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Background: Production of [ 11 C]CH 4 from gas targets is notorious for weak performance with respect to yield, especially when using high beam currents. Post-target conversion of [ 11 C]CO 2 to [ 11 C]CH 4 is a widely used roundabout method in 11 C-radiochemistry, but the added complexity increase the challenge to control carrier carbon. Thus in-target-produced [ 11 C]CH 4 is superior with respect to molar activity. We studied the in-target production of [ 11 C]CO 2 and [ 11 C]CH 4 from nitrogen gas targets as a function of beam current, irradiation time, and target temperature., Results: [ 11 C]CO 2 production was practically unchanged across the range of varied parameters, but the [ 11 C]CH 4 yield, presented in terms of saturation yield Y SAT ( 11 CH 4 ), had a negative correlation with beam current and a positive correlation with target chamber temperature. A formulated model equation indicates behavior where the [ 11 C]CH 4 formation follows a parabolic graph as a function of beam current. The negative square term, i.e., the yield loss, is postulated to arise from Haber-Bosch-like NH 3 formation: N 2  + 3H 2  → 2NH 3 . The studied conditions suggest that the NH 3 (liq.) would be condensed on the target chamber walls, thus depleting the hydrogen reserve needed for the conversion of nascent 11 C to [ 11 C]CH 4 ., Conclusions: [ 11 C]CH 4 production can be improved by increasing the target chamber temperature, which is presented in a mathematical formula. Our observations have implications for targetry design (geometry, gas volume and composition, pressure) and irradiation conditions, providing specific knowledge to enhance [ 11 C]CH 4 production at high beam currents. Increased [ 11 C]CH 4 radioactivity is an obvious benefit in radiosynthesis in terms of product yield and molar radioactivity., (© 2024. The Author(s).)

Background: The neurobiological mechanisms of gambling disorder are not yet fully characterized, limiting the development of treatments. Defects in frontostriatal connections have been shown to play a major role in substance use disorders, but data on behavioral addictions, such as gambling disorder, are scarce. The aim of this study was to 1) investigate whether gambling disorder is associated with abnormal frontostriatal connectivity and 2) characterize the key neurotransmitter systems underlying the connectivity abnormalities., Methods: Fifteen individuals with gambling disorder and 17 matched healthy controls were studied with resting-state functional connectivity MRI and three brain positron emission tomography scans, investigating dopamine (18F-FDOPA), opioid (11C-carfentanil) and serotonin (11C-MADAM) function. Frontostriatal connectivity was investigated using striatal seed-to-voxel connectivity and compared between the groups. Neurotransmitter systems underlying the identified connectivity differences were investigated using region-of-interest and voxelwise approaches., Results: Individuals with gambling disorder showed loss of functional connectivity between the right nucleus accumbens (NAcc) and a region in the right dorsolateral prefrontal cortex (DLPFC) (PFWE <0.05). Similarly, there was a significant Group x right NAcc interaction in right DLPFC 11C-MADAM binding (p = 0.03) but not in 18F-FDOPA uptake or 11C-carfentanil binding. This was confirmed in voxelwise analyses showing a widespread Group x right NAcc interaction in the prefrontal cortex 11C-MADAM binding (PFWE <0.05). Right NAcc 11C-MADAM binding potential correlated with attentional impulsivity in individuals with gambling disorder (r = -0.73, p = 0.005)., Discussion: Gambling disorder is associated with right hemisphere abnormal frontostriatal connectivity and serotonergic function. These findings will contribute to understanding the neurobiological mechanism and may help identify potential treatment targets for gambling disorder.

Background: Risk is an essential trait of most daily decisions. Our behaviour when faced with risks involves evaluation of many factors including the outcome probabilities, the valence (gains or losses) and past experiences. Several psychiatric disorders belonging to distinct diagnostic categories, including pathological gambling and addiction, show pathological risk-taking and implicate abnormal dopaminergic, opioidergic and serotonergic neurotransmission. In this study, we adopted a transdiagnostic approach to delineate the neurochemical substrates of decision making under risk., Methods: We recruited 39 participants, including 17 healthy controls, 15 patients with pathological gambling and seven binge eating disorder patients, who completed an anticipatory risk-taking task. Separately, participants underwent positron emission tomography (PET) imaging with three ligands, [ 18 F]fluorodopa (FDOPA), [ 11 C]MADAM and [ 11 C]carfentanil to assess presynaptic dopamine synthesis capacity and serotonin transporter and mu-opioid receptor binding respectively., Results: Risk-taking behaviour when faced with gains positively correlated with dorsal cingulate [ 11 C]carfentanil binding and risk-taking to losses positively correlated with [ 11 C]MADAM binding in the caudate and putamen across all subjects., Conclusions: We show distinct neurochemical substrates underlying risk-taking with the dorsal cingulate cortex mu-opioid receptor binding associated with rewards and dorsal striatal serotonin transporter binding associated with losses. Risk-taking and goal-directed control appear to dissociate between dorsal and ventral fronto-striatal systems. Our findings thus highlight the potential role of pharmacological agents or neuromodulation on modifying valence-specific risk-taking biases.

