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Background: There is growing evidence that the serotonergic system, in particular serotonin 2A receptors, is involved in neuropsychiatric symptoms in Parkinson's disease (PD), including cognitive processing and visual hallucinations. However, the relationship between serotonin 2A receptor availability, visual hallucinations, and cognitive profile is unknown. The objective of this study was to investigate the level of serotonin 2A receptor availability in brain regions affected by visual hallucinations and to test the association with cognitive/behavioral changes in patients who have PD with visual hallucinations. Methods: Nondemented patients who had PD with (n = 11) and without (n = 8) visual hallucinations and age‐matched controls (n = 10) were recruited. All participants completed neuropsychological testing, which consisted of visuoperceptual, executive, memory, language, and frontal‐behavioral function. Positron emission tomography scans using [18F]setoperone, a serotonin 2A antagonist radioligand, were acquired in patients with PD, and a parametric binding potential map of [18F]setoperone was calculated with the simplified reference tissue model using the cerebellum as a reference. Results: Patients who had PD with visual hallucinations exhibited significantly lower scores on measures of executive and visuoperceptual functions compared with age‐matched controls. These changes were paralleled by decreased [18F]setoperone binding in the right insula, bilateral dorsolateral prefrontal cortex, right orbitofrontal cortex, right middle temporal gyrus, and right fusiform gyrus. The psychometric correlation analysis revealed significant relationships among tests associated with visuoperceptual function, memory and learning, and serotonin 2A binding in different prefrontal and ventral visual stream regions. There was also reduced serotonin 2A receptor binding in patients who had PD with depression. Conclusions: These findings support a complex interaction between serotonin 2A receptor function and cognitive processing in patients who have PD with visual hallucinations. Fil: Cho, Sang Soo. University of Toronto; Canadá Fil: Strafella, Antonio P.. University of Toronto; Canadá Fil: Duff Canning, Sarah. University of Toronto; Canadá Fil: Zurowski, Mateusz. University of Toronto; Canadá Fil: Vijverman, Anne Catherine. Onze‐Lieve‐Vrouw Hospital; Bélgica Fil: Bruno, Veronica Andrea. University of Toronto; Canadá. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina Fil: Aquino, Camila C.. University of Toronto; Canadá Fil: Criaud, Marion. University of Toronto; Canadá Fil: Rusjan, Pablo M.. University of Toronto; Canadá Fil: Houle, Sylvain. University of Toronto; Canadá Fil: Fox, Susan H.. University of Toronto; Canadá

Stress and cannabis use are risk factors for the development of psychosis. We have previously shown that subjects at clinical high risk for psychosis (CHR) exhibit a higher striatal dopamine response to stress compared with healthy volunteers (HV), with chronic cannabis use blunting this response. However, it is unknown if this abnormal dopamine response extends to the prefrontal cortex (PFC). Here, we investigated dorsolateral PFC (dlPFC) and medial PFC (mPFC) dopamine release using [11 C]FLB457 positron emission tomography (PET) and a validated stress task. Thirty-three participants completed two PET scans (14 CHR without cannabis use, eight CHR regular cannabis users [CHR-CUs] and 11 HV) while performing a Sensory Motor Control Task (control scan) and the Montreal Imaging Stress Task (stress scan). Stress-induced dopamine release (ΔBPND ) was defined as percent change in D2/3 receptor binding potential between both scans using a novel correction for injected mass of [11 C]FLB457. ΔBPND was significantly different between groups in mPFC (F(2,30) = 5.40, .010), with CHR-CUs exhibiting lower ΔBPND compared with CHR (.008). Similarly, salivary cortisol response (ΔAUCI ) was significantly lower in CHR-CU compared with CHR (F(2,29) = 5.08, .013; post hoc .018) and positively associated with ΔBPND . Furthermore, CHR-CUs had higher attenuated psychotic symptoms than CHR following the stress task, which were negatively associated with ΔBPND . Length of cannabis use was negatively associated with ΔBPND in mPFC when controlling for current cannabis use. Given the global trend to legalize cannabis, this study is important as it highlights the effects of regular cannabis use on cortical dopamine function in high-risk youth. published

Objective To investigate the effects of light therapy on serotonin transporter binding (5-HTT BPND), an index of 5-HTT levels, in the anterior cingulate and prefrontal cortices (ACC and PFC) during winter in seasonal affective disorder (SAD). 5-HTT BPND fluctuates seasonally to a greater extent in SAD relative to health. We hypothesized that in SAD, 5-HTT BPND would be reduced in the ACC and PFC following light therapy. Methods Eleven SAD participants underwent [11C] DASB positron emission tomography (PET) scans to measure 5-HTT BPND before and after 2 weeks of daily morning light therapy. Results The primary finding was a main effect of treatment on 5-HTT BPND in the ACC and PFC (repeated-measures manova, F(2,9) = 6.82, P = 0.016). This effect was significant in the ACC (F(1,10) = 15.11 and P = 0.003, magnitude of decrease, 11.94%) and PFC (F(1,10) = 8.33, P = 0.016, magnitude of decrease, 9.13%). 5-HTT BPND also decreased in other regions assayed following light therapy (repeated-measures manova, F(4,7) = 8.54, P = 0.028) including the hippocampus, ventral striatum, dorsal putamen, thalamus and midbrain (F(1,10) = 8.02–36.94, P < 0.0001–0.018; magnitude −8.83% to −16.74%). Conclusions These results demonstrate that light therapy reaches an important therapeutic target in the treatment of SAD and provide a basis for improvement of this treatment via application of [11C]DASB PET.

