An improved synthesis of [18 F]VAT and its precursor.

The vesicular acetylcholine transporter (VAChT) in the brain is an important presynaptic cholinergic biomarker, and neuroimaging studies of VAChT may provide in vivo information about psychiatric and neurologic conditions including Alzheimer's disease that are not accessible by other methods. The 18 F-labeled radiotracer, ((-)-(1-(-8-(2-[18 F]fluoroethoxy)-3-hydroxy-1,2,3,4-tetrahydronaphthalen-2-yl)piperidin-4-yl)(4-fluorophenyl)-methanone ([18 F]VAT, 1), was reported as a selective and high affinity ligand for the in vivo imaging of VAChT. The synthesis of [18 F]VAT has been reported in a two-step procedure with total 140 min, which includes preparation of 2-[18 F]fluoroethyltosylate and alkylation of benzovesamicol (-)-5 precursor with this radiosynthon using two different automated production modules consecutively. A multiple step synthetic route was employed for the synthesis of stereospecific precursor benzovesamicol (-)-5, which is difficult to be adapted for scale-up. To make the production of this tracer more amenable for clinical imaging, we present an improved total synthesis protocol to attain [18 F]VAT: (1) a tosylethoxy group being pre-installed tosylate precursor (-)-8 is synthesized to render a simple one-step radiofluorination under mild conditions; (2) The key optically active intermediate benzovesamicol (-)-5 was obtained via the regio- and enantio-enriched ring-opening amination of meso-epoxide 3 with 4-phenylpiperidine derivative 2 under catalysis of a chiral salenCo(III) catalyst 4b, which dramatically simplifies the synthetic route of the tosylate precursor (-)-8. [18 F]VAT 1 was prepared within ~65 min with desired chemical and radiochemical purities, via a fully automated procedure, using a commercial PET tracer production module. The final drug product was obtained as a sterile, pyrogen-free solution that conforms United States Pharmacopeia (USP) <823> requirements.

Imaging synaptic dopamine availability in individuals at clinical high-risk for psychosis: a [11C]-(+)-PHNO PET with methylphenidate challenge study.

Patients at clinical high-risk (CHR) for psychosis show elevations in [18F]DOPA uptake, an estimate of dopamine (DA) synthesis capacity, in the striatum predictive of conversion to schizophrenia. Intrasynaptic DA levels can be inferred from imaging the change in radiotracer binding at D2 receptors due to a pharmacological challenge. Here, we used methylphenidate, a DA reuptake inhibitor, and [11C]-(+)-PHNO, to measure synaptic DA availability in CHR both in striatal and extra-striatal brain regions. Fourteen unmedicated, nonsubstance using CHR individuals and 14 matched control subjects participated in the study. Subjects underwent two [11C]-(+)-PHNO scans, one at baseline and one following administration of a single oral dose (60 mg) of methylphenidate. [11C]-(+)-PHNO BPND, the binding potential relative to the nondisplaceable compartment, was derived using the simplified reference tissue model with cerebellum as reference tissue. The percent change in BPND between scans, ΔBPND, was computed as an index of synaptic DA availability, and group comparisons were performed with a linear mixed model. An overall trend was found for greater synaptic DA availability (∆BPND) in CHR than controls (p = 0.06). This was driven entirely by ∆BPND in ventral striatum (-34 ± 14% in CHR, -20 ± 12% in HC; p = 0.023). There were no significant group differences in any other brain region. There were no significant differences in DA transmission in any striatal region between converters and nonconverters, although this finding is limited by the small sample size (N = 2). There was a strong and negative correlation between ΔBPND in VST and severity of negative symptoms at baseline in the CHR group (r = -0.66, p < 0.01). We show abnormally increased DA availability in the VST in CHR and an inverse relationship with negative symptoms. Our results suggest a potential early role for mesolimbic dopamine overactivity in CHR. Longitudinal studies are needed to ascertain the significance of the differential topography observed here with the [18F]DOPA literature.

Multitask Learning Based Three-Dimensional Striatal Segmentation of MRI: fMRI and PET Objective Assessments.

