Vaccine hesitancy educational tools for healthcare providers and trainees: A scoping review.

In the era of vaccine hesitancy, highlighted by the current SARS-CoV2 pandemic, there is an acute need to develop an approach to reduce and address apprehension towards vaccinations. We sought to map and present an overview of existing educational interventions for healthcare providers (HCPs) on strategies to engage in effective vaccine discussion. We applied the Joanna Briggs Institute methodology framework in this scoping review. We searched five relevant databases (MEDLINE, CINAHL, EMBASE, PsycInfo, and SCOPUS) and grey literature through the Google search engine using keywords and subject headings that were systematically identified. We identified 3384 citations in peer-reviewed literature and 41 citations in grey literature. After screening for our inclusion criteria, we included 28 citations from peer reviewed literature and 16 citations from grey literature for analysis. We identified a total of 41 unique education interventions. Interventions were available from multiple disciplines, training levels, clinical settings, and diseases/vaccines. Interventions predominantly centered around two foci: knowledge sharing and communication training. Most interventions identified from peer-reviewed literature were facilitated and were applied with multiple modes of delivery. Interventions from grey literature were more topical and generally self-directed. We identified several gaps in knowledge. Firstly, accessibility and generalizability of interventions was limited. Secondly, distribution of interventions did not adequately address nursing and pharmacy disciplines, and did not cover the breadth of medical specialties for whom vaccine discussions apply. Thirdly, no interventions addressed self monitoring and the clinicians' recognition and management of emotions during difficult conversations. There is a need to address this gap and provide available, credible and comprehensive educational interventions that will support our healthcare providers in effective communication with vaccine hesitant patients.

Elevated fatty acid amide hydrolase in the prefrontal cortex of borderline personality disorder: a [11C]CURB positron emission tomography study.

Amygdala-prefrontal cortex (PFC) functional impairments have been linked to emotion dysregulation and aggression in borderline personality disorder (BPD). Fatty acid amide hydrolase (FAAH), the major catabolic enzyme for the endocannabinoid anandamide, has been proposed as a key regulator of the amygdala-PFC circuit that subserves emotion regulation. We tested the hypothesis that FAAH levels measured with [11C]CURB positron emission tomography in amygdala and PFC would be elevated in BPD and would relate to hostility and aggression. Twenty BPD patients and 20 healthy controls underwent FAAH genotyping (rs324420) and scanning with [11C]CURB. BPD patients were medication-free and were not experiencing a current major depressive episode. Regional differences in [11C]CURB binding were assessed using multivariate analysis of covariance with PFC and amygdala [11C]CURB binding as dependent variables, diagnosis as a fixed factor, and sex and genotype as covariates. [11C]CURB binding was marginally elevated across the PFC and amygdala in BPD (p = 0.08). In a priori selected PFC, but not amygdala, [11C]CURB binding was significantly higher in BPD (11.0%, p = 0.035 versus 10.6%, p = 0.29). PFC and amygdala [11C]CURB binding was positively correlated with measures of hostility in BPD (r > 0.4; p < 0.04). This study is the first to provide preliminary evidence of elevated PFC FAAH binding in any psychiatric condition. Findings are consistent with the model that lower endocannabinoid tone could perturb PFC circuitry that regulates emotion and aggression. Replication of these findings could encourage testing of FAAH inhibitors as innovative treatments for BPD.

New detection configuration for low activity levels of PET tracers during the analysis of plasma samples.

A new radio-HPLC detection system for measuring radioactivity in plasma samples during Positron Emission Tomography [PET] studies was developed. It is based on detecting both the positron and one of the annihilation photons. The system focused on improving the measurement of radioactivity concentrations on an unmetabolized positron emitting a radiopharmaceutical [PER] in the presence of its radioactive metabolites, all containing the same positron emitter. This paper presents a new detection configuration that improves the minimal detectible activity (MDA), simplify the measuring systems and reduces the error caused by the metabolites. The detector is based on a plastic scintillator and a BGO scintillation crystal, that produces different light output spectra for signal and noise events. By summing the positron and the annihilated photon light outputs, different spectra are obtained for the metabolite and for the parent compound tracer and for tracer marked by different positron emitting isotopes. This new detection system can improve quantitative analysis of plasma samples. The spectrum change provides up to a three-fold improvement in sensitivity compared to the currently used detection systems that measure only the annihilation coincidence events. Results showed that for 11C the MDA was improved by approximately 520%. Furthermore, it provides the additional advantage of reliability by providing a method for separating the signal and noise readings from the gross detector readout. Accurate reconstruction algorithm of the signal was achieved over a wide measuring range even when the signal was only 5% of the gross measurement.

