First-in-Human PET Imaging of [18F]SDM-4MP3: A Cautionary Tale.

[18F]SynVesT-1 is a PET radiopharmaceutical that binds to the synaptic vesicle protein 2A (SV2A) and serves as a biomarker of synaptic density with widespread clinical research applications in psychiatry and neurodegeneration. The initial goal of this study was to concurrently conduct PET imaging studies with [18F]SynVesT-1 at our laboratories. However, the data in the first two human PET studies had anomalous biodistribution despite the injected product meeting all specifications during the prerelease quality control protocols. Further investigation, including imaging in rats as well as proton and carbon 2D-NMR spectroscopic studies, led to the discovery that a derivative of the precursor had been received from the manufacturer. Hence, we report our investigation and the first-in-human study of [18F]SDM-4MP3, a structural variant of [18F]SynVesT-1, which does not have the requisite characteristics as a PET radiopharmaceutical for imaging SV2A in the central nervous system.

Fatty acid amide hydrolase binding is inversely correlated with amygdalar functional connectivity: a combined positron emission tomography and magnetic resonance imaging study in healthy individuals.

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

Microglia imaging in methamphetamine use disorder: a positron emission tomography study with the 18 kDa translocator protein radioligand [F-18]FEPPA.

Activation of brain microglial cells, microgliosis, has been linked to methamphetamine (MA)-seeking behavior, suggesting that microglia could be a new therapeutic target for MA use disorder. Animal data show marked brain microglial activation following acute high-dose MA, but microglial status in human MA users is uncertain, with one positron emission tomography (PET) investigation reporting massively and globally increased translocator protein 18 kDa (TSPO; [C-11](R)-PK11195) binding, a biomarker for microgliosis, in MA users. Our aim was to measure binding of a second-generation TSPO radioligand, [F-18]FEPPA, in brain of human chronic MA users. Regional total volume of distribution (VT ) of [F-18]FEPPA was estimated with a two-tissue compartment model with arterial plasma input function for 10 regions of interest in 11 actively using MA users and 26 controls. A RM-ANOVA corrected for TSPO rs6971 polymorphism was employed to test significance. There was no main effect of group on [F-18]FEPPA VT (P = .81). No significant correlations between [F-18]FEPPA VT and MA use duration, weekly dosage, blood MA concentrations, regional brain volumes, and self-reported craving were observed. Our preliminary findings, consistent with our earlier postmortem data, do not suggest substantial brain microgliosis in MA use disorder but do not rule out microglia as a therapeutic target in MA addiction. Absence of increased [F-18]FEPPA TSPO binding might be related to insufficient MA dose or blunting of microglial response following repeated MA exposure, as suggested by some animal data.

Fatty acid amide hydrolase is lower in young cannabis users.

We have recently shown that levels of fatty acid amide hydrolase (FAAH), the enzyme that metabolizes the endocannabinoid anandamide, are lower in the brains of adult cannabis users (CUs) (34 ± 11 years of age), tested during early abstinence. Here, we examine replication of the lower FAAH levels in a separate, younger cohort (23 ± 5 years of age). Eighteen healthy volunteers (HVs) and fourteen CUs underwent a positron emission tomography scan using the FAAH radioligand [11 C]CURB. Regional [11 C]CURB binding was calculated using an irreversible two-tissue compartment model with a metabolite-corrected arterial plasma input function. The FAAH C385A genetic polymorphism (rs324420) was included as a covariate. All CUs underwent a urine screen to confirm recent cannabis use and had serum cannabinoids measured. One CU screened negative for cannabinoids via serum and was removed from analysis. All HVs reported less than five lifetime cannabis exposures more than a month prior to study initiation. There was a significant effect of group (F1,26 = 4.31; P = .048) when two A/A (rs324420) HVs were removed from analysis to match the genotype of the CU group (n = 16 HVs, n = 13 CUs). Overall, [11 C]CURB λk3 was 12% lower in CU compared with HV. Exploratory correlations showed that lower brain [11 C]CURB binding was related to greater use of cannabis throughout the past year. We confirmed our previous report and extended these findings by detecting lower [11 C]CURB binding in a younger cohort with less cumulative cannabis exposure.

Stress-induced cortical dopamine response is altered in subjects at clinical high risk for psychosis using cannabis.

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.

Decreased pallidal vesicular monoamine transporter type 2 availability in Parkinson's disease: The contribution of the nigropallidal pathway.