Introduction: Central μ-opioid receptors (MORs) modulate affective responses to physical exercise. Individuals with higher aerobic fitness report greater exercise-induced mood improvements than those with lower fitness, but the link between cardiorespiratory fitness and the MOR system remains unresolved. Here we tested whether maximal oxygen uptake (V̇O2peak) and physical activity level are associated with cerebral MOR availability and whether these phenotypes predict endogenous opioid release after a session of exercise., Methods: We studied 64 healthy lean men who performed a maximal incremental cycling test for V̇O2peak determination, completed a questionnaire assessing moderate-to-vigorous physical activity (MVPA; in minutes per week), and underwent positron emission tomography with [11C]carfentanil, a specific radioligand for MOR. A subset of 24 subjects underwent additional positron emission tomography scan also after a 1-h session of moderate-intensity exercise and 12 of them also after a bout of high-intensity interval training., Results: Higher self-reported MVPA level predicted greater opioid release after high-intensity interval training, and both V̇O2peak and MVPA level were associated with a larger decrease in cerebral MOR binding after aerobic exercise in the ventral striatum, orbitofrontal cortex, and insula. That is, more trained individuals showed greater opioid release acutely after exercise in brain regions especially relevant for reward and cognitive processing. Fitness was not associated with MOR availability., Conclusions: We conclude that regular exercise training and higher aerobic fitness may induce neuroadaptation within the MOR system, which might contribute to improved emotional and behavioral responses associated with long-term exercise., (Copyright © 2022 by the American College of Sports Medicine.)

Background: Availability of the α 2C -adrenoceptor (α 2C -AR) positron emission tomography (PET) tracer, [ 11 C]ORM-13070, and the α 2C -AR antagonist ORM-12741 allows probing of the roles of this G-protein coupled receptor subtype in brain function, both in healthy humans and in patients with various brain disorders. This translational study employed [ 11 C]ORM-13070 autoradiography and PET to determine α 2C -AR occupancy by ORM-12741 in rat and human brain, respectively., Results: ORM-12741 has high affinity (K i : 0.08 nM) and potent antagonist activity (K b : 0.04 nM) as well as selectivity (K i estimates for the human α 2A -AR and α 2B -AR were 8.3 nM and 0.8 nM, respectively) for the human α 2C -AR subtype. [ 11 C]ORM-13070 had highest uptake in the basal ganglia of rat and human brain. Pretreatment with ORM-12741 inhibited [ 11 C]ORM-13070 binding in rat striatum in a time- and dose-dependent manner at 10 and 50 µg/kg (s.c.) with an EC 50 estimate of 1.42 ng/mL in rat plasma, corresponding to protein-free drug concentration of 0.23 nM. In the living human brain, time- and dose-related α 2C -AR occupancy was detected with EC 50 estimates of 24 ng/mL and 31 ng/mL for the caudate nucleus and putamen, respectively, corresponding to protein-free concentrations in plasma of 0.07 nM and 0.1 nM. Modelling-based maximum α 2C -AR occupancy estimates were 63% and 52% in the caudate nucleus and the putamen, respectively., Conclusions: ORM-12741 is a selective α 2C -AR antagonist which penetrates the rat and human brain to occupy α 2C -ARs in a manner consistent with its receptor pharmacology. Trial registration number and date of registration: ClinicalTrial.cov NCT00829907. Registered 11 December 2008. https://clinicaltrials.gov/ .