BACKGROUND: Recent studies have established a clear topographical and functional organization of projections to and from complex subdivisions of the striatum. Manual segmentation of these functional subdivisions is labor-intensive and time-consuming, and automated methods are not as reliable as manual segmentation. PURPOSE: To utilize multitask learning (MTL) as a method to segment subregions of the striatum consisting of pre-commissural putamen (prePU), pre-commissural caudate (preCA), post-commissural putamen (postPU), post-commissural caudate (postCA), and ventral striatum (VST). STUDY TYPE: Retrospective. POPULATION: Eighty-seven total data sets from patients with schizophrenia and matched controls. FIELD STRENGTH/SEQUENCE: 1.5 T and 3.0 T, T1 -weighted (SPGR SENSE, 3D BRAVO). ASSESSMENT: MTL-generated segmentations were compared to the Imperial College London Clinical Imaging Center (CIC) atlas. Dice similarity coefficient (DSC) was used to compare the automated methods to manual segmentations. Positron emission tomography (PET) imaging: 60 minutes of emission data were acquired using [11 C]raclopride. Data were reconstructed by filtered back projection (FBP) with computed tomography (CT) used for attenuation correction. Binding potential values, BPND , and region of interest (ROI) time series and whole-brain connectivity using functional magnetic resonance imaging (fMRI) images were compared between manual and both automated segmentations. STATISTICAL TESTS: Pearson correlation and paired t-test. RESULTS: MTL-generated segmentations showed excellent spatial agreement with manual (DSC ≥0.72 across all striatal subregions). BPND values from MTL-generated segmentations were shown to correlate well with manual segmentations with R2 ≥ 0.91 in all caudate and putamen subregions, and R2  = 0.69 in VST. Mean Pearson correlation coefficients of the fMRI data between MTL-generated and manual segmentations were also high in time series (≥0.86) and whole-brain connectivity (≥0.89) across all subregions. DATA CONCLUSION: Across both PET and fMRI task-based assessments, results from MTL-generated segmentations more closely corresponded to results from manually drawn ROIs than CIC-generated segmentations did. Therefore, the proposed MTL approach is a fast and reliable method for three-dimensional striatal subregion segmentation with results comparable to manually segmented ROIs. LEVEL OF EVIDENCE: 2 TECHNICAL EFFICACY STAGE: 1.

Baseline reward processing and ventrostriatal dopamine function are associated with pramipexole response in depression.

The efficacy of dopamine agonists in treating major depressive disorder has been hypothesized to stem from effects on ventrostriatal dopamine and reward function. However, an important question is whether dopamine agonists are most beneficial for patients with reward-based deficits. This study evaluated whether measures of reward processing and ventrostriatal dopamine function predicted response to the dopamine agonist, pramipexole (ClinicalTrials.gov Identifier: NCT02033369). Individuals with major depressive disorder (n = 26) and healthy controls (n = 26) (mean ± SD age = 26.5 ± 5.9; 50% female) first underwent assessments of reward learning behaviour and ventrostriatal prediction error signalling (measured using functional MRI). 11C-(+)-PHNO PET before and after oral amphetamine was used to assess ventrostriatal dopamine release. The depressed group then received open-label pramipexole treatment for 6 weeks (0.5 mg/day titrated to a maximum daily dose of 2.5 mg). Symptoms were assessed weekly, and reward learning was reassessed post-treatment. At baseline, relative to controls, the depressed group showed lower reward learning (P = 0.02), a trend towards blunted reward-related prediction error signals (P = 0.07), and a trend towards increased amphetamine-induced dopamine release (P = 0.07). Despite symptom improvements following pramipexole (Cohen's d ranging from 0.51 to 2.16 across symptom subscales), reward learning did not change after treatment. At a group level, baseline reward learning (P = 0.001) and prediction error signalling (P = 0.004) were both associated with symptom improvement, albeit in a direction opposite to initial predictions: patients with stronger pretreatment reward learning and reward-related prediction error signalling improved most. Baseline D2/3 receptor availability (P = 0.02) and dopamine release (P = 0.05) also predicted improvements in clinical functioning, with lower D2/3 receptor availability and lower dopamine release predicting greater improvements. Although these findings await replication, they suggest that measures of reward-related mesolimbic dopamine function may hold promise for identifying depressed individuals likely to respond favourably to dopaminergic pharmacotherapy.

Dynamic Connectivity between Brain Networks Supports Working Memory: Relationships to Dopamine Release and Schizophrenia.

