Noninvasive quantification of [18F]SynVesT-1 binding using simplified reference tissue model 2.

PURPOSE: [18F]SynVesT-1, a positron emission tomography (PET) radiotracer for the synaptic vesicle glycoprotein 2A (SV2A), demonstrates kinetics similar to [11C]UCB-J, with high brain uptake, fast kinetics fitting well with the one-tissue compartment (1TC) model, and excellent test-retest reproducibility. Challenges arise due to the similarity between k2 and [Formula: see text] (efflux rate of the reference region), when applying the simplified reference tissue model (SRTM) and related methods in [11C]UCB-J studies to accurately estimate [Formula: see text]. This study evaluated the suitability of these methods to estimate [18F]SynVesT-1 binding using centrum semiovale (CS) or cerebellum (CER) as reference regions. METHOD: Seven healthy participants underwent 120-min PET scans on the HRRT scanner with [18F]SynVesT-1. Six participants underwent test and retest scans. Arterial blood sampling and metabolite analysis provided input functions for the 1TC model, serving as the gold standard for kinetic parameters values. SRTM, coupled SRTM (SRTMC) and SRTM2 estimated were applied to estimate [Formula: see text](ref: CS) and DVRCER(ref: CER) values. For SRTM2, the population average of [Formula: see text] was determined from the 1TC model applied to the reference region. Test-retest variability and minimum scan time were also calculated. RESULTS: The 1TC k2 (1/min) values for CS and CER were 0.031 ± 0.004 and 0.021 ± 0.002, respectively. Although SRTMC [Formula: see text] was much higher than 1TC [Formula: see text], SRTMC underestimated BPND(ref: CS) and DVRCER by an average of 3% and 1% across regions, respectively, due to similar bias in k2 and [Formula: see text] estimation. SRTM underestimated BPND(ref: CS) by an average of 3%, but with the CER as reference region, SRTM estimation was unstable and DVRCER underestimation varied by region (mean 10%). Using population average [Formula: see text] values, SRTM2 BPND and DVRCER showed the best agreement with 1TC estimates. CONCLUSION: Our findings support the use of population [Formula: see text] value in SRTM2 with [18F]SynVesT-1 for the estimation of [Formula: see text] or DVRCER, regardless of the choice of reference region.

Microglia-mediated neuroimmune suppression in PTSD is associated with anhedonia.

Dynamic brain immune function in individuals with posttraumatic stress disorder is rarely studied, despite evidence of peripheral immune dysfunction. Positron emission tomography brain imaging using the radiotracer [11C]PBR28 was used to measure the 18-kDa translocator protein (TSPO), a microglial marker, at baseline and 3 h after administration of lipopolysaccharide (LPS), a potent immune activator. Data were acquired in 15 individuals with PTSD and 15 age-matched controls. The PTSD group exhibited a significantly lower magnitude LPS-induced increase in TSPO availability in an a priori prefrontal-limbic circuit compared to controls. Greater anhedonic symptoms in the PTSD group were associated with a more suppressed neuroimmune response. In addition, while a reduced granulocyte-macrophage colony-stimulating factor response to LPS was observed in the PTSD group, other measured cytokine responses and self-reported sickness symptoms did not differ between groups; these findings highlight group differences in central-peripheral immune system relationships. The results of this study provide evidence of a suppressed microglia-mediated neuroimmune response to a direct immune system insult in individuals with PTSD that is associated with the severity of symptoms. They also provide further support to an emerging literature challenging traditional concepts of microglial and immune function in psychiatric disease.

Imaging a putative marker of brain cortisol regulation in alcohol use disorder.