Serotonin transporter binding is reduced in seasonal affective disorder following light therapy.

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 [11 C] 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 [11 C]DASB PET.

Light therapy and serotonin transporter binding in the anterior cingulate and prefrontal cortex.

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, [(11) C]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.

In-vivo imaging of grey and white matter neuroinflammation in Alzheimer's disease: a positron emission tomography study with a novel radioligand, [18F]-FEPPA.

Our primary aim was to compare neuroinflammation in cognitively intact control subjects and patients with Alzheimer's disease (AD) by using positron emission tomography (PET) with translocator protein 18 kDa (TSPO)-specific radioligand [(18)F]-FEPPA. [(18)F]-FEPPA PET scans were acquired on a high-resolution research tomograph in 21 patients with AD (47- 81 years) and 21 control subjects (49-82 years). They were analyzed by using a 2-tissue compartment model with arterial plasma input function. Differences in neuroinflammation, indexed as [(18)F]-FEPPA binding were compared, adjusting for differences in binding affinity class as determined by a single polymorphism in the TSPO gene (rs6971). In grey matter areas, [(18)F]-FEPPA was significantly higher in AD compared with healthy control subjects. Large increases were seen in the hippocampus, prefrontal, temporal, parietal and occipital cortex (average Cohen's d= 0.89). Voxel-based analyses confirmed significant clusters of neuroinflammation in the frontal, temporal and parietal cortex in patients with AD. In white matter, [(18)F]-FEPPA binding was elevated in the posterior limb of the internal capsule, and the cingulum bundle. Higher neuroinflammation in the parietal cortex (r= -0.7, P= 0.005), and posterior limb of the internal capsule (r= -0.8, P=0.001) was associated with poorer visuospatial function. In addition, a higher [(18)F]-FEPPA binding in the posterior limb of the internal capsule was associated with a greater impairment in language ability (r= -0.7, P=0.004). Elevated neuroinflammation can be detected in AD patients throughout the brain grey and white matter by using [(18)F]-FEPPA PET. Our results also suggest that neuroinflammation is associated with some cognitive deficits.

In vivo evidence for greater amphetamine-induced dopamine release in pathological gambling: a positron emission tomography study with [(11)C]-(+)-PHNO.

Drug addiction has been associated with deficits in mesostriatal dopamine (DA) function, but whether this state extends to behavioral addictions such as pathological gambling (PG) is unclear. Here we used positron emission tomography and the D3 receptor-preferring radioligand [(11)C]-(+)-PHNO during a dual-scan protocol to investigate DA release in response to oral amphetamine in pathological gamblers (n=12) and healthy controls (n=11). In contrast with human neuroimaging findings in drug addiction, we report the first evidence that PG is associated with greater DA release in dorsal striatum (54-63% greater [(11)C]-(+)-PHNO displacement) than controls. Importantly, dopaminergic response to amphetamine in gamblers was positively predicted by D3 receptor levels (measured in substantia nigra), and related to gambling severity, allowing for construction of a mechanistic model that could help explain DA contributions to PG. Our results are consistent with a hyperdopaminergic state in PG, and support the hypothesis that dopaminergic sensitization involving D3-related mechanisms might contribute to the pathophysiology of behavioral addictions.

Neuroinflammation in healthy aging: a PET study using a novel Translocator Protein 18kDa (TSPO) radioligand, [(18)F]-FEPPA.