To date, the contribution of the nigropallidal pathway degeneration to Parkinson's disease (PD) motor symptoms has received little attention and is generally poorly understood in spite of solid evidence that the globus pallidus (GP) receives a dense neuronal projection from the substantia nigra. To explore the dopaminergic (DA) changes of the GP in PD, we measured the availability of vesicular monoamine transporter 2 (VMAT2) using [11C]DTBZ and positron emission tomography in 30 PD patients and 12 controls. PD patients were classified in two groups based on severity of disease. VMAT2 reduction was found to be significant in the external GP (GPe) regardless of the disease stage, while the internal GP (GPi) showed reduction only in more severe patients. Pallidal VMAT2 binding correlated with dopaminergic changes in the striatum, with the GPe showing a stronger association than GPi. Our findings showed DA terminals in the GPe and GPi may be differentially vulnerable in different stages of the disease, possibly playing a distinctive role in the development of motor complications with GPi DA deficiency contributing more to later-stage symptoms.

GABA levels and TSPO expression in people at clinical high risk for psychosis and healthy volunteers: a PET-MRS study.

BACKGROUND: γ-Aminobutyric acidergic (GABAergic) dysfunction and immune activation have been implicated in the pathophysiology of schizophrenia. Preclinical evidence suggests that inflammation-related abnormalities may contribute to GABAergic alterations in the brain, but this has never been investigated in vivo in humans. In this multimodal imaging study, we quantified cerebral GABA plus macromolecule (GABA+) levels in antipsychotic-naive people at clinical high risk for psychosis and in healthy volunteers. We investigated for the first time the association between GABA+ levels and expression of translocator protein 18 kDa (TSPO; a marker of microglial activation) using positron emission tomography (PET). METHODS: Thirty-five people at clinical high risk for psychosis and 18 healthy volunteers underwent 3 T proton magnetic resonance spectroscopy to obtain GABA+ levels in the medial prefrontal cortex (mPFC). A subset (29 people at clinical high risk for psychosis and 15 healthy volunteers) also underwent a high-resolution [18F]FEPPA PET scan to quantify TSPO expression. Each participant was genotyped for the TSPO rs6971 polymorphism. RESULTS: We found that GABA+ levels were significantly associated with TSPO expression in the mPFC (F1,40 = 10.45, p = 0.002). We found no significant differences in GABA+ levels in the mPFC (F1,51 = 0.00, p > 0.99) between people at clinical high risk for psychosis and healthy volunteers. We found no significant correlations between GABA+ levels or residuals of the association with TSPO expression and the severity of prodromal symptoms or cognition. LIMITATIONS: Given the cross-sectional nature of this study, we could determine no cause-and-effect relationships for GABA alterations and TSPO expression. CONCLUSION: Our findings suggest that TSPO expression is negatively associated with GABA+ levels in the prefrontal cortex, independent of disease status.

Single-Photon Emission Computed Tomography and Positron Emission Tomography Studies of Antisocial Personality Disorder and Aggression: a Targeted Review.

PURPOSE OF REVIEW: This paper aims to provide a comprehensive discussion of single-photon emission computed tomography (SPECT) and positron emission tomography (PET) studies of antisocial personality disorder (ASPD) and aggression. RECENT FINDINGS: Among ASPD males with high impulsivity, the density of brainstem serotonin (5-HT) transporters shows a relationship with impulsivity, aggression, and ratings of childhood trauma. 5-HT1B receptor (R) binding in the striatum, anterior cingulate cortex, and orbitofrontal cortex (OFC) correlated with anger, aggression, and psychopathic traits in another study of violent offenders, most of whom were diagnosed with ASPD. Finally, the density of monoamine oxidase-A (MAO-A), a mitochondrial enzyme that degrades 5-HT, norepinephrine, and dopamine (DA), was reported as lower in the OFC and ventral striatum of ASPD. Among non-clinical populations, 5-HT4R binding, as an index of low cerebral 5-HT levels, has been associated with high trait aggression, but only in males. Furthermore, evidence suggests that individuals with high-activity MAO-A genetic variants compared with low-activity MAO-A allelic variants release more DA in the ventral caudate and putamen when exposed to violent imagery. There are very few PET or SPECT studies that exclusively sample individuals with ASPD. However, among ASPD samples, there is evidence of regional serotonergic abnormalities in the brain and alteration of neural MAO-A levels. Future studies should consider employing additional molecular probes that could target alternative neurotransmitter systems to investigate ASPD. Furthermore, examining different typologies of aggression in clinical and non-clinical populations using SPECT/PET is another important area to pursue and could shed light on the neurochemical origins of these traits in ASPD.