Background: Stress is a potent activator of the hypothalamic-pituitary-adrenal (HPA) axis, initiating the release of glucocorticoid hormones, such as cortisol. Alcohol consumption can lead to HPA axis dysfunction, including altered cortisol levels. Until recently, research has only been able to examine peripheral cortisol associated with alcohol use disorder (AUD) in humans. We used positron emission tomography (PET) brain imaging with the radiotracer [18F]AS2471907 to measure 11ß-hydroxysteroid dehydrogenase type 1 (11ß-HSD1), a cortisol-regenerating enzyme, in people with AUD compared to healthy controls. Methods: We imaged 9 individuals with moderate to severe AUD (5 men, 4 women; mean age = 38 years) and 12 healthy controls (8 men, 4 women; mean age = 29 years). Participants received 93.5 ± 15.6 MBq of the 11ß-HSD1 inhibitor radiotracer [18F]AS2471907 as a bolus injection and were imaged for 150-180 min on the High-Resolution Research Tomograph. 11ß-HSD1 availability was quantified by [18F]AS2471907 volume of distribution (VT; mL/cm3). A priori regions of interest included amygdala, anterior cingulate cortex (ACC), hippocampus, ventromedial PFC (vmPFC) and caudate. Results: Individuals with AUD consumed 52.4 drinks/week with 5.8 drinking days/week. Healthy controls consumed 2.8 drinks/week with 1.3 drinking days/week. Preliminary findings suggest that [18F]AS2471907 VT was higher in amygdala, ACC, hippocampus, vmPFC, and caudate of those with AUD compared to healthy controls (p < 0.05). In AUD, vmPFC [18F]AS2471907 VT was associated with drinks per week (r = 0.81, p = 0.01) and quantity per drinking episode (r = 0.75, p = 0.02). Conclusions: This is the first in vivo examination of 11ß-HSD1 availability in individuals with AUD. Our data suggest higher brain availability of the cortisol-regenerating enzyme 11ß-HSD1 in people with AUD (vs. controls), and that higher vmPFC 11ß-HSD1 availability is related to greater alcohol consumption. Thus, in addition to the literature suggesting that people with AUD have elevated peripheral cortisol, our findings suggest there may also be heightened central HPA activity. These findings set the foundation for future hypotheses on mechanisms related to HPA axis function in this population.

Synaptic loss and its association with symptom severity in Parkinson's disease.

Parkinson's disease (PD) is the fastest growing neurodegenerative disease, but at present there is no cure, nor any disease-modifying treatments. Synaptic biomarkers from in vivo imaging have shown promise in imaging loss of synapses in PD and other neurodegenerative disorders. Here, we provide new clinical insights from a cross-sectional, high-resolution positron emission tomography (PET) study of 30 PD individuals and 30 age- and sex-matched healthy controls (HC) with the radiotracer [11C]UCB-J, which binds to synaptic vesicle glycoprotein 2A (SV2A), and is therefore, a biomarker of synaptic density in the living brain. We also examined a measure of relative brain perfusion from the early part of the same PET scan. Our results provide evidence for synaptic density loss in the substantia nigra that had been previously reported, but also extend this to other early-Braak stage regions known to be affected in PD (brainstem, caudate, olfactory cortex). Importantly, we also found a direct association between synaptic density loss in the nigra and severity of symptoms in patients. A greater extent and wider distribution of synaptic density loss in PD patients with longer illness duration suggests that [11C]UCB-J PET can be used to measure synapse loss with disease progression. We also demonstrate lower brain perfusion in PD vs. HC groups, with a greater extent of abnormalities in those with longer duration of illness, suggesting that [11C]UCB-J PET can simultaneously provide information on changes in brain perfusion. These results implicate synaptic imaging as a useful PD biomarker for future disease-modifying interventions.

First-in-Human Study of 18F-SynVesT-2: An SV2A PET Imaging Probe with Fast Brain Kinetics and High Specific Binding.