Background Pittsburgh compound B ([11C]-PIB) identifies amyloid-β (Aβ) deposition in vivo. Asymptomatic Aβ deposition has been reported consistently in some healthy older subjects. Of patients with frontotemporal dementia, those who have later onset have a higher potential for Aβ deposition. Objective Comparison of Aβ deposition in Alzheimer's disease (AD), healthy older controls, and patients with early- and late-onset semantic dementia (SD), a subtype of frontotemporal dementia. Methods Subjects were recruited from tertiary academic care centers specializing in assessment and management of patients with neurodegenerative disease. We used the radiotracer [11C]-PIB in a high-resolution positron emission tomography scanner to evaluate 11 participants with SD (six with onset before age 65 and five with later onset), 9 with probable AD, and 10 controls over age 60. The main outcome measures were frontal, temporal, parietal, and total [11C]-PIB standardized uptake value ratios to establish PIB-positive (PIB+) cutoff. Results The five patients with late-onset SD were PIB-negative. Two of six with early-onset SD, seven of nine with AD, and 1 of 10 controls were PIB+. The SD participants who were PIB+ did not have memory or visuospatial deficits that are typical in AD. Conclusions Aβ deposition does not seem to be associated with late-onset SD. Future larger studies might confirm whether a significant minority of early-onset SD patients exhibit Aβ deposition. Copyright © 2016 John Wiley & Sons, Ltd.

Objective To investigate the effects of light therapy on serotonin transporter binding (5-HTT BPND), an index of 5-HTT levels, in the anterior cingulate and prefrontal cortices (ACC and PFC) of healthy individuals during the fall and winter. Twenty-five per cent of healthy individuals experience seasonal mood changes that affect functioning. 5-HTT BPND has been found to be higher across multiple brain regions in the fall and winter relative to spring and summer, and elevated 5-HTT BPND may lead to extracellular serotonin loss and low mood. We hypothesized that, during the fall and winter, light therapy would reduce 5-HTT BPND in the ACC and PFC, which sample brain regions involved in mood regulation. Method In a single-blind, placebo-controlled, counterbalanced, crossover design, [11C]DASB positron emission tomography was used measure 5-HTT BPND following light therapy and placebo conditions during fall and winter. Results In winter, light therapy significantly decreased 5-HTT BPND by 12% in the ACC relative to placebo (F1,9 = 18.04, P = 0.002). In the fall, no significant change in 5-HTT BPND was found in any region across conditions. Conclusion These results identify, for the first time, a central biomarker associated with the intervention of light therapy in humans which may be applied to further develop this treatment for prevention of seasonal depression.

Dopamine agonist medications with high affinity for the D3 dopamine receptor are commonly used to treat Parkinson's disease, and have been associated with pathological behaviors categorized under the umbrella of impulse control disorders (ICD). The aim of this study was to investigate whether ICD in Parkinson's patients are associated with greater D3 dopamine receptor availability. We used positron emission tomography (PET) radioligand imaging with the D3 dopamine receptor preferring agonist [11C]-(+)-propyl-hexahydro-naphtho-oxazin (PHNO) in Parkinson's patients with (n = 11) and without (n = 21) ICD, and age-, sex-, and education-matched healthy control subjects (n = 18). Contrary to hypotheses, [11C]-(+)-PHNO binding in D3-rich brain areas was not elevated in Parkinson's patients with ICD compared with those without; instead, [11C]-(+)-PHNO binding in ventral striatum was 20% lower (P = 0.011), correlating with two measures of ICD severity (r = −0.8 and −0.9), which may reflect higher dopamine tone in ventral striatum. In dorsal striatum, where [11C]-(+)-PHNO binding is associated with D2 receptor levels, [11C]-(+)-PHNO binding was elevated across patients compared with controls. We conclude that although D3 dopamine receptors have been linked to the occurrence of ICD in Parkinson's patients. Our findings do not support the hypothesis that D3 receptor levels are elevated in Parkinson's patients with ICD. We also did not find ICD-related abnormalities in D2 receptor levels. Our findings argue against the possibility that differences in D2/3 receptor levels can account for the development of ICD in PD; however, we cannot rule out that differences in dopamine levels (particularly in ventral striatum) may be involved. © 2015 International Parkinson and Movement Disorder Society