Connectivity between brain networks may adapt flexibly to cognitive demand, a process that could underlie adaptive behaviors and cognitive deficits, such as those observed in neuropsychiatric conditions like schizophrenia. Dopamine signaling is critical for working memory but its influence on internetwork connectivity is relatively unknown. We addressed these questions in healthy humans using functional magnetic resonance imaging (during ann-back working-memory task) and positron emission tomography using the radiotracer [(11)C]FLB457 before and after amphetamine to measure the capacity for dopamine release in extrastriatal brain regions. Brain networks were defined by spatial independent component analysis (ICA) and working-memory-load-dependent connectivity between task-relevant pairs of networks was determined via a modified psychophysiological interaction analysis. For most pairs of task-relevant networks, connectivity significantly changed as a function of working-memory load. Moreover, load-dependent changes in connectivity between left and right frontoparietal networks (Δ connectivity lFPN-rFPN) predicted interindividual differences in task performance more accurately than other fMRI and PET imaging measures. Δ Connectivity lFPN-rFPN was not related to cortical dopamine release capacity. A second study in unmedicated patients with schizophrenia showed no abnormalities in load-dependent connectivity but showed a weaker relationship between Δ connectivity lFPN-rFPN and working memory performance in patients compared with matched healthy individuals. Poor working memory performance in patients was, in contrast, related to deficient cortical dopamine release. Our findings indicate that interactions between brain networks dynamically adapt to fluctuating environmental demands. These dynamic adaptations underlie successful working memory performance in healthy individuals and are not well predicted by amphetamine-induced dopamine release capacity. SIGNIFICANCE STATEMENT: It is unclear how communication between brain networks responds to changing environmental demands during complex cognitive processes. Also, unknown in regard to these network dynamics is the role of neuromodulators, such as dopamine, and whether their dysregulation could underlie cognitive deficits in neuropsychiatric illness. We found that connectivity between brain networks changes with working-memory load and greater increases predict better working memory performance; however, it was not related to capacity for dopamine release in the cortex. Patients with schizophrenia did show dynamic internetwork connectivity; however, this was more weakly associated with successful performance in patients compared with healthy individuals. Our findings indicate that dynamic interactions between brain networks may support the type of flexible adaptations essential to goal-directed behavior.

Dynamic shifts in brain network activation during supracapacity working memory task performance.

Despite significant advances in understanding how brain networks support working memory (WM) and cognitive control, relatively little is known about how these networks respond when cognitive capabilities are overtaxed. We used a fine-grained manipulation of memory load within a single trial to exceed WM capacity during functional magnetic resonance imaging to investigate how these networks respond to support task performance when WM capacity is exceeded. Analyzing correct trials only, we observed a nonmonotonic (inverted-U) response to WM load throughout the classic WM network (including bilateral dorsolateral prefrontal cortex, posterior parietal cortex, and presupplementary motor areas) that peaked later in individuals with greater WM capacity. We also observed a relative increase in activity in medial anterior prefrontal cortex, posterior cingulate/precuneus, and lateral temporal and parietal regions at the highest WM loads, and a set of predominantly subcortical and prefrontal regions whose activation was greatest at the lowest WM loads. At the individual subject level, the inverted-U pattern was associated with poorer performance while expression of the early and late activating patterns was predictive of better performance. In addition, greater activation in bilateral fusiform gyrus and right occipital lobe at the highest WM loads predicted better performance. These results demonstrate dynamic and behaviorally relevant changes in the level of activation of multiple brain networks in response to increasing WM load that are not well accounted for by present models of how the brain subserves the cognitive ability to hold and manipulate information on-line.

Imaging the Vesicular Acetylcholine Transporter in Schizophrenia: A Positron Emission Tomography Study Using [18F]-VAT.