PET imaging of synaptic vesicle glycoprotein 2A allows for noninvasive quantification of synapses. This first-in-human study aimed to evaluate the kinetics, test-retest reproducibility, and extent of specific binding of a recently developed synaptic vesicle glycoprotein 2A PET ligand, (R)-4-(3-(18F-fluoro)phenyl)-1-((3-methylpyridin-4-yl)methyl)pyrrolidine-2-one (18F-SynVesT-2), with fast brain kinetics. Methods: Nine healthy volunteers participated in this study and were scanned on a High Resolution Research Tomograph scanner with 18F-SynVesT-2. Five volunteers were scanned twice on 2 different days. Five volunteers were rescanned with preinjected levetiracetam (20 mg/kg, intravenously). Arterial blood was collected to calculate the plasma free fraction and generate the arterial input function. Individual MR images were coregistered to a brain atlas to define regions of interest for generating time-activity curves, which were fitted with 1- and 2-tissue-compartment (1TC and 2TC) models to derive the regional distribution volume (V T). The regional nondisplaceable binding potential (BP ND) was calculated from 1TC V T, using the centrum semiovale (CS) as the reference region. Results: 18F-SynVesT-2 was synthesized with high molar activity (187 ± 69 MBq/nmol, n = 19). The parent fraction of 18F-SynVesT-2 in plasma was 28% ± 8% at 30 min after injection, and the plasma free fraction was high (0.29 ± 0.04). 18F-SynVesT-2 entered the brain quickly, with an SUVpeak of 8 within 10 min after injection. Regional time-activity curves fitted well with both the 1TC and the 2TC models; however, V T was estimated more reliably using the 1TC model. The 1TC V T ranged from 1.9 ± 0.2 mL/cm3 in CS to 7.6 ± 0.8 mL/cm3 in the putamen, with low absolute test-retest variability (6.0% ± 3.6%). Regional BP ND ranged from 1.76 ± 0.21 in the hippocampus to 3.06 ± 0.29 in the putamen. A 20-min scan was sufficient to provide reliable V T and BP ND Conclusion: 18F-SynVesT-2 has fast kinetics, high specific uptake, and low nonspecific uptake in the brain. Consistent with the nonhuman primate results, the kinetics of 18F-SynVesT-2 is faster than the kinetics of 11C-UCB-J and 18F-SynVesT-1 in the human brain and enables a shorter dynamic scan to derive physiologic information on cerebral blood flow and synapse density.

Intense exercise increases dopamine transporter and neuromelanin concentrations in the substantia nigra in Parkinson's disease.

Parkinson's disease (PD) is characterized by a progressive loss of dopaminergic neurons. Exercise has been reported to slow the clinical progression of PD. We evaluated the dopaminergic system of patients with mild and early PD before and after a six-month program of intense exercise. Using 18F-FE-PE2I PET imaging, we measured dopamine transporter (DAT) availability in the striatum and substantia nigra. Using NM-MRI, we evaluated the neuromelanin content in the substantia nigra. Exercise reversed the expected decrease in DAT availability into a significant increase in both the substantia nigra and putamen. Exercise also reversed the expected decrease in neuromelanin concentration in the substantia nigra into a significant increase. These findings suggest improved functionality in the remaining dopaminergic neurons after exercise. Further research is needed to validate our findings and to pinpoint the source of any true neuromodulatory and neuroprotective effects of exercise in PD in large clinical trials.

The regional pattern of age-related synaptic loss in the human brain differs from gray matter volume loss: in vivo PET measurement with [11C]UCB-J.

PURPOSE: Aging is a major societal concern due to age-related functional losses. Synapses are crucial components of neural circuits, and synaptic density could be a sensitive biomarker to evaluate brain function. [11C]UCB-J is a positron emission tomography (PET) ligand targeting synaptic vesicle glycoprotein 2A (SV2A), which can be used to evaluate brain synaptic density in vivo. METHODS: We evaluated age-related changes in gray matter synaptic density, volume, and blood flow using [11C]UCB-J PET and magnetic resonance imaging (MRI) in a wide age range of 80 cognitive normal subjects (21-83 years old). Partial volume correction was applied to the PET data. RESULTS: Significant age-related decreases were found in 13, two, and nine brain regions for volume, synaptic density, and blood flow, respectively. The prefrontal cortex showed the largest volume decline (4.9% reduction per decade: RPD), while the synaptic density loss was largest in the caudate (3.6% RPD) and medial occipital cortex (3.4% RPD). The reductions in caudate are consistent with previous SV2A PET studies and likely reflect that caudate is the site of nerve terminals for multiple major tracts that undergo substantial age-related neurodegeneration. There was a non-significant negative relationship between volume and synaptic density reductions in 16 gray matter regions. CONCLUSION: MRI and [11]C-UCB-J PET showed age-related decreases of gray matter volume, synaptic density, and blood flow; however, the regional patterns of the reductions in volume and SV2A binding were different. Those patterns suggest that MR-based measures of GM volume may not be directly representative of synaptic density.

Assessment of Gray Matter Microstructure and Synaptic Density in Alzheimer's Disease: A Multimodal Imaging Study With DTI and SV2A PET.