Throughout daily life, new memories are formed and past memories are constantly drawn upon to guide behavior. Parkinson disease (PD) patients often experience memory deficits characterized by the inability to recall information, and memory impairment is a significant predictor of future dementia.1,2 Dopamine (DA) transmission is known to be crucial to normal memory function. DA signaling in the striatum facilitates learning, 3 and mesocorticolimbic DA modulates memory consolidation and retrieval in both the medial temporal lobe and cortex.4,5 Recently, we demonstrated that striatal DA depletion in a region involved in cognitive processing (associative striatum) as well as D2 receptor reductions in the bilateral insula contribute to executive dysfunction in PD.6 However, the contribution of dopaminergic dysfunction to memory impairment remains unclear. The insula along with the anterior cingulate cortex (ACC) is part of a salience network, known to causally influence activation and enable switching between the central executive network7 and the default mode network, 8,9 which cooperate to facilitate memory.10,11 It has been suggested that memory deficits in PD may be the result of dysfunctional executive networks that participate in memory retrieval and organization.12–15 Thus, due to their roles in executive processing, dopaminergic dysfunction in the salience network, the central executive network, or the striatum, which is highly interconnected with these cortical regions,16,17 could have a profound impact on memory. Alternatively, there is evidence that points to memory deficits in PD as the result of DA dysfunction in the medial temporal lobe,18,19 suggesting that memory impairment may be the result of abnormal encoding or storage of memory. The aim of this study was to assess whether dopaminergic differences in (1) the central executive network, salience network, or striatum or (2) the medial temporal lobe contribute to memory deficits in PD patients with mild cognitive impairment (MCI). We used positron emission tomography (PET) imaging to examine cortical D2 receptor availability in the dorsolateral prefrontal cortex (DLPFC) and posterior parietal cortex (PPC; central executive network); the insula and ACC (salience network); and the medial temporal lobe, as well as DA neuron integrity in the striatum in a sample of PD patients with significant memory impairment, as assessed by a full neuropsychological test battery. Furthermore, we aimed to determine whether dopaminergic changes could explain variance in memory performance, and whether changes related to memory and executive dysfunction coincide in the brain.

The ability to quantify translocator protein 18 kDa (TSPO) in white matter (WM) is important to understand the role of neuroinflammation in neurological disorders with WM involvement. This article aims to extend the utility of TSPO imaging in WM using a second-generation radioligand, [18F]-FEPPA, and high-resolution research tomograph (HRRT) positron emission tomography (PET) camera system. Four WM regions of interests (WM-ROI), relevant to the study of aging and neuroinflammatory diseases, were examined. The corpus callosum, cingulum bundle, superior longitudinal fasciculus, and posterior limb of internal capsule were delineated automatically onto subject's T1-weighted magnetic resonance image using a diffusion tensor imaging-based WM template. The TSPO polymorphism (rs6971) stratified individuals to three genetic groups: high-affinity binders (HAB), mixed-affinity binders (MAB), and low-affinity binders. [18F]-FEPPA PET scans were acquired on 32 healthy subjects and analyzed using a full kinetic compartment analysis. The two-tissue compartment model showed moderate identifiability (coefficient of variation 15–19%) for [18F]-FEPPA total volume distribution (VT) in WM-ROIs. Noise affects VT variability, although its effect on bias was small (6%). In a worst-case scenario, ≤6% of simulated data did not fit reliably. A simulation of increased TSPO density exposed minimal effect on variability and identifiability of [18F]-FEPPA VT in WM-ROIs. We found no association between age and [18F]-FEPPA VT in WM-ROIs. The VT values were 15% higher in HAB than in MAB, although the difference was not statistically significant. This study provides evidence for the utility and limitations of [18F]-FEPPA PET to measure TSPO expression in WM. Synapse 68:536–547, 2014. © 2014 Wiley Periodicals, Inc.

r r Abstract: The control of impulse behavior is a multidimensional concept subdivided into separate sub- components, which are thought to represent different underlying mechanisms due to either disinhibitory processes or poor decision-making. In patients with Parkinson's disease (PD), dopamine-agonist (DA) therapy has been associated with increased impulsive behavior. However, the relationship among these different components in the disease and the role of DA is not well understood. In this imaging study, we investigated in PD patients the effects of DA medication on patterns of brain activation during tasks test- ing impulsive choices and actions. Following overnight withdrawal of antiparkinsonian medication, PD patients were studied with a H2 (15) O PET before and after administration of DA (1 mg of pramipexole), while they were performing the delay discounting task (DDT) and the GoNoGo Task (GNG). We observed that pramipexole augmented impulsivity during DDT, depending on reward magnitude and activated the medial prefrontal cortex and posterior cingulate cortex and deactivated ventral striatum. In contrast, the effect of pramipexole during the GNG task was not significant on behavioral performance and involved different areas (i.e., lateral prefrontal cortex). A voxel-based correlation analysis revealed a significant negative correlation between the discounting value (k) and the activation of medial prefrontal cortex and posterior cingulate suggesting that more impulsive patients had less activation in those corti- cal areas. Here we report how these different subcomponents of inhibition/impulsivity are differentially sensitive to DA treatment with pramipexole influencing mainly the neural network underlying impulsive choices but not impulsive action. Hum Brain Mapp 35:2499-2506, 2014. V C 2013 Wiley Periodicals, Inc.