BACKGROUND: Despite longstanding interest in the central cholinergic system in schizophrenia (SCZ), cholinergic imaging studies with patients have been limited to receptors. Here, we conducted a proof-of-concept positron emission tomography study using [18F]-VAT, a new radiotracer that targets the vesicular acetylcholine transporter as a proxy measure of acetylcholine transmission capacity, in patients with SCZ and explored relationships of vesicular acetylcholine transporter with clinical symptoms and cognition. METHODS: A total of 18 adult patients with SCZ or schizoaffective disorder (the SCZ group) and 14 healthy control participants underwent a positron emission tomography scan with [18F]-VAT. Distribution volume (VT) for [18F]-VAT was derived for each region of interest, and group differences in VT were assessed with 2-sample t tests. Functional significance was explored through correlations between VT and scores on the Positive and Negative Syndrome Scale and a computerized neurocognitive battery (PennCNB). RESULTS: No group differences in [18F]-VAT VT were observed. However, within the SCZ group, psychosis symptom severity was positively associated with VT in multiple regions of interest, with the strongest effects in the hippocampus, thalamus, midbrain, cerebellum, and cortex. In addition, in the SCZ group, working memory performance was negatively associated with VT in the substantia innominata and several cortical regions of interest including the dorsolateral prefrontal cortex. CONCLUSIONS: In this initial study, the severity of 2 important features of SCZ-psychosis and working memory deficit-was strongly associated with [18F]-VAT VT in several cortical and subcortical regions. These correlations provide preliminary evidence of cholinergic activity involvement in SCZ and, if replicated in larger samples, could lead to a more complete mechanistic understanding of psychosis and cognitive deficits in SCZ and the development of therapeutic targets.

Loss of cholinergic input to the entorhinal cortex is an early indicator of cognitive impairment in natural aging of humans and mice.

In a series of translational experiments using fully quantitative positron emission tomography (PET) imaging with a new tracer specific for the vesicular acetylcholine transporter ([18F]VAT) in vivo in humans, and genetically targeted cholinergic markers in mice, we evaluated whether changes to the cholinergic system were an early feature of age-related cognitive decline. We found that deficits in cholinergic innervation of the entorhinal cortex (EC) and decline in performance on behavioral tasks engaging the EC are, strikingly, early features of the aging process. In human studies, we recruited older adult volunteers that were physically healthy and without prior clinical diagnosis of cognitive impairment. Using [18F]VAT PET imaging, we demonstrate that there is measurable loss of cholinergic inputs to the EC that can serve as an early signature of decline in EC cognitive performance. These deficits are specific to the cholinergic circuit between the medial septum and vertical limb of the diagonal band (MS/vDB; CH1/2) to the EC. Using diffusion imaging, we further demonstrate impaired structural connectivity in the tracts between the MS/vDB and EC in older adults with mild cognitive impairment. Experiments in mouse, designed to parallel and extend upon the human studies, used high resolution imaging to evaluate cholinergic terminal density and immediate early gene (IEG) activity of EC neurons in healthy aging mice and in mice with genetic susceptibility to accelerated accumulation amyloid beta plaques and hyperphosphorylated mouse tau. Across species and aging conditions, we find that the integrity of cholinergic projections to the EC directly correlates with the extent of EC activation and with performance on EC-related object recognition memory tasks. Silencing EC-projecting cholinergic neurons in young, healthy mice during the object-location memory task impairs object recognition performance, mimicking aging. Taken together we identify a role for acetylcholine in normal EC function and establish loss of cholinergic input to the EC as an early, conserved feature of age-related cognitive decline in both humans and rodents.

Monoamine transporter occupancy of a novel triple reuptake inhibitor in baboons and humans using positron emission tomography.