Our daily decisions are governed by the arbitration between goal-directed and habitual strategies. However, the neurochemical basis of this arbitration is unclear. We assessed the contribution of dopaminergic, serotonergic, and opioidergic systems to this balance across reward and loss domains. Thirty-nine participants (17 healthy controls, 15 patients with pathological gambling, and 7 with binge eating disorder) underwent positron emission tomography (PET) imaging with [ 18 F]FDOPA, [ 11 C]MADAM and [ 11 C]carfentanil to assess presynaptic dopamine, and serotonin transporter and mu-opioid receptor binding potential. Separately, participants completed a modified two-step task, which quantifies the degree to which decision-making is influenced by goal-directed or habitual strategies. All participants completed a version with reward outcomes; healthy controls additionally completed a version with loss outcomes. In the context of rewarding outcomes, we found that greater serotonin transporter binding potential in prefrontal regions was associated with habitual control, while greater serotonin transporter binding potential in the putamen was marginally associated with goal-directed control; however, the findings were no longer significant when controlling for the opposing valence (loss). In blocks with loss outcomes, we found that the opioidergic system, specifically greater [ 11 C]carfentanil binding potential, was positively associated with goal-directed control and negatively associated with habit-directed control. Our findings illuminate the complex neurochemical basis of goal-directed and habitual behavior, implicating differential roles for prefrontal and subcortical serotonin in decision-making across healthy and pathological populations.

Animal studies have suggested that dopamine and opioid neurotransmitter systems interact in brain regions that are relevant for reward functions, but data in humans are very limited. The interaction is potentially important in disorders affecting these neurotransmitter systems, such as addiction. Here, we investigated whether subcortical μ-opioid receptor (MOR) availability and presynaptic dopamine synthesis capacity are correlated in the healthy human brain or in pathological gamblers (PGs) using positron emission tomography with 6-[ 18 F]fluoro-l-dopa and [ 11 C]carfentanil. The specificity of the findings was further investigated by including a serotonin transporter ligand, [ 11 C]MADAM, as a negative control. Thirteen PG patients and 15 age-, sex- and weight-matched controls underwent the scans. In both groups, presynaptic dopamine synthesis capacity was associated with MOR availability in the putamen, caudate nucleus and globus pallidus. No similar associations were observed between dopamine synthesis capacity and [ 11 C]MADAM binding, supporting a specific interplay between presynaptic dopamine neurotransmission and opioid receptor function in the basal ganglia. Correlations were similar between the groups, suggesting that the dopamine-opioid link is general and unaffected by behavioral addiction. The results provide in vivo human evidence of a connection between endogenous opioid and dopamine signaling in the brain., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Physical exercise modulates food reward and helps control body weight. The endogenous µ-opioid receptor (MOR) system is involved in rewarding aspects of both food and physical exercise, yet interaction between endogenous opioid release following exercise and anticipatory food reward remains unresolved. Here we tested whether exercise-induced opioid release correlates with increased anticipatory reward processing in humans. We scanned 24 healthy lean men after rest and after a 1 h session of aerobic exercise with positron emission tomography (PET) using MOR-selective radioligand [ 11 C]carfentanil. After both PET scans, the subjects underwent a functional magnetic resonance imaging (fMRI) experiment where they viewed pictures of palatable versus nonpalatable foods to trigger anticipatory food reward responses. Exercise-induced changes in MOR binding in key regions of reward circuit (amygdala, thalamus, ventral and dorsal striatum, and orbitofrontal and cingulate cortices) were used to predict the changes in anticipatory reward responses in fMRI. Exercise-induced changes in MOR binding correlated negatively with the exercise-induced changes in neural anticipatory food reward responses in orbitofrontal and cingulate cortices, insula, ventral striatum, amygdala, and thalamus: higher exercise-induced opioid release predicted higher brain responses to palatable versus nonpalatable foods. We conclude that MOR activation following exercise may contribute to the considerable interindividual variation in food craving and consumption after exercise, which might promote compensatory eating and compromise weight control., (© 2018 Wiley Periodicals, Inc.)

Central opioidergic mechanisms may modulate the positive effects of physical exercise such as mood elevation and stress reduction. How exercise intensity and concomitant effective changes affect central opioidergic responses is unknown. We studied the effects of acute physical exercise on the cerebral μ-opioid receptors (MOR) of 22 healthy recreationally active males using positron emission tomography (PET) and the MOR-selective radioligand [ 11 C]carfentanil. MOR binding was measured in three conditions on separate days: after a 60-min aerobic moderate-intensity exercise session, after a high-intensity interval training (HIIT) session, and after rest. Mood was measured repeatedly throughout the experiment. HIIT significantly decreased MOR binding selectively in the frontolimbic regions involved in pain, reward, and emotional processing (thalamus, insula, orbitofrontal cortex, hippocampus, and anterior cingulate cortex). Decreased binding correlated with increased negative emotionality. Moderate-intensity exercise did not change MOR binding, although increased euphoria correlated with decreased receptor binding. These observations, consistent with endogenous opioid release, highlight the role of the μ-opioid system in mediating affective responses to high-intensity training as opposed to recreational moderate physical exercise.