OBJECTIVE: Multimodal imaging techniques have furthered our understanding of how different aspects of Alzheimer's disease (AD) pathology relate to one another. Diffusion tensor imaging (DTI) measures such as mean diffusivity (MD) may be a surrogate measure of the changes in gray matter structure associated with AD. Positron emission tomography (PET) imaging of synaptic vesicle glycoprotein 2A (SV2A) has been used to quantify synaptic loss, which is the major pathological correlate of cognitive impairment in AD. In this study, we investigated the relationship between gray matter microstructure and synaptic density. METHODS: DTI was used to measure MD and [11C]UCB-J PET to measure synaptic density in 33 amyloid-positive participants with AD and 17 amyloid-negative cognitively normal (CN) participants aged 50-83. Univariate regression analyses were used to assess the association between synaptic density and MD in both the AD and CN groups. RESULTS: Hippocampal MD was inversely associated with hippocampal synaptic density in participants with AD (r = -0.55, p <0.001, df = 31) but not CN (r = 0.13, p = 0.62, df = 15). Exploratory analyses across other regions known to be affected in AD suggested widespread inverse associations between synaptic density and MD in the AD group. CONCLUSION: In the setting of AD, an increase in gray matter MD is inversely associated with synaptic density. These co-occurring changes may suggest a link between synaptic loss and gray matter microstructural changes in AD. Imaging studies of gray matter microstructure and synaptic density may allow important insights into AD-related neuropathology.

Evaluating infusion methods and simplified quantification of synaptic density in vivo with [11C]UCB-J and [18F]SynVesT-1 PET.

For some positron emission tomography studies, radiotracer is administered as bolus plus continuous infusion (B/I) to achieve a state of equilibrium. This approach can reduce scanning time and simplify data analysis; however, the method must be validated and optimized for each tracer. This study aimed to validate a B/I method for in vivo quantification of synaptic density using radiotracers which target the synaptic vesicle glycoprotein 2 A: [11C]UCB-J and [18F]SynVesT-1. Observed mean standardized uptake values (SUV) in target tissue relative to that in plasma (CT/CP) or a reference tissue (SUVR-1) were calculated for 30-minute intervals across 120 or 150-minute dynamic scans and compared against one-tissue compartment (1TC) model estimates of volume of distribution (VT) and binding potential (BPND), respectively. We were unable to reliably achieve a state of equilibrium with [11C]UCB-J, and all 30-minute windows yielded overly large bias and/or variability for CT/CP and SUVR-1. With [18F]SynVesT-1, a 30-minute scan 90-120 minutes post-injection yielded CT/CP and SUVR-1 values that estimated their respective kinetic parameter with sufficient accuracy and precision (within 7±6%) . This B/I approach allows a clinically feasible scan at equilibrium with potentially better accuracy than a static scan SUVR following a bolus injection.

Imaging the brain's immune response to alcohol with [11C]PBR28 TSPO Positron Emission Tomography.

In humans, the negative effects of alcohol are linked to immune dysfunction in both the periphery and the brain. Yet acute effects of alcohol on the neuroimmune system and its relationships with peripheral immune function are not fully understood. To address this gap, immune response to an alcohol challenge was measured with positron emission tomography (PET) using the radiotracer [11C]PBR28, which targets the 18-kDa translocator protein, a marker sensitive to immune challenges. Participants (n = 12; 5 F; 25-45 years) who reported consuming binge levels of alcohol (>3 drinks for females; >4 drinks for males) 1-3 months before scan day were enrolled. Imaging featured a baseline [11C]PBR28 scan followed by an oral laboratory alcohol challenge over 90 min. An hour later, a second [11C]PBR28 scan was acquired. Dynamic PET data were acquired for at least 90 min with arterial blood sampling to measure the metabolite-corrected input function. [11C]PBR28 volume of distributions (VT) was estimated in the brain using multilinear analysis 1. Subjective effects, blood alcohol levels (BAL), and plasma cytokines were measured during the paradigm. Full completion of the alcohol challenge and data acquisition occurred for n = 8 (2 F) participants. Mean peak BAL was 101 ± 15 mg/dL. Alcohol significantly increased brain [11C]PBR28 VT (n = 8; F(1,49) = 34.72, p > 0.0001; Cohen's d'=0.8-1.7) throughout brain by 9-16%. Alcohol significantly altered plasma cytokines TNF-α (F(2,22) = 17.49, p < 0.0001), IL-6 (F(2,22) = 18.00, p > 0.0001), and MCP-1 (F(2,22) = 7.02, p = 0.004). Exploratory analyses identified a negative association between the subjective degree of alcohol intoxication and changes in [11C]PBR28 VT. These findings provide, to our knowledge, the first in vivo human evidence for an acute brain immune response to alcohol.