Cortical stress regulation is disrupted in schizophrenia but not in clinical high risk for psychosis.

While alterations in striatal dopamine in psychosis and stress have been well studied, the role of dopamine in prefrontal cortex is poorly understood. To date, no study has investigated the prefrontocortical dopamine response to stress in the psychosis spectrum, even though the dorsolateral and medial prefrontal cortices are key regions in cognitive and emotional regulation, respectively. The present study uses the high-affinity dopamine D2/3 receptor radiotracer 11C-FLB457 and PET together with a validated psychosocial stress challenge to investigate the dorsolateral and medial prefrontocortical dopamine response to stress in schizophrenia and clinical high risk for psychosis. Forty participants completed two 11C-FLB457 PET scans (14 antipsychotic-free schizophrenia, 14 clinical high risk for psychosis and 12 matched healthy volunteers), one while performing a Sensory Motor Control Task (control) and another while performing the Montreal Imaging Stress Task (stress). Binding potential (BPND) was estimated using Simplified Reference Tissue Model with cerebellar cortex as reference region. Dopamine release was defined as per cent change in BPND between control and stress scans (ΔBPND) using a novel correction for injected mass. Salivary cortisol response (ΔAUCI) was assessed throughout the tasks and its relationship with dopamine release examined. 11C-FLB457 binding at control conditions was significantly different between groups in medial [F(2,37) = 7.98, P = 0.0013] and dorsolateral [F(2,37) = 6.97, P = 0.0027] prefrontal cortex with schizophrenia patients having lower BPND than participants at clinical high risk for psychosis and healthy volunteers, but there was no difference in ΔBPND among groups [dorsolateral prefrontal cortex: F(2,37) = 1.07, P = 0.35; medial prefrontal cortex: F(2,37) = 0.54, P = 0.59]. We report a positive relationship between ΔAUCI and 11C-FLB457 ΔBPND in dorsolateral and medial prefrontal cortex in healthy volunteers (r = 0.72, P = 0.026; r = 0.76, P = 0.014, respectively) and in participants at clinical high risk for psychosis (r = 0.76, P = 0.0075; r = 0.72, P = 0.018, respectively), which was absent in schizophrenia (r = 0.46, P = 1.00; r = 0.19, P = 1.00, respectively). Furthermore, exploratory associations between ΔBPND or ΔAUCI and stress or anxiety measures observed in clinical high risk for psychosis were absent in schizophrenia. These findings provide first direct evidence of a disrupted prefrontocortical dopamine-stress regulation in schizophrenia.

Influence of Nicotine Metabolism Ratio on [11C]-(+)-PHNO PET Binding in Tobacco Smokers.

Background: Identifying the biological basis of smoking cessation success is of growing interest. The rate of nicotine metabolism, measured by the nicotine metabolite ratio, affects multiple aspects of nicotine dependence. Fast nicotine metabolizers tend to smoke more, experience more withdrawal and craving, and have lower cessation rates compared with slow metabolizers. The nicotine metabolite ratio predicts treatment response, and differences in brain activation between fast metabolizers and slow metabolizers have been reported in fMRI studies. As reinforcing/rewarding effects of tobacco are associated with dopamine transmission, the purpose of the present study was to study the dopaminergic system in human smokers based on their nicotine metabolite ratio. Methods: The first aim of the study was to explore if there were differences in D2 and D3 receptor binding between fast metabolizers and slow metabolizers during abstinence. The second aim was to explore smoking-induced dopamine release in both groups. Participants underwent 2 [11C]-(+)-PHNO PET scans: one scan during abstinence and the other after smoking a tobacco cigarette. Subjective measures were recorded and blood was drawn for measurement of nicotine and cotinine levels. Results: During abstinence, slow metabolizers (n = 13) had lower [11C]-(+)-PHNO binding potential than fast metabolizers (n = 15) restricted to the D2 regions of the associative striatum and sensorimotor striatum. After smoking a cigarette, [11C]-(+)-PHNO binding potential was decreased in the limbic striatum and ventral pallidum, suggestive of increases in dopamine, but there were no nicotine metabolite ratio differences. Conclusions: Further studies are required to delineate if differences in [11C]-(+)-PHNO binding between slow metabolizers and fast metabolizers at abstinence baseline are preexisting traits or induced by prolonged tobacco use.