Aims Pathological gambling (PG) shares diagnostic features with substance use disorder (SUD), but the neurochemical mechanisms underlying PG are poorly understood. Because dopamine (DA), a neurotransmitter implicated in reward and reinforcement, is probably involved, we used positron emission tomography (PET) to test whether PG is associated with abnormalities in D2 and D3 receptor levels, as observed in SUD. Design Case–control study comparing PG to healthy control (HC) subjects. Setting Academic research imaging centre. Participants Thirteen non-treatment-seeking males meeting DSM-IV criteria for PG, and 12 matched HC (11 of whom completed PET). Measurements Two PET scans (one with the D3 receptor preferring agonist [11C]-(+)-propyl-hexahydro-naphtho-oxazin (PHNO) and the other with [11C]raclopride) to assess D2/3 DA receptor availability, and behavioural measures (self-report questionnaires and slot-machine game) to assess subjective effects and relationships to PET measures. Findings Binding of both radiotracers did not differ between groups in striatum or substantia nigra (SN) (all P > 0.1). Across PG, [11C]-(+)-PHNO binding in SN, where the signal is attributable primarily to D3 receptors, correlated with gambling severity (r = 0.57, P = 0.04) and impulsiveness (r = 0.65, P = 0.03). In HC, [11C]raclopride binding in dorsal striatum correlated inversely with subjective effects of gambling (r = −0.70, P = 0.03) and impulsiveness (r = −0.70, P = 0.03). Conclusions Unlike with substance use disorder, there appear to be no marked differences in D2/D3 levels between healthy subjects and pathological gamblers, suggesting that low receptor availability may not be a necessary feature of addiction. However, relationships between [11C]-(+)-PHNO binding and gambling severity/impulsiveness suggests involvement of the D3 receptor in impulsive/compulsive behaviours.

Objectives To follow up on the increases we reported in normalized metabolic activity in salience network hubs from a 2-month open-label study of memantine in frontotemporal dementia (FTD). Methods We repeated fluorodeoxyglucose positron emission tomography (FDG-PET) after 6 months of drug use and subjected the data to Statistical Parametrical Mapping (SPM) analysis to reveal clusters of significant change from baseline. We also sought correlations between changes in behavioral disturbances on the Frontal Behavioral Inventory (FBI) and the PET signal. Results Recruitment of one progressive nonfluent aphasia and one behavioral variant FTD precluded statistical analysis for any FTD subtype other than semantic dementia (SD). The baseline-to-6-month interval showed increased normalized metabolic activity in the left orbitofrontal cortex (p

The main pattern of cognitive impairments seen in early to moderate stages of Parkinson's disease (PD) includes deficits of executive functions. These nonmotor complications have a significant impact on the quality of life and day-to-day activities of PD patients and are not effectively managed by current therapies, a problem which is almost certainly due to the fact that the disease extends beyond the nigrostriatal system. To investigate the role of extrastriatal dopamine in executive function in PD, PD patients and a control group were studied with positron-emission-tomography using a high-affinity dopamine D2/D3 receptor tracer, [(11) C]FLB-457. All participants were scanned twice while performing an executive task and a control task. Patients were off medication for at least 12 h. The imaging analysis revealed that parkinsonian patients had lower [(11) C]FLB-457 binding than control group independently of task conditions across different brain regions. Cognitive assessment measures were positively correlated with [(11) C]FLB-457 binding in the bilateral dorsolateral prefrontal cortex and anterior cingulate cortex only in control group, but not in PD patients. Within the control group, during the executive task (as compared to control task), there was evidence of reduced [(11) C]FLB-457 binding (indicative of increased dopamine release) in the right orbitofrontal cortex. In contrast, PD patients did not show any reduction in binding during the executive task (as compared with control task). These findings suggest that PD patients present significant abnormalities in extrastriatal dopamine associated with executive processing. These observations provide important insights on the pathophysiology of cognitive dysfunction in PD.

Carbon-11 labeled isocyanates are efficiently prepared by dehydration of [(11) C]carbamate salts, which in turn are easily formed from cyclotron-produced [(11) C]CO(2) and amines in the presence of a CO(2) fixation agent. The [(11) C]isocyanates are useful radiosynthons for the synthesis of a variety of [carbonyl-(11) C]-labeled asymmetrical ureas and carbamate esters. The method is well suited to incorporate any isotope of carbon, and is especially useful for positron emission tomography (PET) radiotracers for in vivo imaging. This is demonstrated by using the method to make [carbonyl-(11) C]-6-hydroxy-[1,1'-biphenyl]-3-yl cyclohexylcarbamate which is a novel radiotracer for PET imaging of fatty acid amide hydrolase.

We previously reported increased binding of (+)[11C]DTBZ (dihydrotetrabenazine), the vesicular monoamine transporter (VMAT2) positron emission tomography (PET) radioligand, in striatum of some methamphetamine users. This finding might be explained by stimulant-induced vesicular DA depletion resulting in decreased DA (+)[11C]DTBZ competition at VMAT2. In a prospective PET study, we now find that administration of an acute oral dose of amphetamine (0.4 mg/kg) to humans does not cause increased striatal (+)[11C]DTBZ binding but a slight 5% decrease. Our data suggest that a low amphetamine dose is unlikely to cause sufficient DA depletion to detect increased (+)[11C]DTBZ binding and that a higher dose might be required. Synapse 64:417–420, 2010. © 2010 Wiley-Liss, Inc.