Principal component analysis of synaptic density measured with [11C]UCB-J PET in early Alzheimer's disease.

BACKGROUND: Synaptic loss is considered an early pathological event and major structural correlate of cognitive impairment in Alzheimer's disease (AD). We used principal component analysis (PCA) to identify regional patterns of covariance in synaptic density using [11C]UCB-J PET and assessed the association between principal components (PC) subject scores with cognitive performance. METHODS: [11C]UCB-J binding was measured in 45 amyloid + participants with AD and 19 amyloid- cognitively normal participants aged 55-85. A validated neuropsychological battery assessed performance across five cognitive domains. PCA was applied to the pooled sample using distribution volume ratios (DVR) standardized (z-scored) by region from 42 bilateral regions of interest (ROI). RESULTS: Parallel analysis determined three significant PCs explaining 70.2% of the total variance. PC1 was characterized by positive loadings with similar contributions across the majority of ROIs. PC2 was characterized by positive and negative loadings with strongest contributions from subcortical and parietooccipital cortical regions, respectively, while PC3 was characterized by positive and negative loadings with strongest contributions from rostral and caudal cortical regions, respectively. Within the AD group, PC1 subject scores were positively correlated with performance across all cognitive domains (Pearson r = 0.24-0.40, P = 0.06-0.006), PC2 subject scores were inversely correlated with age (Pearson r = -0.45, P = 0.002) and PC3 subject scores were significantly correlated with CDR-sb (Pearson r = 0.46, P = 0.04). No significant correlations were observed between cognitive performance and PC subject scores in CN participants. CONCLUSIONS: This data-driven approach defined specific spatial patterns of synaptic density correlated with unique participant characteristics within the AD group. Our findings reinforce synaptic density as a robust biomarker of disease presence and severity in the early stages of AD.

Investigating CNS distribution of PF-05212377, a P-glycoprotein substrate, by translation of 5-HT6 receptor occupancy from non-human primates to humans.

PF-05212377 (SAM760) is a potent and selective 5-HT6 antagonist, previously under development for the treatment of Alzheimer's disease. In vitro, PF-05212377 was determined to be a P-gp/non-BCRP human transporter substrate. Species differences were observed in the in vivo brain penetration of PF-05212377 with a ratio of the unbound concentration in brain/unbound concentration in plasma (Cbu /Cpu ) of 0.05 in rat and 0.64 in non-human primates (NHP). Based on pre-clinical evidence, brain penetration and target engagement of PF-05212377 was confirmed in NHP using positron emission tomography (PET) measured 5-HT6 receptor occupancy (%RO). The NHP Cpu EC50 of PF-05212377 was 0.31 nM (consistent with the in vitro human 5HT6 Ki : 0.32 nM). P-gp has been reported to be expressed in higher abundance at the rat BBB and in similar abundance at the BBB of non-human primates and human; brain penetration of PF-05212377 in humans was postulated to be similar to that in non-human primates. In humans, PF-05212377 demonstrated dose and concentration dependent increases in 5-HT6 RO; maximal 5-HT6 RO of ∼80% was measured in humans at doses of ≥15 mg with an estimated unbound plasma EC50 of 0.37 nM (which was similar to the in vitro human 5HT6 binding Ki 0.32 nM). In conclusion, cumulative evidence from NHP and human PET RO assessments confirmed that NHP is more appropriate than the rat for the prediction of human brain penetration of PF-05212377, a P-gp/non-BCRP substrate. Clinical trial number: NCT01258751.

Differences in Quantification of the Metabotropic Glutamate Receptor 5 Across Bipolar Disorder and Major Depressive Disorder.