One of the cellular markers of neuroinflammation is increased microglia activation, characterized by overexpression of mitochondrial 18kDa Translocator Protein (TSPO). TSPO expression can be quantified in-vivo using the positron emission tomography (PET) radioligand [(18)F]-FEPPA. This study examined microglial activation as measured with [(18)F]-FEPPA PET across the adult lifespan in a group of healthy volunteers. We performed genotyping for the rs6971 TS.PO gene polymorphism to control for the known variability in binding affinity. Thirty-three healthy volunteers (age range: 19-82years; 22 high affinity binders (HAB), 11 mixed affinity binders (MAB)) underwent [(18)F]-FEPPA PET scans, acquired on the High Resolution Research Tomograph (HRRT) and analyzed using a 2-tissue compartment model. Regression analyses were performed to examine the effect of age adjusting for genetic status on [(18)F]-FEPPA total distribution volumes (VT) in the hippocampus, temporal, and prefrontal cortex. We found no significant effect of age on [(18)F]-FEPPA VT (F (1,30)=0.918; p=0.346), and a significant effect of genetic polymorphism (F (1,30)=8.767; p=0.006). This is the first in-vivo study to evaluate age-related changes in TSPO binding, using the new generation TSPO radioligands. Increased neuroinflammation, as measured with [(18)F]-FEPPA PET was not associated with normal aging, suggesting that healthy elderly individuals may serve as useful benchmark against patients with neurodegenerative disorders where neuroinflammation may be present.

Stimulation of the pre-SMA influences cerebral blood flow in frontal areas involved with inhibitory control of action.

Selection of the most appropriate response necessitates inhibition of competing or prepotent responses. It is important to characterize which cortical areas are relevant to achieve response inhibition. Using the stop signal task, previous imaging studies revealed consistent activation in the right pre-supplementary motor area (pre-SMA). However, imaging alone suffers from the limitation that it can only provide neuronal correlates and cannot establish causality between brain activation and behavior. Repetitive transcranial magnetic stimulation (rTMS) can be used to temporarily interfere with the function of a cortical area considered to play a specific role in the behavior. Thus, we combined rTMS with H(2)(15)O positron emission tomography (PET) scans during the stop signal task, to test whether rTMS-induced changes in excitability of the right pre-SMA influenced response inhibition. We found that rTMS over the pre-SMA increased the efficiency of the inhibitory control over prepotent ongoing responses. A significant interaction was present in the left inferior frontal gyrus (IFG) along with an increase in regional cerebral blood flow (rCBF) in the left pre-SMA, left IFG, right premotor and right inferior parietal cortex. These areas best fitted the path analysis model in the effective connectivity model. The results of this study suggest that stimulation of the right pre-SMA, by interfering with its activity, may have a significant impact on response inhibition.

Relationship of monoamine oxidase A binding to adaptive and maladaptive personality traits.

BACKGROUND: Monoamine oxidase A (MAOA) is an important enzyme that metabolizes monoamines such as serotonin, norepinephrine and dopamine in the brain. In prefrontal cortex, low MAOA binding is associated with aggression and high binding is associated with major depressive disorder (MDD) and also risk for recurrence of depressive episodes. In rodent models, low MAOA levels are associated with increased aggression and fear conditioning, and decreased social and exploratory investigative behaviors. Our objective was to measure MAOA binding in prefrontal cortex and concurrently evaluate a broad range of validated personality traits. We hypothesized that prefrontal MAOA binding would correlate negatively with angry-hostility, a trait related to aggression/anger, and positively with traits intuitively related to adaptive investigative behavior. METHOD: Participants were aged 19-49 years, healthy and non-smoking. MAOA binding was measured with [11C]harmine positron emission tomography (PET) in prefrontal brain regions and personality traits were measured with the NEO Personality Inventory Revised (NEO PI-R). RESULTS: Prefrontal MAOA binding correlated negatively with angry-hostility (r=-0.515, p=0.001) and positively with deliberation (r=0.514, p=0.001). In a two-factor regression model, these facets explained 38% of variance in prefrontal MAOA binding. A similar relationship was found in prefrontal cortex subregions. CONCLUSIONS: We propose a new continuum describing the relationship between personality and MAOA: deliberate/thoughtful contrasting aggressive/impulsive. Additionally, the association between high MAOA binding and greater deliberation may explain why some people have moderately high levels of MAOA, although very high levels occur during MDD. In health, higher MAOA binding is associated with an adaptive personality facet.