Objective: To investigate quantitative positron emission tomography (PET) findings and to study whether the cholinergic function differs between respondents to cholinergic medication versus nonrespondents., Setting: Outpatient clinic and university PET imaging center., Participants: We studied 17 subjects for more than 1 year after at least moderate traumatic brain injury. Ten of the subjects were respondents and 7 nonrespondents to cholinergic medication., Design: Cholinergic function was assessed with [methyl-C] N-methylpiperidyl-4-acetate-PET (C-MP4A-PET), which reflects the activity of the acetylcholinesterase (AChE) enzyme. The subjects were PET scanned twice: without medication and after a 4-week treatment with rivastigmine 1.5 mg twice a day., Measures: Regional cerebral AChE activity was measured with PET., Results: At baseline Statistical Parametric Mapping analyses showed significantly lower AChE activity in respondents bilaterally in the frontal cortex as compared with nonrespondents. Region of interest (ROI) analysis revealed that the difference was most pronounced in the lateral frontal cortex (-9.4%, P = .034) and anterior cingulate (-6.0%, P = .049). After rivastigmine treatment, AChE activity was notably lower throughout the cortex in both respondents and nonrespondents, without significant differences between them., Conclusion: Our study suggests that frontal cholinergic dysfunction is associated with the clinical response to cholinergic stimulation in patients with traumatic brain injury.

Behavioral addictions, such as pathological gambling (PG) and binge eating disorder (BED), appear to be associated with specific changes in brain dopamine and opioid function, but the role of other neurotransmitter systems is less clear. Given the crucial role of serotonin in a number of psychiatric disorders, we aimed to compare brain serotonergic function among individuals with BED, PG and healthy controls. Seven BED patients, 13 PG patients and 16 healthy controls were scanned with high-resolution positron emission tomography (PET) using the serotonin transporter (SERT) tracer [ 11 C]MADAM. Both region-of-interest and voxel-wise whole brain analyses were performed. Patients with BED showed increased SERT binding in the parieto-occipital cortical regions compared to both PG and healthy controls, with parallel decreases in binding in the nucleus accumbens, inferior temporal gyrus and lateral orbitofrontal cortex. No differences between PG patients and controls were observed. None of the subjects were on SSRI medications at the time of imaging, and there were no differences in the level of depression between PG and BED patients. The results highlight differences in brain SERT binding between individuals with BED and PG and provide further evidence of different neurobiological underpinnings in behavioral addictions that are unrelated to the co-existing mood disorder. The results aid in the conceptualization of behavioral addictions by characterizing the underlying serotonin changes and provide a framework for additional studies to examine syndrome-specific pharmaceutical treatments., (Copyright © 2017 Elsevier B.V. and ECNP. All rights reserved.)

The size of human social networks significantly exceeds the network that can be maintained by social grooming or touching in other primates. It has been proposed that endogenous opioid release after social laughter would provide a neurochemical pathway supporting long-term relationships in humans (Dunbar, 2012), yet this hypothesis currently lacks direct neurophysiological support. We used PET and the μ-opioid-receptor (MOR)-specific ligand [ 11 C]carfentanil to quantify laughter-induced endogenous opioid release in 12 healthy males. Before the social laughter scan, the subjects watched laughter-inducing comedy clips with their close friends for 30 min. Before the baseline scan, subjects spent 30 min alone in the testing room. Social laughter increased pleasurable sensations and triggered endogenous opioid release in thalamus, caudate nucleus, and anterior insula. In addition, baseline MOR availability in the cingulate and orbitofrontal cortices was associated with the rate of social laughter. In a behavioral control experiment, pain threshold-a proxy of endogenous opioidergic activation-was elevated significantly more in both male and female volunteers after watching laughter-inducing comedy versus non-laughter-inducing drama in groups. Modulation of the opioidergic activity by social laughter may be an important neurochemical pathway that supports the formation, reinforcement, and maintenance of human social bonds. SIGNIFICANCE STATEMENT Social contacts are vital to humans. The size of human social networks significantly exceeds the network that can be maintained by social grooming in other primates. Here, we used PET to show that endogenous opioid release after social laughter may provide a neurochemical mechanism supporting long-term relationships in humans. Participants were scanned twice: after a 30 min social laughter session and after spending 30 min alone in the testing room (baseline). Endogenous opioid release was stronger after laughter versus the baseline scan. Opioid receptor density in the frontal cortex predicted social laughter rates. Modulation of the opioidergic activity by social laughter may be an important neurochemical mechanism reinforcing and maintaining social bonds between humans., (Copyright © 2017 the authors 0270-6474/17/376125-07$15.00/0.)