TSPO expression and brain structure in the psychosis spectrum.

Psychosis is associated with abnormal structural changes in the brain including decreased regional brain volumes and abnormal brain morphology. However, the underlying causes of these structural abnormalities are less understood. The immune system, including microglial activation, has been implicated in the pathophysiology of psychosis. Although previous studies have suggested a connection between peripheral proinflammatory cytokines and structural brain abnormalities in schizophrenia, no in-vivo studies have investigated whether microglial activation is also linked to brain structure alterations previously observed in schizophrenia and its putative prodrome. In this study, we investigated the link between mitochondrial 18 kDa translocator protein (TSPO) and structural brain characteristics (i.e. regional brain volume, cortical thickness, and hippocampal shape) in key brain regions such as dorsolateral prefrontal cortex and hippocampus of a large group of participants (N = 90) including individuals at clinical high risk (CHR) for psychosis, first-episode psychosis (mostly antipsychotic-naïve) patients, and healthy volunteers. The participants underwent structural brain MRI scan and [18F]FEPPA positron emission tomography (PET) targeting TSPO. A significant [18F]FEPPA binding-by-group interaction was observed in morphological measures across the left hippocampus. In first-episode psychosis, we observed associations between [18F]FEPPA VT (total volume of distribution) and outward and inward morphological alterations, respectively, in the dorsal and ventro-medial portions of the left hippocampus. These associations were not significant in CHR or healthy volunteers. There was no association between [18F]FEPPA VT and other structural brain characteristics. Our findings suggest a link between TSPO expression and alterations in hippocampal morphology in first-episode psychosis.

Fatigue in Parkinson's disease: The contribution of cerebral metabolic changes.

Fatigue is a common and disabling non-motor symptom in Parkinson's disease associated with a feeling of overwhelming lack of energy. The aim of this study was to identify the neural substrates that may contribute to the development of fatigue in Parkinson's disease. Twenty-three Parkinson's disease patients meeting UK Brain Bank criteria for the diagnosis of idiopathic Parkinson's disease were recruited and completed the 2-[18 F]fluoro-2-deoxy-D-glucose (FDG)-PET scan. The metabolic activities of Parkinson's disease patients with fatigue were compared to those without fatigue using statistical parametric mapping analysis. The Parkinson's disease group exhibiting higher level of fatigue showed anti-correlated metabolic changes in cortical regions associated with the salience (i.e., right insular region) and default (i.e., bilateral posterior cingulate cortex) networks. The metabolic abnormalities detected in these brain regions displayed a significant correlation with level of fatigue and were associated with a disruption of the functional correlations with different cortical areas. These observations suggest that fatigue in Parkinson's disease may be the expression of metabolic abnormalities and impaired functional interactions between brain regions linked to the salience network and other neural networks. Hum Brain Mapp 38:283-292, 2017. © 2016 Wiley Periodicals, Inc.

Microglial activation in Parkinson's disease using [18F]-FEPPA.

BACKGROUND: Neuroinflammatory processes including activated microglia have been reported to play an important role in Parkinson's disease (PD). Increased expression of translocator protein (TSPO) has been observed after brain injury and inflammation in neurodegenerative diseases. Positron emission tomography (PET) radioligand targeting TSPO allows for the quantification of neuroinflammation in vivo. METHODS: Based on the genotype of the rs6791 polymorphism in the TSPO gene, we included 25 mixed-affinity binders (MABs) (14 PD patients and 11 age-matched healthy controls (HC)) and 27 high-affinity binders (HABs) (16 PD patients and 11 age-matched HC) to assess regional differences in the second-generation radioligand [18F]-FEPPA between PD patients and HC. FEPPA total distribution volume (V T) values in cortical as well as subcortical brain regions were derived from a two-tissue compartment model with arterial plasma as an input function. RESULTS: Our results revealed a significant main effect of genotype on [18F]-FEPPA V T in every brain region, but no main effect of disease or disease × genotype interaction in any brain region. The overall percentage difference of the mean FEPPA V T between HC-MABs and HC-HABs was 32.6% (SD = 2.09) and for PD-MABs and PD-HABs was 43.1% (SD = 1.21). CONCLUSIONS: Future investigations are needed to determine the significance of [18F]-FEPPA as a biomarker of neuroinflammation as well as the importance of the rs6971 polymorphism and its clinical consequence in PD.