The selection of a therapeutically meaningful dose of a novel pharmaceutical is a crucial step in drug development. Positron emission tomography (PET) allows the in vivo estimation of the relationship between the plasma concentration of a drug and its target occupancy, optimizing dose selection and reducing the time and cost of early development. Triple reuptake inhibitors (TRIs), also referred to as serotonin-norepinephrine-dopamine reuptake inhibitors, enhance monoaminergic neurotransmission by blocking the action of the monoamine transporters, raising extracellular concentrations of those neurotransmitters. GSK1360707 [(1R,6S)-1-(3,4-dichlorophenyl)-6-(methoxymethyl)-4-azabicyclo[4.1.0]heptane] is a novel TRI that until recently was under development for the treatment of major depressive disorder; its development was put on hold for strategic reasons. We present the results of an in vivo assessment of the relationship between plasma exposure and transporter blockade (occupancy). Studies were performed in baboons (Papio anubis) to determine the relationship between plasma concentration and occupancy of brain serotonin reuptake transporter (SERT), dopamine reuptake transporter (DAT), and norepinephrine uptake transporter (NET) using the radioligands [(11)C]DASB [(N,N-dimethyl-2-(2-amino-4-cyanophenylthio) benzylamine], [(11)C]PE2I [N-(3-iodoprop-2E-enyl)-2ß-carbomethoxy-3ß-(4-methylphenyl)nortropane], and [(11)C]2-[(2-methoxyphenoxy)phenylmethyl]morpholine (also known as [(11)C]MRB) and in humans using [(11)C]DASB and [(11)C]PE2I. In P. anubis, plasma concentrations resulting in half-maximal occupancy at SERT, DAT, and NET were 15.16, 15.56, and 0.97 ng/ml, respectively. In humans, the corresponding values for SERT and DAT were 6.80 and 18.00 ng/ml. GSK1360707 dose-dependently blocked the signal of SERT-, DAT-, and NET-selective PET ligands, confirming its penetration across the blood-brain barrier and blockade of all three monoamine transporters in vivo.

Medial Prefrontal Cortex Dysfunction Mediates Working Memory Deficits in Patients With Schizophrenia.

Background: Schizophrenia (SCZ) is marked by working memory (WM) deficits, which predict poor functional outcome. While most functional magnetic resonance imaging studies of WM in SCZ have focused on the dorsolateral prefrontal cortex (PFC), some recent work suggests that the medial PFC (mPFC) may play a role. We investigated whether task-evoked mPFC deactivation is associated with WM performance and whether it mediates deficits in SCZ. In addition, we investigated associations between mPFC deactivation and cortical dopamine release. Methods: Patients with SCZ (n = 41) and healthy control participants (HCs) (n = 40) performed a visual object n-back task during functional magnetic resonance imaging. Dopamine release capacity in mPFC was quantified with [11C]FLB457 in a subset of participants (9 SCZ, 14 HCs) using an amphetamine challenge. Correlations between task-evoked deactivation and performance were assessed in mPFC and dorsolateral PFC masks and were further examined for relationships with diagnosis and dopamine release. Results: mPFC deactivation was associated with WM task performance, but dorsolateral PFC activation was not. Deactivation in the mPFC was reduced in patients with SCZ relative to HCs and mediated the relationship between diagnosis and WM performance. In addition, mPFC deactivation was significantly and inversely associated with dopamine release capacity across groups and in HCs alone, but not in patients. Conclusions: Reduced WM task-evoked mPFC deactivation is a mediator of, and potential substrate for, WM impairment in SCZ, although our study design does not rule out the possibility that these findings could relate to cognition in general rather than WM specifically. We further present preliminary evidence of an inverse association between deactivation during WM tasks and dopamine release capacity in the mPFC.

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.

Extended characterisation of the serotonin 2A (5-HT2A) receptor-selective PET radiotracer 11C-MDL100907 in humans: quantitative analysis, test-retest reproducibility, and vulnerability to endogenous 5-HT tone.

INTRODUCTION: Scanning properties and analytic methodology of the 5-HT2A receptor-selective positron emission tomography (PET) tracer 11C-MDL100907 have been partially characterised in previous reports. We present an extended characterisation in healthy human subjects. METHODS: 64 11C-MDL100907 PET scans with metabolite-corrected arterial input function were performed in 39 healthy adults (18-55 years). 12 subjects were scanned twice (duration 150 min) to provide data on plasma analysis, model order estimation, and stability and test-retest characteristics of outcome measures. All other scans were 90 min duration. 3 subjects completed scanning at baseline and following 5-HT2A receptor antagonist medication (risperidone or ciproheptadine) to provide definitive data on the suitability of the cerebellum as reference region. 10 subjects were scanned under reduced 5-HT and control conditions using rapid tryptophan depletion to investigate vulnerability to competition with endogenous 5-HT. 13 subjects were scanned as controls in clinical protocols. Pooled data were used to analyse the relationship between tracer injected mass and receptor occupancy, and age-related decline in 5-HT2A receptors. RESULTS: Optimum analytic method was a 2-tissue compartment model with arterial input function. However, basis function implementation of SRTM may be suitable for measuring between-group differences non-invasively and warrants further investigation. Scan duration of 90 min achieved stable outcome measures in all cortical regions except orbitofrontal which required 120 min. Binding potential (BPP and BPND) test-retest variability was very good (7-11%) in neocortical regions other than orbitofrontal, and moderately good (14-20%) in orbitofrontal cortex and medial temporal lobe. Saturation occupancy of 5-HT2A receptors by risperidone validates the use of the cerebellum as a region devoid of specific binding for the purposes of PET. We advocate a mass limit of 4.6 µg to remain below 5% receptor occupancy. 11C-MDL100907 specific binding is not vulnerable to competition with endogenous 5-HT in humans. Paradoxical decreases in BPND were found in right prefrontal cortex following reduced 5-HT, possibly representing receptor internalisation. Mean age-related decline in brain 5-HT2A receptors was 14.0±5.0% per decade, and higher in prefrontal regions. CONCLUSIONS: Our data confirm and extend support for 11C-MDL100907 as a PET tracer with very favourable properties for quantifying 5-HT2A receptors in the human brain.