Drug-induced deactivation of inhibitory networks predicts pathological gambling in PD.

OBJECTIVE: Some patients with Parkinson disease (PD) develop pathological gambling when treated with dopamine agonists (DAs). However, little is known about DA-induced changes in neuronal networks that may underpin this drug-induced change in behavior in vulnerable individuals. In this case-control study, we aimed to investigate DA-induced changes in brain activity that may differentiate patients with PD with DA-induced pathological gambling (gamblers) from patients with PD without such a history (controls). METHODS: Following overnight withdrawal of antiparkinsonian medication, patients were studied with H2(15)O PET before and after administration of DA (3 mg apomorphine) to measure changes in regional cerebral blood flow as an index of regional brain activity during a card selection game with probabilistic feedback. RESULTS: We observed that the direction of DA-related activity change in brain areas that are implicated in impulse control and response inhibition (lateral orbitofrontal cortex, rostral cingulate zone, amygdala, external pallidum) distinguished gamblers from controls. DA significantly increased activity in these areas in controls, while gamblers showed a significant DA-induced reduction of activity. CONCLUSIONS: We propose that in vulnerable patients with PD, DAs produce an abnormal neuronal pattern that resembles those found in nonparkinsonian pathological gambling and drug addiction. DA-induced disruption of inhibitory key functions--outcome monitoring (rostral cingulate zone), acquisition and retention of negative action-outcome associations (amygdala and lateral orbitofrontal cortex)--together with restricted access of those areas to executive control (external pallidum)--may well explain loss of impulse control and response inhibition in vulnerable patients with PD, thereby fostering the development of pathological gambling.

Increased striatal dopamine release in Parkinsonian patients with pathological gambling: a [11C] raclopride PET study.

Pathological gambling is an impulse control disorder reported in association with dopamine agonists used to treat Parkinson's disease. Although impulse control disorders are conceptualized as lying within the spectrum of addictions, little neurobiological evidence exists to support this belief. Functional imaging studies have consistently demonstrated abnormalities of dopaminergic function in patients with drug addictions, but to date no study has specifically evaluated dopaminergic function in Parkinson's disease patients with impulse control disorders. We describe results of a [(11)C] raclopride positron emission tomography (PET) study comparing dopaminergic function during gambling in Parkinson's disease patients, with and without pathological gambling, following dopamine agonists. Patients with pathological gambling demonstrated greater decreases in binding potential in the ventral striatum during gambling (13.9%) than control patients (8.1%), likely reflecting greater dopaminergic release. Ventral striatal bindings at baseline during control task were also lower in patients with pathological gambling. Although prior imaging studies suggest that abnormality in dopaminergic binding and dopamine release may be markers of vulnerability to addiction, this study presents the first evidence of these phenomena in pathological gambling. The emergence of pathological gambling in a number of Parkinson's disease patients may provide a model into the pathophysiology of this disorder.

Brain serotonin transporter binding in non-depressed patients with Parkinson's disease.

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 [11C]-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.

Antagonist, partial agonist and antiproliferative actions of B-9870 (CU201) as a function of the expression and density of the bradykinin B1 and B2 receptors.

BACKGROUND AND PURPOSE: A bradykinin (BK) B2 receptor (B2R) antagonist, B-9870 (CU201), has been proposed to behave as a 'biased agonist' at B2Rs and to exert anti-neoplasic effects. It was unclear whether these effects were determined by the activation of B2Rs by the drug. B-9870 was evaluated for antagonism or stimulation of several responses mediated by the rabbit B2R or B1 receptor (B1R); its anti-proliferative activity was also characterized. EXPERIMENTAL APPROACH AND KEY RESULTS: B-9870 was an insurmountable B2R antagonist in the rabbit jugular vein contractility assay, but a partial agonist in HEK 293 cells expressing the rabbit B2R or a green fluorescent protein (GFP) conjugate of the latter (ERK1/2 phosphorylation, [Ca2+]i, [3H]-arachidonate release, endocytosis). The agonist-like effects of B-9870 were inhibited by the B2R antagonist LF 16.0687 and absent in untransfected cells. In addition, B-9870 was a surmontable antagonist of the rabbit B1R in the aorta contractility assay, and blocked Lys-des-Arg9-BK-induced ERK1/2 phosphorylation in HEK 293 cells expressing a fluorescent B1R conjugate. B-9870 inhibited the growth of MDA-MB-231 cells. The latter effect was not influenced by B1R or B2R antagonists and was not apoptotic. MDA-MB-231 cells expressed a small population of B2Rs but no B1Rs; they responded to BK (small calcium transients) and B-9870 behaved as an antagonist. CONCLUSION AND IMPLICATIONS: B-9870 is a dual B1R and B2R antagonist with confirmed stimulating effects at the B2R in high expression systems only. Its cell type-specific anti-proliferative effect occurs at a high concentration, independently from kinin receptors and apoptosis.