Contribution of insula in Parkinson's disease: A quantitative meta-analysis study.

The insula region is known to be an integrating hub interacting with multiple brain networks involved in cognitive, affective, sensory, and autonomic processes. There is growing evidence suggesting that this region may have an important role in Parkinson's disease (PD). Thus, to investigate the functional organization of the insular cortex and its potential role in parkinsonian features, we used a coordinate-based quantitative meta-analysis approach, the activation likelihood estimation. A total of 132 insular foci were selected from 96 published experiments comprising the five functional categories: cognition, affective/behavioral symptoms, bodily awareness/autonomic function, sensorimotor function, and nonspecific resting functional changes associated with the disease. We found a significant convergence of activation maxima related to PD in different insular regions including anterior and posterior regions bilaterally. This study provides evidence of an important functional distribution of different domains within the insular cortex in PD, particularly in relation to nonmotor aspects, with an influence of medication effect.

Salience network and parahippocampal dopamine dysfunction in memory-impaired Parkinson disease.

OBJECTIVE: Patients with Parkinson disease (PD) and mild cognitive impairment (MCI) are vulnerable to dementia and frequently experience memory deficits. This could be the result of dopamine dysfunction in corticostriatal networks (salience, central executive networks, and striatum) and/or the medial temporal lobe. Our aim was to investigate whether dopamine dysfunction in these regions contributes to memory impairment in PD. METHODS: We used positron emission tomography imaging to compare D2 receptor availability in the cortex and striatal (limbic and associative) dopamine neuron integrity in 4 groups: memory-impaired PD (amnestic MCI; n = 9), PD with nonamnestic MCI (n = 10), PD without MCI (n = 11), and healthy controls (n = 14). Subjects were administered a full neuropsychological test battery for cognitive performance. RESULTS: Memory-impaired patients demonstrated more significant reductions in D2 receptor binding in the salience network (insular cortex and anterior cingulate cortex [ACC] and the right parahippocampal gyrus [PHG]) compared to healthy controls and patients with no MCI. They also presented reductions in the right insula and right ACC compared to nonamnestic MCI patients. D2 levels were correlated with memory performance in the right PHG and left insula of amnestic patients and with executive performance in the bilateral insula and left ACC of all MCI patients. Associative striatal dopamine denervation was significant in all PD patients. INTERPRETATION: Dopaminergic differences in the salience network and the medial temporal lobe contribute to memory impairment in PD. Furthermore, these findings indicate the vulnerability of the salience network in PD and its potential role in memory and executive dysfunction.

Amyloid deposition in semantic dementia: a positron emission tomography study.

BACKGROUND: Pittsburgh compound B ([11C]-PIB) identifies amyloid-ß (Aß) deposition in vivo. Asymptomatic Aß 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 Aß deposition. OBJECTIVE: Comparison of Aß 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: Aß 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 Aß deposition. Copyright © 2016 John Wiley & Sons, Ltd.

Similar striatal D2/D3 dopamine receptor availability in adults with Tourette syndrome compared with healthy controls: A [(11) C]-(+)-PHNO and [(11) C]raclopride positron emission tomography imaging study.

Pharmacological and anatomical evidence implicates striatal dopamine receptors in Tourette syndrome (TS). Nevertheless, results of positron emission tomography (PET) studies of the dopamine system in TS have been inconsistent. We investigated striatal D2/3 dopamine receptors in TS using the radioligands [(11) C]raclopride and [(11) C]-(+)-PHNO, an agonist that binds preferentially to D3 receptors, thus allowing higher sensitivity and measurement of receptors in a high affinity state. Eleven adults with TS and 11 matched healthy control (HC) participants underwent [(11) C]raclopride and [(11) C]-(+)-PHNO PET scans. General linear model was used for voxelwise contrasts of striatal binding potentials (BPND ) between TS and HC participants. Analysis of variance was performed to investigate main effect of radioligand. In addition, BPND values were extracted for ventral, motor, and associative striatum. Finally, we examined the relationship between BPND measures and symptom severity in TS participants. Main effects analyses showed that [(11) C]-(+)-PHNO BPND was higher in ventral striatum, whereas [(11) C]raclopride BPND was higher in motor and associative striatum. There were no significant group differences between TS and HC. Furthermore, TS and HC participants had similar [(11) C]-(+)-PHNO and [(11) C]raclopride BPND in the three striatal subregions. Moreover, there was no significant correlation between BPND and symptom severity. TS and HC participants had similar striatal D2/3 receptor availability measures. These results challenge the assumption that striatal dopamine receptors have a major role in the pathophysiology of TS. Consistent with previous findings, [(11) C]-(+)-PHNO localized preferentially to ventral striatal, D3 receptor-rich regions, in contrast to [(11) C]raclopride, which localized preferentially in the dorsal striatum.