Affinity and selectivity of [¹¹C]-(+)-PHNO for the D3 and D2 receptors in the rhesus monkey brain in vivo.

Although [¹¹C]-(+)-PHNO has enabled quantification of the dopamine-D3 receptor (D3R) in the human brain in vivo, its selectivity for the D3R is not sufficiently high to allow us to disregard its binding to the dopamine-D2 receptor (D2R). We quantified the affinity of [¹¹C]-(+)-PHNO for the D2R and D3R in the living primate brain. Two rhesus monkeys were examined on four occasions each, with [¹¹C]-(+)-PHNO administered in a bolus + infusion paradigm. Varying doses of unlabeled (+)-PHNO were coadministered on each occasion (total doses ranging from 0.09 to 5.61 µg kg⁻¹). The regional binding potential (BP(ND) ) and the corresponding doses of injected (+)-PHNO were used as inputs in a model that quantified the affinity of (+)-PHNO for the D2R and D3R, as well as the regional fractions of the [¹¹C]-(+)-PHNO signal attributable to D3R binding. (+)-PHNO in vivo affinity for the D3R (K(d)/f(ND) ~0.23-0.56 nM) was 25- to 48-fold higher than that for the D2R (K(d)/f(ND) ~11-14 nM). The tracer limits for (+)-PHNO (dose associated with D3R occupancy ~10%) were estimated at ~0.02-0.04 µg kg⁻¹ injected mass for anesthetized primate and at 0.01-0.02 µg kg⁻¹ for awake human positron emission tomography (PET) studies. Our data enabled a rational design and interpretation of future PET studies with [¹¹C]-(+)-PHNO.

Striatal dopamine in bulimia nervosa: a PET imaging study.

OBJECTIVE: Bulimia nervosa (BN) has been characterized as similar to an addiction, though the empirical support for this characterization is limited. This study utilized PET imaging to determine whether abnormalities in brain dopamine (DA) similar to those described in substance use disorders occur in BN. METHOD: PET imaging with [(11) C]raclopride, pre/post methylphenidate administration, to assess dopamine type 2 (D(2)) receptor binding (BP(ND)) and striatal DA release (ΔBP(ND)). RESULTS: There was a trend toward lower D(2) receptor BP(ND) in two striatal subregions in the patient group when compared with the control group. DA release in the putamen in the patient group was significantly reduced and, overall, there was a trend toward a difference in striatal DA release. Striatal DA release was significantly associated with the frequency of binge eating. DISCUSSION: These data suggest that BN is characterized by abnormalities in brain DA that resemble, in some ways, those described in addictive disorders.

Deep rTMS of the insula and prefrontal cortex in smokers with schizophrenia: Proof-of-concept study.