Protease-activated receptor-4: a novel mechanism of inflammatory pain modulation.

BACKGROUND AND PURPOSE: Protease-activated receptor-4 (PAR(4)), the most recently discovered member of the PARs family, is activated by thrombin, trypsin and cathepsin G, but can also be selectively activated by small synthetic peptides (PAR(4)-activating peptide, PAR(4)-AP). PAR(4) is considered a potent mediator of platelet activation and inflammation. As both PAR(1) and PAR(2) have been implicated in the modulation of nociceptive mechanisms, we investigated the expression of PAR(4) in sensory neurons and the effects of its selective activation on nociception. EXPERIMENTAL APPROACH AND KEY RESULTS: We demonstrated the expression of PAR(4) in sensory neurons isolated from rat dorsal root ganglia by reverse transcription-polymerase chain reaction and immunofluorescence. We found that PAR(4) colocalized with calcitonin gene-related peptide and substance P. We also showed that a selective PAR(4)-AP was able to inhibit calcium mobilization evoked by KCl and capsaicin in rat sensory neurons. Moreover, the intraplantar injection of a PAR(4)-AP significantly increased nociceptive threshold in response to thermal and mechanical noxious stimuli, while a PAR(4) inactive control peptide had no effect. The anti-nociceptive effects of the PAR(4)-AP were dose-dependent and occurred at doses below the threshold needed to cause inflammation. Finally, co-injection of the PAR(4)-AP with carrageenan significantly reduced the carrageenan-induced inflammatory hyperalgesia and allodynia, but had no effect on inflammatory parameters such as oedema and granulocyte infiltration. CONCLUSIONS AND IMPLICATIONS: Taken together, these results identified PAR(4) as a novel potential endogenous analgesic factor, which can modulate nociceptive responses in normal and inflammatory conditions.

Dopamine depletion results in increased neostriatal D(2), but not D(1), receptor binding in humans.

The effect of endogenous dopamine (DA) on neostriatal DA D(1) and D(2) receptor binding potentials (D(1)RBP and D(2)RBP, respectively) in vivo was evaluated with positron emission tomography (PET) and the radiotracers [(11)C]SCH23390 and [(11)C]raclopride, respectively, by comparing the D(1)RBP and D(2)RBP before and after acute DA depletion. DA depletion was achieved by per-oral administration of 4500 mg alpha-methyl-para-tyrosine (AMPT) given in the 25 h prior to [(11)C]SCH23390 PET and of 5250 mg AMPT given in the 29 h prior to [(11)C]raclopride PET. Six healthy subjects completed the protocol. The AMPT treatment decreased plasma levels of the DA metabolite homovanillic acid by 61 +/- 16% (4500 mg; average +/- standard deviation) and 62 +/- 17% (5250 mg), and levels of the norepinephrine metabolite 3-methoxy-4-hydroxyphenethyleneglycol by 58 +/- 7% (4500 mg) and 66 +/- 5% (5250 mg). This AMPT treatment increased D(2)RBP significantly from 3.18 +/- 0.34 to 3.59 +/- 0.30 but no significant change was observed in D(1)RBP (1.64 +/- 0.24 pre AMPT vs 1.70 +/- 0.17 post AMPT). Thus, while DA depletion "uncovers" D(2)receptors, it does not do so for D(1) receptors. The implications of this finding for measuring endogenous DA and its effects on in vivo receptor binding in humans are discussed.

Lower dopamine transporter binding potential in striatum during depression.