BACKGROUND: Understanding the neurobiology underlying bipolar disorder (BD) versus major depressive disorder (MDD) is crucial for accurate diagnosis and for driving the discovery of novel treatments. A promising target is the metabotropic glutamate receptor 5 (mGluR5), a modulator of glutamate transmission associated with synaptic plasticity. We measured mGluR5 availability in individuals with MDD and BD for the first time using positron emission tomography. METHODS: Individuals with BD (n = 17 depressed; n = 10 euthymic) or MDD (n = 17) and healthy control (HC) individuals (n = 18) underwent imaging with [18F]FPEB positron emission tomography to quantify mGluR5 availability in regions of the prefrontal cortex, which was compared across groups and assessed in relation to depressive symptoms and cognitive function. RESULTS: Prefrontal cortex mGluR5 availability was significantly different across groups (F6,116 = 2.18, p = .050). Specifically, mGluR5 was lower in BD versus MDD and HC groups, with no difference between MDD and HC groups. Furthermore, after dividing the BD group, mGluR5 was lower in both BD-depression and BD-euthymia groups versus both MDD and HC groups across regions of interest. Interestingly, lower dorsolateral prefrontal cortex mGluR5 was associated with worse depression in MDD (r = -0.67, p = .005) but not in BD. Significant negative correlations were observed between mGluR5 and working memory in MDD and BD-depression groups. CONCLUSIONS: This work suggests that mGluR5 could be helpful in distinguishing BD and MDD as a possible treatment target for depressive symptoms in MDD and for cognitive alterations in both disorders. Further work is needed to confirm differentiating roles for mGluR5 in BD and MDD and to probe modulation of mGluR5 as a preventive/treatment strategy.

Preclinical evaluation of a brain penetrant PARP PET imaging probe in rat glioblastoma and nonhuman primates.

PURPOSE: Currently, there are multiple active clinical trials involving poly(ADP-ribose) polymerase (PARP) inhibitors in the treatment of glioblastoma. The noninvasive quantification of baseline PARP expression using positron emission tomography (PET) may provide prognostic information and lead to more precise treatment. Due to the lack of brain-penetrant PARP imaging agents, the reliable and accurate in vivo quantification of PARP in the brain remains elusive. Herein, we report the synthesis of a brain-penetrant PARP PET tracer, (R)-2-(2-methyl-1-(methyl-11C)pyrrolidin-2-yl)-1H-benzo[d]imidazole-4-carboxamide ([11C]PyBic), and its preclinical evaluations in a syngeneic RG2 rat glioblastoma model and healthy nonhuman primates. METHODS: We synthesized [11C]PyBic using veliparib as the labeling precursor, performed dynamic PET scans on RG2 tumor-bearing rats and calculated the distribution volume ratio (DVR) using simplified reference region method 2 (SRTM2) with the contralateral nontumor brain region as the reference region. We performed biodistribution studies, western blot, and immunostaining studies to validate the in vivo PET quantification results. We characterized the brain kinetics and binding specificity of [11C]PyBic in nonhuman primates on FOCUS220 scanner and calculated the volume of distribution (VT), nondisplaceable volume of distribution (VND), and nondisplaceable binding potential (BPND) in selected brain regions. RESULTS: [11C]PyBic was synthesized efficiently in one step, with greater than 97% radiochemical and chemical purity and molar activity of 148 ± 85 MBq/nmol (n = 6). [11C]PyBic demonstrated PARP-specific binding in RG2 tumors, with 74% of tracer binding in tumors blocked by preinjected veliparib (i.v., 5 mg/kg). The in vivo PET imaging results were corroborated by ex vivo biodistribution, PARP1 immunohistochemistry and immunoblotting data. Furthermore, brain penetration of [11C]PyBic was confirmed by quantitative monkey brain PET, which showed high specific uptake (BPND > 3) and low nonspecific uptake (VND < 3 mL/cm3) in the monkey brain. CONCLUSION: [11C]PyBic is the first brain-penetrant PARP PET tracer validated in a rat glioblastoma model and healthy nonhuman primates. The brain kinetics of [11C]PyBic are suitable for noninvasive quantification of available PARP binding in the brain, which posits [11C]PyBic to have broad applications in oncology and neuroimaging.

Serotonin transporter availability in physically aggressive personality disordered patients: associations with trait and state aggression, and response to fluoxetine.