Patients with schizophrenia have a high prevalence of cigarette smoking and respond poorly to conventional treatments, highlighting the need for new therapies. We conducted a mechanistic, proof-of-concept study using bilateral deep repetitive transcranial magnetic stimulation (dTMS) of insular and prefrontal cortices at high frequency, using the specialized H4 coil. Feasibility of dTMS was tested for disruption of tobacco self-administration, insula target engagement, and insula circuit modulation, all of which were a priori outcomes of interest. Twenty patients completed the study, consisting of weekday dTMS sessions (randomization to active dTMS or sham; double-blind; 10 patients per group), a laboratory tobacco self-administration paradigm (pre/post assessments), and multimodal imaging (three MRI total sessions). Results showed that participants assigned to active dTMS were slower to initiate smoking their first cigarette compared with sham, consistent with smoking disruption. The imaging analyses did not reveal significant Time × Group interactions, but effects were in the anticipated directions. In arterial spin labeling analyses testing for target engagement, an overall decrease in insula blood flow, measured during a post-treatment MRI versus baseline, was numerically more pronounced in the active dTMS group than sham. In fMRI analyses, resting-state connectivity between the insula and default mode network showed a numerically greater change from baseline in the active dTMS group than sham, consistent with a functional change to insula circuits. Exploratory analyses further suggested a therapeutic effect of dTMS on symptoms of psychosis. These initial observations pave the way for future confirmatory studies of dTMS in smoking patients with schizophrenia.

Dopamine D1R Receptor Stimulation as a Mechanistic Pro-cognitive Target for Schizophrenia.

Decades of research have highlighted the importance of optimal stimulation of cortical dopaminergic receptors, particularly the D1R receptor (D1R), for prefrontal-mediated cognition. This mechanism is particularly relevant to the cognitive deficits in schizophrenia, given the abnormalities in cortical dopamine (DA) neurotransmission and in the expression of D1R. Despite the critical need for D1R-based therapeutics, many factors have complicated their development and prevented this important therapeutic target from being adequately interrogated. Challenges include determination of the optimal level of D1R stimulation needed to improve cognitive performance, especially when D1R expression levels, affinity states, DA levels, and the resulting D1R occupancy by DA, are not clearly known in schizophrenia, and may display great interindividual and intraindividual variability related to cognitive states and other physiological variables. These directly affect the selection of the level of stimulation necessary to correct the underlying neurobiology. The optimal mechanism for stimulation is also unknown and could include partial or full agonism, biased agonism, or positive allosteric modulation. Furthermore, the development of D1R targeting drugs has been complicated by complexities in extrapolating from in vitro affinity determinations to in vivo use. Prior D1R-targeted drugs have been unsuccessful due to poor bioavailability, pharmacokinetics, and insufficient target engagement at tolerable doses. Newer drugs have recently become available, and these must be tested in the context of carefully designed paradigms that address methodological challenges. In this paper, we discuss how a better understanding of these challenges has shaped our proposed experimental design for testing a new D1R/D5R partial agonist, PF-06412562, renamed CVL-562.

Characterization of in vivo pharmacological properties and sensitivity to endogenous serotonin of [11C] P943: a positron emission tomography study in Papio anubis.

[11 C] P943 is a recently developed PET radiotracer for serotonin 5-HT1B receptors. We characterized a number of its in vivo pharmacokinetic properties, including the evaluation of its two stereo-isomers, saturability of specific binding, selectivity for 5-HT1B and 5-HT1D receptors, and vulnerability to pharmacologically induced increases in endogenous 5-HT levels. Six isoflurane-anesthetized baboons were scanned with [11 C] P943 at baseline, and following various pharmacological manipulations. The interventions included the administration of pharmacological doses of P943, SB-616234-S (a 5-HT1B selective antagonist), SB-714786 (a 5-HT1D selective antagonist), as well as the administration of 5-HT releasing agents (fenfluramine, amphetamine) and 5-HT reuptake inhibitor (citalopram). [11 C] P943 was observed to bind saturably and specifically to 5-HT1B receptors and to be sensitive to all three challenges known to alter 5-HT levels in the proximity of receptors. [11 C] P943 shows promise as a tracer to image serotonin function in healthy subjects as well as subjects with psychiatric or neurologic conditions.

Translational characterization of [11C]GSK931145, a PET ligand for the glycine transporter type 1.