Previous studies suggest that there is a dopamine lowering process during major depressive episodes (MDE). To investigate this, we measured the dopamine transporter binding potential (DAT BP) in the striatum of depressed and healthy subjects using [(11)C]RTI-32 PET. The DAT, a predominantly presynaptic receptor, decreases in density after chronic dopamine depletion and the BP is proportional to receptor density. In all striatal regions, subjects with MDE had significantly lower DAT BP. Low striatal DAT BP in MDE is consistent with a downregulation of DAT in response to a dopamine lowering process. There was also a strong, highly significant, inverse correlation between striatal DAT BP and neuropsychological tests of dopamine-implicated symptoms in patients (i.e. patients with lower DAT BP performed better). Lower DAT BP itself reduces extracellular clearance of dopamine. Patients who did not decrease their striatal DAT BP failed to compensate for low dopamine and showed greater impairment on dopamine related tests.

Positron emission tomography quantification of [(11)C]-DASB binding to the human serotonin transporter: modeling strategies.

[(11) C]-DASB, namely [(11) C]-3-amino-4-(2-dimethylaminomethyl-phenylsulfanyl)-benzonitrile, is a new highly selective radioligand for the in vivo visualization of the serotonin transporter (SERT) using positron emission tomography (PET). The current study evaluates different kinetic modeling strategies for quantification of [(11)C]-DASB binding in five healthy humans. Kinetic analyses of tissue data were performed with a one-tissue (1CM) and a two-tissue (2CM) compartment model. Time-activity curves were well described by a 1CM for all regions. A 2CM model with four parameters failed to converge reliably. Reliable fits of the data were obtained only if no more than three parameters were allowed to vary. However, even then, the rate constants k(3) and k(4) were estimated with poor precision. Only the ratio k(3)/k(4) was stable. Goodness of fit was not improved by using a 2CM as compared with a 1CM. The minimal study duration required to obtain stable k(3)/k(4) estimates was 80 minutes. For routine use of [(11)C]-DASB, several simplified methods using the cerebellum as a reference region to estimate nonspecific binding were also evaluated. The transient equilibrium, the linear graphical analysis, the ratio of target to reference region, and the simplified reference tissue methods all gave binding potential values consistent with those obtained with the 2CM. The suitability of [(11)C]-DASB for research on the SERT using PET is thus supported by the observations that tissue data can be described using a kinetic analysis and that simplified quantitative methods, using the cerebellum as reference, provide reliable estimates of SERT binding parameters.

Occupancy of serotonin transporters by paroxetine and citalopram during treatment of depression: a [(11)C]DASB PET imaging study.

OBJECTIVE: Selective serotonin reuptake inhibitors are commonly used to treat major depression; however, the percentage of serotonin (5-HT) transporter (5-HTT) sites occupied during clinical dosing is unknown. This study measured the proportion of 5-HTT sites blocked during paroxetine and citalopram treatment of depression and assessed the relationship between serum paroxetine levels and the proportion of 5-HTT sites blocked. METHOD: Twelve medication-free depressed patients completed a 6-week trial of either paroxetine (N=8) or citalopram (N=4). Striatal 5-HTT binding potential was measured with [(11)C]DASB and positron emission tomography, before and after 4 weeks of treatment. The binding potential is proportional to receptor density. Striatal 5-HTT binding potential was measured twice in six healthy subjects and once in 11 healthy subjects. RESULTS: A significant decrease in striatal 5-HTT binding potential was found after either treatment, compared to changes found over a 4-week period in healthy subjects. For patients treated with 20 mg/day of paroxetine (N=7), the mean proportion of 5-HTT sites occupied was 83%. For patients treated with 20 mg/day of citalopram (N=4), the mean 5-HTT occupancy was 77%. 5-HTT occupancy increased in a nonlinear relationship with serum levels of paroxetine such that a plateau of occupancy around 85% occurred for serum paroxetine levels greater than 28 microg/liter. CONCLUSIONS: During treatment with clinical doses of paroxetine or citalopram, approximately 80% of 5-HTT receptors are occupied. This change in 5-HTT binding potential is greater than the known physiological range of changes in 5-HTT binding potential but may be necessary for some therapeutic effects.