RATIONALE: Characterizing the neuroanatomical basis of serotonergic abnormalities in severe, chronic, impulsive aggression will allow for rational treatment selection, development of novel therapeutics, and biomarkers to identify at-risk individuals. OBJECTIVES: The aim of this study is to identify associations between regional serotonin transporter (5-HTT) availability and trait and state aggression, as well as response to the anti-aggressive effects of fluoxetine. METHODS: We examined 5-HTT availability using positron emission tomography (PET) imaging with [11C]DASB in personality disordered patients with current physical intermittent explosive disorder (IED; n = 18), and healthy comparison participants (HC; n = 11), in the anterior cingulate cortex (ACC), amygdala (AMY), ventral striatum (VST), and midbrain (MID). After PET imaging, IED patients were treated with fluoxetine 20 mg daily (n = 9) or placebo (n = 6) for 12 weeks. Trait and state aggression, trait callousness, and childhood trauma were assessed. RESULTS: In IED patients, trait aggression was positively associated with [11C]DASB binding in the ACC and VST; covarying for trait callousness and childhood trauma enhanced these correlations. Baseline state aggression was positively correlated with ACC [11C]DASB in IED patients. Greater baseline VST [11C]DASB binding predicted greater decreases in state aggression with fluoxetine treatment. CONCLUSIONS: Consistent with prior reports, ACC 5-HTT is related to trait aggression, and adjusting for factors related to proactive (callousness) and reactive (childhood trauma) aggression subtypes further resolves this relationship. Novel findings of the study include a better understanding of the association between regional 5-HTT availability and state aggression, and the involvement of VST 5-HTT with trait aggression, and with the anti-aggressive effects of fluoxetine.

Neurotransmitter transporter occupancy following administration of centanafadine sustained-release tablets: A phase 1 study in healthy male adults.

BACKGROUND: Centanafadine is an inhibitor of reuptake transporters for norepinephrine (NET), dopamine (DAT) and serotonin (SERT). AIMS: This phase 1, adaptive-design positron emission tomography study investigated the occupancy time course of NET, DAT, and SERT and the relationship to centanafadine plasma concentrations. METHODS: Healthy adult males received centanafadine sustained-release 400 mg/day for 4 days (N = 6) or 800 mg in a single day (N = 4). Assessments included safety monitoring; time course of occupancy of NET, DAT, and SERT; and centanafadine plasma concentrations. RESULTS: Transporter occupancy was numerically higher for NET versus DAT or SERT. For NET, estimated (mean ± standard error [SE]) maximal observable target occupancy (TOmax) and concentration at half maximal occupancy (IC50) were 64 ± 7% and 132 ± 65 ng/mL, respectively, for all regions and 82 ± 13% and 135 ± 97 ng/mL after excluding the thalamus, which showed high nonspecific binding. For DAT and SERT, TOmax could not be established and was assumed to be 100%; estimated IC50 (mean ± SE) values were 1580 ± 186 ng/mL and 1,760 ± 309 ng/mL, respectively. For centanafadine, the estimated in vivo affinity ratio was 11.9 ± 6.0 (mean ± SE) for NET/DAT, 13.3 ± 7.0 for NET/SERT, and 1.1 ± 0.2 for DAT/SERT. DAT and SERT occupancies at a plasma concentration of 1400 ng/mL were estimated to be 47 and 44%, respectively. CONCLUSIONS: High occupancy at NET and moderate occupancy at DAT and SERT was observed at peak concentrations achieved following 400 mg total daily doses of centanafadine.

Drug characteristics derived from kinetic modeling: combined 11C-UCB-J human PET imaging with levetiracetam and brivaracetam occupancy of SV2A.

BACKGROUND: Antiepileptic drugs, levetiracetam (LEV) and brivaracetam (BRV), bind to synaptic vesicle glycoprotein 2A (SV2A). In their anti-seizure activity, speed of brain entry may be an important factor. BRV showed faster entry into the human and non-human primate brain, based on more rapid displacement of SV2A tracer 11C-UCB-J. To extract additional information from previous human studies, we developed a nonlinear model that accounted for drug entry into the brain and binding to SV2A using brain 11C-UCB-J positron emission tomography (PET) data and the time-varying plasma drug concentration, to assess the kinetic parameter K1 (brain entry rate) of the drugs. METHOD: Displacement (LEV or BRV p.i. 60 min post-tracer injection) and post-dose scans were conducted in five healthy subjects. Blood samples were collected for measurement of drug concentration and the tracer arterial input function. Fitting of nonlinear differential equations was applied simultaneously to time-activity curves (TACs) from displacement and post-dose scans to estimate 5 parameters: K1 (drug), K1(11C-UCB-J, displacement), K1(11C-UCB-J, post-dose), free fraction of 11C-UCB-J in brain (fND(11C-UCB-J)), and distribution volume of 11C-UCB-J (VT(UCB-J)). Other parameters (KD(drug), KD(11C-UCB-J), fP(drug), fP(11C-UCB-J, displacement), fP(11C-UCB-J, post-dose), fND(drug), koff(drug), koff(11C-UCB-J)) were fixed to literature or measured values. RESULTS: The proposed model described well the TACs in all subjects; however, estimates of drug K1 were unstable in comparison with 11C-UCB-J K1 estimation. To provide a conservative estimate of the relative speed of brain entry for BRV vs. LEV, we determined a lower bound on the ratio BRV K1/LEV K1, by finding the lowest BRV K1 or highest LEV K1 that were statistically consistent with the data. Specifically, we used the F test to compare the residual sum of squares with fixed BRV K1 to that with floating BRV K1 to obtain the lowest possible BRV K1; the same analysis was performed to find the highest LEV K1. The lower bound of the ratio BRV K1/LEV K1 was ~ 7. CONCLUSIONS: Under appropriate conditions, this advanced nonlinear model can directly estimate entry rates of drugs into tissue by analysis of PET TACs. Using a conservative statistical cutoff, BRV enters the brain at least sevenfold faster than LEV.