The current interest in developing Glycine transporter Type 1 (GlyT-1) inhibitors, for diseases such as schizophrenia, has led to the demand for a GlyT-1 PET molecular imaging tool to aid drug development and dose selection. We report on [(11) C]GSK931145 as a novel GlyT-1 imaging probe in primate and man. Primate PET studies were performed to determine the level of specific binding following homologous competition with GSK931145 and the plasma-occupancy relationship of the GlyT-1 inhibitor GSK1018921. Human PET studies were performed to determine the test-retest reproducibility of [(11) C]GSK931145 and the plasma-occupancy relationship of GSK1018921. [(11) C]GSK931145 entered primate and human brain and yielded a heterogeneous pattern of uptake which was similar in both species with highest uptake in midbrain, thalamus, and cerebellum. Homologous competition in primates indicated no viable reference region and gave binding potential estimates between 1.5 and 3 for midbrain, thalamus and cerebellum, While the distribution and binding potential values were similar across species, both the plasma free fraction (f(P) : 0.8 vs. 8%) and delivery (K(1) : 0.025 vs. 0.126 ml cm(-3) min(-1) ) were significantly lower in humans. Test-retest reproducibility in humans calculated using a two tissue compartmental model was poor (VAR(V(T) ): 29-38%), but was improved using a pseudo reference tissue model (VAR(BP(ND) ): 16-23%). GSK1018921 EC(50) estimates were 22.5 and 45.7 ng/ml in primates and humans, respectively.

The 5-HT(2A) receptor and serotonin transporter in Asperger's disorder: A PET study with [¹¹C]MDL 100907 and [¹¹C]DASB.

Evidence from biochemical, imaging, and treatment studies suggest abnormalities of the serotonin system in autism spectrum disorders, in particular in frontolimbic areas of the brain. We used the radiotracers [(11)C]MDL 100907 and [(11)C]DASB to characterize the 5-HT(2A) receptor and serotonin transporter in Asperger's Disorder. Seventeen individuals with Asperger's Disorder (age=34.3 ± 11.1 years) and 17 healthy controls (age=33.0 ± 9.6 years) were scanned with [(11)C]MDL 100907. Of the 17 patients, eight (age=29.7 ± 7.0 years) were also scanned with [¹¹C]DASB, as were eight healthy controls (age=28.7 ± 7.0 years). Patients with Asperger's Disorder and healthy control subjects were matched for age, gender, and ethnicity, and all had normal intelligence. Metabolite-corrected arterial plasma inputs were collected and data analyzed by two-tissue compartment modeling. The primary outcome measure was regional binding potential BP(ND). Neither regional [¹¹C]MDL 100907 BP(ND) nor [¹¹C]DASB BP(ND) was statistically different between the Asperger's and healthy subjects. This study failed to find significant alterations in binding parameters of 5-HT(2A) receptors and serotonin transporters in adult subjects with Asperger's disorder.

Neuroinflammation in World Trade Center responders at midlife: A pilot study using [18F]-FEPPA PET imaging.

BACKGROUND: Neuroinflammation has long been theorized to arise from exposures to fine particulate matter and to be modulated when individuals experience chronic stress, both of which are also though to cause cognitive decline in part as a result of neuroinflammation. OBJECTIVES: Hypothesizing that neuroinflammation might be linked to experiences at the World Trade Center (WTC) events, this study explored associations between glial activation and neuropsychological measures including post-traumatic stress disorder (PTSD) symptom severity and WTC exposure duration. METHODS: Translocator protein 18-kDa (TSPO) is overexpressed by activated glial cells, predominantly microglia and astrocytes, making TSPO distribution a putative biomarker for neuroinflammation. Twenty WTC responders completed neuropsychological assessments and in vivo PET brain scan with [18F]-FEPPA. Generalized linear modeling was used to test associations between PTSD, and WTC exposure duratiioni as the predictor and both global and regional [18F]-FEPPA total distribution volumes as the outcomes. RESULT: Responders were 56.0 â€‹± â€‹4.7 years-old, and 75% were police officers on 9/11/2001, and all had at least a high school education. Higher PTSD symptom severity was associated with global and regional elevations in [18F]-FEPPA binding predominantly in the hippocampus (d â€‹= â€‹0.72, P â€‹= â€‹0.001) and frontal cortex (d â€‹= â€‹0.64, P â€‹= â€‹0.004). Longer exposure duration to WTC sites was associated with higher [18F]-FEPPA binding in the parietal cortex. CONCLUSION: Findings from this study of WTC responders at midlife suggest that glial activation is associated with PTSD symptoms, and WTC exposure duration. Future investigation is needed to understand the important role of neuroinflammation in highly exposed WTC responders.