International audience; Objective: In Parkinson disease (PD) patients, deep brain stimulation (DBS) of the subthalamic nucleus (STN) may contribute to certain impulsive behavior during high-conflict decisions. A neurocomputational model of the basal ganglia has recently been proposed that suggests this behavioral aspect may be related to the role played by the STN in relaying a "hold your horses" signal intended to allow more time to settle on the best option. The aim of the present study was 2-fold: 1) to extend these observations by providing evidence that the STN may influence and prevent the execution of any response even during low-conflict decisions; and 2) to identify the neural correlates of this effect.Methods: We measured regional cerebral blood flow during a Go/NoGo and a control (Go) task to study the motor improvement and response inhibition deficits associated with STN-DBS in patients with PD.Results: Although it improved Unified Parkinson Disease Rating Scale motor ratings and induced a global decrease in reaction time during task performance, STN-DBS impaired response inhibition, as revealed by an increase in commission errors in NoGo trials. These behavioral effects were accompanied by changes in synaptic activity consisting of a reduced activation in the cortical networks responsible for reactive and proactive response inhibition.Interpretation: The present results suggest that although it improves motor functions in PD patients, modulation of STN hyperactivity with DBS may tend at the same time to favor the appearance of impulsive behavior by acting on the gating mechanism involved in response initiation.

Tobacco dependence is highly prevalent in depressed patients. We assessed changes in [(11)C]-raclopride binding potential (BP) using positron emission tomography (PET) before and after the oral administration of d-amphetamine in healthy controls and unmedicated patients with current depression with and without current tobacco dependence. Over a single study day 2 [(11)C]-raclopride positron emission tomography scans were taken in 38 subjects: at baseline and 2 h following oral d-amphetamine 30 mg. Twenty controls (9 smokers, 11 nonsmokers) and 18 subjects with current major depressive episode (8 smokers, 10 non-smokers). Striatal [(11)C]-raclopride binding potential was measured before and after d-amphetamine administration. Depressed smokers had a lower baseline [(11)C]-raclopride binding potential compared with both control non-smokers (P < 0.007) and depressed non-smokers (P < 0.001). There was a main effect of smoking status on amphetamine-induced change in [(11)C]-raclopride binding potential (P < 0.02), but no main effect of depression. This may be due to a floor effect because of the low BP at baseline. Depressed subjects reported significant increase of positive mood after d-amphetamine administration compared with controls (depressed smokers vs. control smokers: P < 0.05; depressed non-smokers vs. controls: P < 0.055). Tobacco dependence appears to decrease d-amphetamine-induced changes in [(11)C]-raclopride binding potential as measured by positron emission tomography. Comorbid major depression and tobacco dependence exacerbates this effect, suggesting an altered dopamine system in comorbid patients.

The prefrontostriatal network is considered to play a key role in executive functions. Previous neuroimaging studies have shown that executive processes tested with card-sorting tasks requiring planning and set-shifting [e.g. Montreal-card-sorting-task (MCST)] may engage the dorsolateral prefrontal cortex (DLPFC) while inducing dopamine release in the striatum. However, functional imaging studies can only provide neuronal correlates of cognitive performance and cannot establish a causal relation between observed brain activity and task performance. In order to investigate the contribution of the DLPFC during set-shifting and its effect on the striatal dopaminergic system, we applied continuous theta burst stimulation (cTBS) to left and right DLPFC. Our aim was to transiently disrupt its function and to measure MCST performance and striatal dopamine release during [(11)C]raclopride PET. A significant hemispheric asymmetry was observed. cTBS of the left DLPFC impaired MCST performance and dopamine release in the ipsilateral caudate-anterior putamen and contralateral caudate nucleus, as compared to cTBS of the vertex (control). These effects appeared to be limited only to left DLPFC stimulation while right DLPFC stimulation did not influence task performance or [(11)C]raclopride binding potential in the striatum. This is the first study showing that cTBS, by disrupting left prefrontal function, may indirectly affect striatal dopamine neurotransmission during performance of executive tasks. This cTBS-induced regional prefrontal effect and modulation of the frontostriatal network may be important for understanding the contribution of hemisphere laterality and its neural bases with regard to executive functions, as well as for revealing the neurochemical substrate underlying cognitive deficits.

Early post-mortem data suggest that damage to brain serotonin neurones might play a role in some features (e.g., depression) of Parkinson's disease (PD). However, it is not known whether such damage is a typical characteristic of living patients with PD or whether the changes are regionally widespread. To address this question we measured, by positron emission tomography imaging, levels of the brain serotonin transporter (SERT), a marker for serotonin neurones, as inferred from binding of [ 11 C]-3-amino-4-(2-dimethylaminomethyl-phenylsulfanyl)-benzonitrile (DASB), a second generation SERT radioligand, in subcortical and cerebral cortical brain areas of clinically advanced non-depressed (confirmed by structured psychiatric interview) patients with PD. SERT binding levels in PD were lower than those in controls in all examined brain areas, with the changes statistically significant in orbitofrontal cortex (-22%), caudate (-30%), putamen (-26%), and midbrain (-29%). However, only a slight non-significant reduction (-7%) was observed in dorsolateral pre-frontal cortex, an area implicated in major depression. Our imaging data suggests that a modest, regionally widespread loss of brain serotonergic innervation might be a common feature of advanced PD. Further investigation will be required to establish whether SERT binding is more or less decreased in those patients with PD who also have major depressive disorder.