Age, gender and body-mass-index relationships with in vivo CB1 receptor availability in healthy humans measured with [11C]OMAR PET.

Brain cannabinoid 1 receptors (CB1Rs) contribute importantly to the regulation of autonomic tone, appetite, mood and cognition. Inconsistent results have been reported from positron emission tomography (PET) studies using different radioligands to examine relationships between age, gender and body mass index (BMI) and CB1R availability in healthy individuals. In this study, we examined these variables in 58 healthy individuals (age range: 18-55 years; 44 male; BMI=27.01±5.56), the largest cohort of subjects studied to date using the CB1R PET ligand [11C]OMAR. There was a significant decline in CB1R availability (VT) with age in the pallidum, cerebellum and posterior cingulate. Adjusting for BMI, age-related decline in VT remained significant in the posterior cingulate among males, and in the cerebellum among women. CB1R availability was higher in women compared to men in the thalamus, pallidum and posterior cingulate. Adjusting for age, CB1R availability negatively correlated with BMI in women but not men. These findings differ from those reported using [11C]OMAR and other radioligands such as [18F]FMPEP-d2 and [18F]MK-9470. Although reasons for these seemingly divergent findings are unclear, the choice of PET radioligand and range of BMI in the current dataset may contribute to the observed differences. This study highlights the need for cross-validation studies using both [11C]OMAR and [18F]FMPEP-d2 within the same cohort of subjects.

Systemic inflammation enhances stimulant-induced striatal dopamine elevation in tobacco smokers.

Immune-brain interactions influence the pathophysiology of addiction. Lipopolysaccharide (LPS)-induced systemic inflammation produces effects on reward-related brain regions and the dopamine system. We previously showed that LPS amplifies dopamine elevation induced by methylphenidate (MP), compared to placebo (PBO), in eight healthy controls. However, the effects of LPS on the dopamine system of tobacco smokers have not been explored. The goal of Study 1 was to replicate previous findings in an independent cohort of tobacco smokers. The goal of Study 2 was to combine tobacco smokers with the aforementioned eight healthy controls to examine the effect of LPS on dopamine elevation in a heterogenous sample for power and effect size determination. Eight smokers were each scanned with [11C]raclopride positron emission tomography three times-at baseline, after administration of LPS (0.8 ng/kg, intravenously) and MP (40 mg, orally), and after administration of PBO and MP, in a double-blind, randomized order. Dopamine elevation was quantified as change in [11C]raclopride binding potential (ΔBPND) from baseline. A repeated-measures ANOVA was conducted to compare LPS and PBO conditions. Smokers and healthy controls were well-matched for demographics, drug dosing, and scanning parameters. In Study 1, MP-induced striatal dopamine elevation was significantly higher following LPS than PBO (p = 0.025, 18 ± 2.9 % vs 13 ± 2.7 %) for smokers. In Study 2, MP-induced striatal dopamine elevation was also significantly higher under LPS than under PBO (p < 0.001, 18 ± 1.6 % vs 11 ± 1.5 %) in the combined sample. Smoking status did not interact with the effect of condition. This is the first study to translate the phenomenon of amplified dopamine elevation after experimental activation of the immune system to an addicted sample which may have implications for drug reinforcement, seeking, and treatment.