regions, with distribution in major gray matter areas ranked generally similar to that of PET binding in second-generation radiotracer studies. TSPO protein concentration in frontal cortex was high at birth, declined precipitously during the first three months, and increased modestly during adulthood/senescence (10%/decade; vs. 30% for comparison astrocytic marker GFAP). As expected, TSPO protein levels were significantly increased (+114%) in degenerating putamen in multiple system atrophy, providing further circumstantial support for TSPO as a gliosis marker. Overall, findings show some similarities between TSPO protein and PET binding characteristics in the human brain but also suggest that part of the TSPO protein pool might be less available for radioligand binding.

Background One of the major mechanisms for terminating the actions of the endocannabinoid anandamide is hydrolysis by fatty acid amide hydrolase (FAAH), and inhibitors of the enzyme were suggested as potential treatment for human cannabis dependence. However, the status of brain FAAH in cannabis use disorder is unknown. Methods Brain FAAH binding was measured with positron emission tomography and [ 11 C]CURB in 22 healthy control subjects and ten chronic cannabis users during early abstinence. The FAAH genetic polymorphism (rs324420) and blood, urine, and hair levels of cannabinoids and metabolites were determined. Results In cannabis users, FAAH binding was significantly lower by 14%–20% across the brain regions examined than in matched control subjects (overall Cohen's d = 0.96). Lower binding was negatively correlated with cannabinoid concentrations in blood and urine and was associated with higher trait impulsiveness. Conclusions Lower FAAH binding levels in the brain may be a consequence of chronic and recent cannabis exposure and could contribute to cannabis withdrawal. This effect should be considered in the development of novel treatment strategies for cannabis use disorder that target FAAH and endocannabinoids. Further studies are needed to examine possible changes in FAAH binding during prolonged cannabis abstinence and whether lower FAAH binding predates drug use.

In a recent clinical trial, the drug BIA 10-2474, a putative fatty acid amide hydrolase(FAAH) inhibitor, was responsible for severe adverse events (SAEs), including one death. To date, there has been little reliable information divulged about the potency of BIA 10-2474 at FAAH in the central nervous system. We synthesised BIA 10-2474 and determined its ability to inhibit FAAH ex vivo in rat brain using a FAAH selective radiotracer. BIA 10-2474 proved to be a potent FAAH inhibitor with IC50s of 50–70 µg/kg (i.p.) in various brain regions. This information may be useful for determining the cause of the SAEs.

Neuroimaging studies in stimulant use (eg, cocaine, methamphetamine) disorders show that diminished dopamine release by dopamine-elevating drugs is a potential marker of relapse and suggest that increasing dopamine at the D2/3 receptors may be therapeutically beneficial. In contrast, recent investigations indicate heightened D3 receptor levels in stimulant users prompting the view that D3 antagonism may help prevent relapse. Here we tested whether a 'blunted' response to amphetamine in methamphetamine (MA) users extends to D3-rich brain areas. Fourteen MA users and 15 healthy controls completed two positron emission tomographic scans with a D3-preferring probe [11C]-(+)-PHNO at baseline and after amphetamine (0.4 mg/kg). Relative to healthy controls, MA users had greater decreases in [11C]-(+)-PHNO binding (increased dopamine release) after amphetamine in D3-rich substantia nigra (36 vs 20%, p=0.03) and globus pallidus (30 vs 17%, p=0.06), which correlated with self-reported 'drug wanting'. We did not observe a 'blunted' dopamine response to amphetamine in D2-rich striatum; however, drug use severity was negatively associated with amphetamine-induced striatal changes in [11C]-(+)-PHNO binding. Our study provides evidence that dopamine transmission in extrastriatal 'D3-areas' is not blunted but rather increased in MA users. Together with our previous finding of elevated D3 receptor level in MA users, the current observation suggests that greater dopaminergic transmission at the D3 dopamine receptor may contribute to motivation to use drugs and argues in favor of D3 antagonism as a possible therapeutic tool to reduce craving and relapse in MA addiction.

For the past 60 years a major theory of "aging" is that age-related damage is largely caused by excessive uncompensated oxidative stress. The ubiquitous tripeptide glutathione is a major antioxidant defense mechanism against reactive free radicals and has also served as a marker of changes in oxidative stress. Some (albeit conflicting) animal data suggest a loss of glutathione in brain senescence, which might compromise the ability of the aging brain to meet the demands of oxidative stress. Our objective was to establish whether advancing age is associated with glutathione deficiency in human brain. We measured reduced glutathione (GSH) levels in multiple regions of autopsied brain of normal subjects (n=74) aged one day to 99 years. Brain GSH levels during the infancy/teenage years were generally similar to those in the oldest examined adult group (76-99 years). During adulthood (23-99 years) GSH levels remained either stable (occipital cortex) or increased (caudate nucleus, frontal and cerebellar cortices). To the extent that GSH levels represent glutathione antioxidant capacity, our postmortem data suggest that human brain aging is not associated with declining glutathione status. We suggest that aged healthy human brains can maintain antioxidant capacity related to glutathione and that an age-related increase in GSH levels in some brain regions might possibly be a compensatory response to increased oxidative stress. Since our findings, although suggestive, suffer from the generic limitations of all postmortem brain studies, we also suggest the need for "replication" investigations employing the new (1)H MRS imaging procedures in living human brain.

There has been considerable interest in the development of dopamine D3 receptor (DRD(3)) partial agonists and antagonists for the treatment of substance use disorders. Pre-clinical evidence overwhelmingly supports the use of these drugs, but translation to humans has remained elusive due to the lack of selective compounds that are suitable for use in humans. Although it has been established for full antagonists, little in vivo occupancy data are available with DRD(3) partial agonists. Here we investigate for the first time in healthy controls, the in vivo occupancy of a novel D3 partial agonist (BP1.4979) at the DRD(3) and DRD(2). Participants received either a single dose (1, 3, 10 or 30 mg) or a subchronic regimen (5–7 days, q.d. or b.i.d) of BP1.4979, with the last dose given at 1, 12 or 24 h prior to scanning with [(11)C]-(+)-PHNO. Single and subchronic administration of BP1.4979 dose-dependently occupied the DRD(3) and DRD(2), and this occupancy was preferential for the DRD(3), notably at longer time points after administration of BP1.4979. Also consistent with preference for the DRD(3), prolactin levels were minimally increased, and no subjective effects of BP1.4979 were reported. Serum levels of BP1.4979 were higher than its active metabolite, BP1.6239, while no notable increases in the inactive metabolite, BP1.6197, were found. These findings indicate the range of doses that can be used to occupy selectively the DRD(3) over the DRD(2) with BP1.4979 and speak to the use of in vivo imaging approaches in dose finding studies.