The promising β-amyloid PET imaging agent, [11C]-6-OH-BTA-1, has been radiolabelled in one step using [11C]-methyl triflate. No protection of the 6-hydroxy group is required, greatly simplifying the synthetic method. The reaction may be carried out in solution or by the captive solvent ‘loop’ method. Copyright © 2004 John Wiley & Sons, Ltd.

Clinical effects of antipsychotic drugs are thought to be mediated primarily through antagonism of the dopamine D2 receptors. Recent studies have demonstrated increased aromatic decarboxylase activity following acute administration of dopamine D2 receptor antagonists both in vivo and ex vivo. However, this effect has never been demonstrated in human subjects. We studied the effect of acute antipsychotic administration on dopamine synthesis in rodents and healthy human subjects using 6-[18F]-L-m-tyrosine. In rats, we studied the effect of a single subcutaneous injection of haloperidol and risperidone on dopamine synthesis using 6-[18F]-L-m-tyrosine. In our human study, six healthy volunteers underwent two 6-[18F]-L-m-tyrosine PET scans, before and after 3 mg risperidone to measure the rate of accumulation of radioactivity in the striatum as an index of dopamine synthesis. The striatal/cerebellar radioactivity count ratio and the ratio of dopamine metabolites to dopamine concentration was significantly higher in all rodent treatment groups compared to controls. In the PET study we found no significant change in the rate of uptake in the striatum. Our results suggest that 6-[18F]-L-m-tyrosine PET may not be a useful tool in the study of the effect of antipsychotics on dopamine synthesis in human subjects. Synapse 52:153–162, 2004. © 2004 Wiley-Liss, Inc.

Parenterally administered D-amphetamine has been used as a challenge drug to release dopamine, which in turns inhibits [11C]raclopride binding to dopaminergic D2 receptors as measured using positron emission tomography (PET) techniques. The primary objective of this study was to determine whether orally administered D-amphetamine would inhibit [11C]raclopride binding in a manner similar to that produced by intravenously administered D-amphetamine. The secondary objective was to assess the timeline of these effects. Twelve healthy human volunteers participated in this study. Subjects were scanned at baseline and 2 h after D-amphetamine administration (n = 5); at baseline, 2 and 6 h postdrug (n = 4); or at baseline, 2 and 24 h postdrug (n = 3). Orally administered D-amphetamine caused a significant decrease in [11C]raclopride binding at 2 h (13% +/- 5%). Receptor availability was still decreased at 6 h (18% +/- 6%), even though physiological effects had completely returned to baseline. [11C]Raclopride binding returned to baseline at 24 h. The percentage of [11C]raclopride displacement was not correlated with plasma D-amphetamine concentrations. In conclusion, orally administered D-amphetamine caused a reliable and prolonged [11C]raclopride displacement, the magnitude of which is similar to that observed after intravenous administration. Possible mechanisms for the observed prolonged displacement may include persistence of intrasynaptic dopamine and/or receptor internalization.

The in vivo pharmacological profile of [(11)C]-DASB, a new radioligand developed for in vivo imaging of the serotonin transporter (SERT), was evaluated in the cat brain using positron emission tomography (PET). The in vivo distribution of [(11)C]-DASB binding was consistent with the known distribution of SERT sites in the cat brain in vitro with high uptakes of radioactivity in the midbrain and thalamus, intermediate levels in striatum, and modest to low levels of radioactivity in the neocortex and cerebellum, respectively. [(11)C]-DASB binding potential (BP) values ranged from about 0.2 in the neocortex to 2.2 in the midbrain. Radioligand binding in all brain regions except cerebellum was markedly reduced following pretreatment with fluoxetine and citalopram, but was unaffected by pretreatment with GBR12909, maprotiline, and haloperidol, indicating specificity of [(11)C]-DASB binding to the SERT. Two cats were each examined using PET and [(11)C]-DASB in a longitudinal fashion (from 30 min and up to 24 days) following a single i.v. dose of: 1) fluoxetine, and 2) citalopram at different dosages. Both drugs induced similar degrees of SERT occupancy at 30 min postinjection (approximately 90%). A comparison of citalopram and fluoxetine pharmacokinetics in the same animal and at the same dosage (1 mg/kg) showed that citalopram SERT occupancy and plasma half-lives were 9 times and 14 times shorter, respectively, than those of fluoxetine and norfluoxetine. In addition, studies performed after injection of the monoamine oxidase inhibitor tranylcypromine suggested that high levels of synaptic serotonin may compete with [(11)C]-DASB for binding on the SERT. These studies indicate that [(11)C]-DASB is a suitable PET radioligand for measuring drug occupancy of the SERT in vivo and has potential for monitoring in vivo changes in serotonin levels.