Monoamine Oxidase-A Occupancy by Moclobemide and Phenelzine: Implications for the Development of Monoamine Oxidase Inhibitors.

BACKGROUND: Monoamine oxidase inhibitors (MAOIs) are being developed for major depressive disorder, Alzheimer's, and Parkinson's Disease. Newer MAOIs have minimal sensitivity to tyramine, but a key limitation for optimizing their development is that standards for in vivo monoamine oxidase-A (MAO-A) occupancy in humans are not well established. The objectives were to determine the dose-occupancy relationship of moclobemide and the occupancy of phenelzine at typical clinical dosing. METHODS: Major depressive episode (MDE) subjects underwent [(11)C]harmine positron emission tomography scanning prior to and following 6 weeks of treatment with moclobemide or phenelzine. RESULTS: Mean brain MAO-A occupancies were 74.23±8.32% for moclobemide at 300-600 mg daily (n = 11), 83.75±5.52% for moclobemide at 900-1200 mg daily (n = 9), and 86.82±6.89% for phenelzine at 45-60 mg daily (n = 4). The regional dose-occupancy relationship of moclobemide fit a hyperbolic function [F(x) = a(x/[b + x]); F(1,18) = 5.57 to 13.32, p = 0.002 to 0.03, mean 'a': 88.62±2.38%, mean 'b': 69.88±4.36 mg]. Multivariate analyses of variance showed significantly greater occupancy of phenelzine (45-60mg) and higher-dose moclobemide (900-1200 mg) compared to lower-dose moclobemide [300-600 mg; F(7,16) = 3.94, p = 0.01]. CONCLUSIONS: These findings suggest that for first-line MDE treatment, daily moclobemide doses of 300-600mg correspond to a MAO-A occupancy of 74%, whereas for treatment-resistant MDE, either phenelzine or higher doses of moclobemide correspond to a MAO-A occupancy of at least 84%. Therefore, novel MAO inhibitor development should aim for similar thresholds. The findings provide a rationale in treatment algorithm design to raise moclobemide doses to inhibit more MAO-A sites, but suggest switching from high-dose moclobemide to phenelzine is best justified by binding to additional targets.

[¹¹C]-(+)-PHNO PET imaging of dopamine D(2/3) receptors in Parkinson's disease with impulse control disorders.

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.

Radiosynthesis and ex vivo evaluation of [(18)F]-(S)-3-(6-(3-fluoropropoxy)benzo[d]isoxazol-3-yl)-5-(methoxymethyl)oxazolidin-2-one for imaging MAO-B with PET.

Carbon-11 labeled SL25.1188 ((S)-5-(methoxymethyl)-3-(6-(4,4,4-trifluorobutoxy)benzo[d]isoxazol-3-yl)oxazolidin-2-one) is a reversible radiotracer for monoamine oxidase B that was recently evaluated in healthy volunteers by positron emission tomography (PET). Herein we report the preparation and ex vivo evaluation of a fluorinated SL25.1188 derivative as a candidate (18)F-labeled PET radiotracer. (S)-3-(6-(3-fluoropropoxy)benzo[d]isoxazol-3-yl)-5-(methoxy methyl)oxazolidin-2-one (1) was labeled with fluorine-18 in 51% uncorrected radiochemical yield having high radiochemical purity (>98%) and specific activity (109±26GBq/µmol). Ex vivo biodistribution studies demonstrated low radioactivity retention, specific binding and metabolic stability within rat brains. High uptake of radioactivity in bone is consistent with metabolic defluorination. In vitro binding assays of longer chain fluoroalkoxy derivatives revealed that the length of the carbon chain is an integral feature in MAO-B inhibitor potency and selectivity within this scaffold.