Carbon-11-labelled (S)-5-methoxymethyl-3-[6-(4,4,4-trifluorobutoxy)benzo[d]isoxazol-3-yl]oxazolidin-2-[11C]-one ([11C]SL25.1188), a promising reversibly binding radiotracer for imaging central monoamine oxidase B, was rapidly prepared via an intramolecular cyclization reaction in an automated one-pot procedure directly from [11C]CO2, thereby precluding the use of [11C]COCl2. Formulated [11C]SL25.1188 was isolated in 12 ± 1% uncorrected radiochemical yield, based on starting [11C]CO2, with a specific activity of 37 ± 2 GBq/µmol at the end of synthesis (30 min; n = 3). Radiochemical and enantiomeric purities were both >99%. The methodology described herein offers an efficient production of [11C]SL25.1188 at ambient temperature and is suitable for human imaging studies.

The high affinity and selective cAMP-specific phosphodiesterase-4 inhibitors Ro 20-1724, R-, R/S- and S-rolipram were labeled with 11C by O-[11C]methylation of their respective phenolic precursors using [11C]methyl iodide. The desmethyl precursor of Ro 20-1724 was prepared by selective dealkylation with iodotrimethylsilane, whereas, dealkylation of racemic rolipram was not selective and yielded several products. Enantiomeric separation of R- and S-desmethylrolipram was carried out by chiral semi-preparative high performance liquid chromatography. The final 11C-labeled products were prepared in high radiochemical purity (>99%), yields (45-75%, decay-corrected) and specific activities [18.5-92.5 GBq/µmol], within 30 min from end-of-bombardment. Copyright © 2001 John Wiley & Sons, Ltd.

Carbon-11 labelled d-threo-methylphenidate ([11C]-(1)), a radiopharmaceutical commonly used to image the dopamine transporter, has been labelled in one step using [11C]-methyl triflate. No protection of the nitrogen atom on the piperidine ring of d-threo-ritalinic acid·HCl was required, as O-methylation was favored over N-methylation by performing the methylation in buffered solutions which effectively protonate and protect the amine functionality. The reaction was effectively carried out at room temperature in solution by captive solvent ‘LOOP’ methods or using conventional glass vials. Copyright © 2010 John Wiley & Sons, Ltd.

The utility of commercial radiosynthetic modules to prepare [11C]-radiotracers using the captive solvent ‘LOOP’ method is demonstrated with the common radiosynthons [11C]-iodomethane and [11C]-methyl triflate. Several widely utilized radiotracers are prepared by this technique to demonstrate the versatility of the method. Copyright © 2009 John Wiley & Sons, Ltd.

The potent and selective serotonin reuptake inhibitor, N,N-dimethyl-2-(2-amino-4-trifluoromethylphenylthio)benzylamine (1), and a potential metabolite, N-methyl-2-(2-amino-4-trifluoromethylphenylthio)benzyl amine (2) were radiolabelled with Carbon-11 as potential positron emission tomography (PET) radiotracers. Both [ 11 C]-(1) and [ 11 C]-(2) were obtained in good radiochemical yield by alkylation of their respective normethyl precursors with [ 11 C]-iodomethane in dimethylformamide. Upon HPLC purification and formulation radiochemically pure products were obtained in 25-30% yield (from [ 11 C]-iodomethane, uncorrected) with specific activities of 25-40 GBq/mole. To further establish the site of labeling, [ 13 C]-(1) and [ 13 C]-(2) were also synthesised, using [ 13 C]-iodomethane, for 13 C NMR analysis. Preliminary biodistribution studies in rats show that both [ 11 C]-(1) and [ 11 C]-(2) efficiently and rapidly cross the blood brain barrier.

Two diastereoisomeric analogues of the potent 5-HT 1A antagonist WAY 100635 have been synthesized and radiolabelled with 11 C; namely trans-and cis-N-[2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl]-N-(2-pyridinyl)-cyclohexanecarboxamide (3 and 4). Both [ 11 C]-3 and [ 11 C]-4 were obtained in modest yields at high specific activities by O-[ 11 C]-alkylation of their respective alkoxide precursors with [ 11 C]-iodomethane. The labelled diastereoisomers were isolated by reverse-phase HPLC and isolated as radiochemically pure formulations for in vivo experiments. Biodistribution studies in rats showed moderate brain uptake for [ 11 C]-4 with little differentiation of uptake between regions rich in 5-HT 1A receptors (e.g. hippocampus) and receptor poor regions (e.g. cerebellum). However the diastereoisomeric [ 11 C]-3 possessed better brain uptake with moderate differentiation between 5-HT 1A receptor rich and poor regions at early time points (5-30 min post-injection). The results suggest that [ 11 C]-3 may have potential as an in vivo imaging agent for 5-HT 1A receptors .

The phosphodiesterase type IV (PDEIV) family of enzymes contributes to the metabolism of cAMP formed by the stimulation of β-adrenergic, A2-adenosine, and H2-histamine receptors in the brain. Disturbances in cAMP-mediated signaling have been implicated in several neuropsychiatric disorders, and there is evidence that increasing cAMP levels through PDEIV inhibition improves the symptoms of these disorders. In the present study, the selective PDEIV inhibitors rolipram and Ro 20–1724, labeled with C-11, were evaluated in vivo in rats, as potential radioligands for imaging PDEIV enzymes with positron emission tomography (PET). Biodistribution experiments revealed a greater than threefold increased regional brain retention of [11C]rolipram as compared to [11C]Ro 20–1724. [11C]Rolipram uptake was higher in rat brain areas (e.g., cortical regions and olfactory system) showing higher expression of PDEIV enzymes, as determined previously using [3H]rolipram autoradiography or molecular genetic techniques. Binding of [11C]rolipram and [11C]Ro 20–1724 was specific, since coadministration of high doses of unlabeled rolipram (10 mg/Kg, i.v.) or Ro 20–1724 (30 mg/Kg with [11C]rolipram and 10 mg/Kg with [11C]Ro 20–1724, i.v.) reduced radioactivity uptake in brain regions. Pretreatment with high doses of the PDEI selective inhibitor vinpocetine (10 mg/Kg, i.p., 15 min prior), or the noradrenaline reuptake inhibitor desipramine (10 mg/Kg, i.p., 30 min prior), or coinjection with the adenylyl cyclase activator forskolin (6.5 or 15 mg/Kg, i.v.), did not inhibit [11C]rolipram uptake in brain areas, suggesting binding selectivity for PDEIV enzymes. We conclude that [11C]rolipram, but not [11C]Ro 20–1724, is a promising radioligand for imaging the PDEIV enzymes with PET. Synapse 31:41–50, 1999. © 1999 Wiley-Liss, Inc.

An efficient, fast and simple method is described for the radiosynthesis of the potent and selective 5-HT 1A antagonist [O-methyl- 11 C]-N-[2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl]-N-(2-pyridinyl)cyclohexane carboxamide ([ 11 C]WAY 100635). [ 11 C]Iodomethane was effectively trapped on a C 18 reverse-phase cartridge at ambient temperature where it reacted rapidly with the normethyl precursor, N-[2-[4-(2-hydroxyphenyl)-1-piperazinyl]ethyl]-N-(2-pyridinyl)cyclohexane carboxamide. Following high performance liquid chromatography purification and formulation, [ 11 C]WAY 100635 was obtained in high radiochemical yields (40%, uncorrected from [ 11 C]Iiodomethane) in a synthesis time of 25 min with an average specific actvity of (at end-of-synthesis) 33 GBq/μmole (900 mCi/μmole).

Two premovement potentials, the bereitschaftspotential (BP) and negative slope (NS'), can be recorded prior to the execution of self-paced hand movements using back-averaging of scalp electrical recordings. The contributions of the contralateral and ipsilateral primary motor cortex (M1) and the mesial dorsal frontal cortex (MFC) to the generation of the potentials were examined by simultaneously collecting positron emission tomography (PET) scans and scalp recorded electrical activity for dipole source analysis in eight right-handed normal subjects. Subjects performed simple unilateral thumb-finger opposition movements intermittently with an average inter-movement interval of 7.4 s. PET was also collected for the same movement performed repetitively with inter-movement intervals of 0.5 s such that finger movements were nearly continuous. PET studies of the intermittent movement revealed marked activation of the MFC in the region of the rostral supplementary motor area (SMA) and cingulate motor area, contralateral sensorimotor cortex and no activation of the ipsilateral sensorimotor cortex. When the same movements were performed in a continuous repetitive manner, PET revealed strong contralateral sensorimotor and caudal MFC activation, and no ipsilateral sensorimotor or rostral MFC activation. Dipole source solutions of the back-averaged potentials for the intermittent movements were analyzed by testing dipole vectors placed into the regions of PET activation. The premovement potentials were dominated by dipoles in the region of the MFC, with minimal contribution from either the contralateral or ipsilateral M1. Activation in the region of the contralateral M1 began near the onset of muscle activity. The orientation and timing of the MFC dipoles were consistent with both the BP and NS' potentials originating from neurons in the rostral SMA and dorsal tier of the cingulate sulcus and were appropriate for MFC activity to contribute to both the preparation for movement and the descending activation of spinal motor networks. © 1996 Wiley-Liss, Inc.

Two potent dopamine transporter ligands, 2β-[O-11CH3]-carbomethoxy-3β-(4-methylphenyl)tropane and its 4-chlorophenyl analogue, were synthesized by O-alkylation at the 2β-carboxy position with [11C]-iodomethane. Separation of the [11C]-labelled tropane from excess carboxylic acid precursor was readily achieved by semipreparative HPLC providing pure radiotracers at high specific activities (800–3000 mCi/μmole) suitable for in vivo PET studies. Radiosynthesis of this class of compounds by [O-11CH3]-methylation offers advantages over previously reported [N-11CH3]-methylation methods.

Although primary hepatocellular carcinoma (HCC) is a common tumor worldwide, it is relatively rare in North America, resulting in an estimated 3000-4000 deaths annually.’,’ HCC is almost always lethal because most

Kruger S, Goldapple K, Kennedy S, Houle S, Mayberg H. Regional cerebral blood flow in bipolar disorder measured with PET: trait effects at rest and after mood induction. Bipolar Disord 2002: 4(Suppl. 1): 88. © Blackwell Munksgaard, 2002