Although behavioral addictions share many clinical features with drug addictions, they show strikingly large variation in their behavioral phenotypes (such as in uncontrollable gambling or eating). Neurotransmitter function in behavioral addictions is poorly understood, but has important implications in understanding its relationship with substance use disorders and underlying mechanisms of therapeutic efficacy. Here, we compare opioid and dopamine function between two behavioral addiction phenotypes: pathological gambling (PG) and binge eating disorder (BED). Thirty-nine participants (15 PG, 7 BED, and 17 controls) were scanned with [ 11 C]carfentanil and [ 18 F]fluorodopa positron emission tomography using a high-resolution scanner. Binding potentials relative to non-displaceable binding (BP ND ) for [ 11 C]carfentanil and influx rate constant (K i ) values for [ 18 F]fluorodopa were analyzed with region-of-interest and whole-brain voxel-by-voxel analyses. BED subjects showed widespread reductions in [ 11 C]carfentanil BP ND in multiple subcortical and cortical brain regions and in striatal [ 18 F]fluorodopa K i compared with controls. In PG patients, [ 11 C]carfentanil BP ND was reduced in the anterior cingulate with no differences in [ 18 F]fluorodopa K i compared with controls. In the nucleus accumbens, a key region involved in reward processing, [ 11 C]Carfentanil BP ND was 30-34% lower and [ 18 F]fluorodopa K i was 20% lower in BED compared with PG and controls (p<0.002). BED and PG are thus dissociable as a function of dopaminergic and opioidergic neurotransmission. Compared with PG, BED patients show widespread losses of mu-opioid receptor availability together with presynaptic dopaminergic defects. These findings highlight the heterogeneity underlying the subtypes of addiction and indicate differential mechanisms in the expression of pathological behaviors and responses to treatment.

Intravenous use of a psychostimulant drug containing methcathinone (ephedrone) and manganese causes an irreversible extrapyramidal syndrome in drug abusers. We aimed to reproduce the syndrome in mice to evaluate dopaminergic damage. C57/B6 mice were intraperitoneally injected once a day with the study drug or saline for a period of 27 weeks. Motor activity was recorded in an automated motility-box. After 13 and 27 weeks of treatment, ex vivo digital autoradiography was performed using [ 11 C]dihydrotetrabenazine ([ 11 C]DTBZ). After 27 weeks of treatment [ 11 C]DTBZ autoradiography demonstrated a significant increase in the striatum-to-cerebellum binding ratio compared with saline treated controls. At the same time point, there was no evident change in motor activity. Increased [ 11 C]DTBZ binding may indicate vesicular monoamine transporter type 2 (VMAT2) function is altered. The lack of extrapyramidal symptoms in animals could be attributed to low dosing regimen or high metabolic rate., (Copyright © 2016 Elsevier B.V. All rights reserved.)

In non-human primates, opioid-receptor blockade increases social grooming, and the endogenous opioid system has therefore been hypothesized to support maintenance of long-term relationships in humans as well. Here we tested whether social touch modulates opioidergic activation in humans using in vivo positron emission tomography (PET). Eighteen male participants underwent two PET scans with [11C]carfentanil, a ligand specific to μ-opioid receptors (MOR). During the social touch scan, the participants lay in the scanner while their partners caressed their bodies in a non-sexual fashion. In the baseline scan, participants lay alone in the scanner. Social touch triggered pleasurable sensations and increased MOR availability in the thalamus, striatum, and frontal, cingulate, and insular cortices. Modulation of activity of the opioid system by social touching might provide a neurochemical mechanism reinforcing social bonds between humans., (Copyright © 2016 Elsevier Inc. All rights reserved.)

PET imaging can for some neurotransmitters be used to measure synaptic neurotransmitter concentrations. The objective of this study was to test whether the receptor binding of the α2C -AR antagonist PET tracer [(11)C]ORM-13070 would increase in response to reductions in synaptic noradrenaline, evoked by dexmedetomidine as a sympatholytic drug challenge. Six subjects underwent a control PET scan and two dexmedetomidine PET scans. Dexmedetomidine was infused with target plasma concentrations of 0.6 and 0.2 ng/ml. Tracer binding was measured by voxel-based analysis of bound per free (B/F) images. ROI-based analysis was performed in the dorsal striatum and in the thalamus. Vital signs and drug concentrations in plasma were measured and the sedative effect was estimated with the visual analog scale. In the voxel-based analysis, dexmedetomidine administration was associated with a tendency to increased B/F tracer in the right thalamus (mean, +17%, P = 0.14, and +19%, P = 0.05, with the low and high dose, respectively). Tracer binding in the dorsal striatum was unaffected by dexmedetomidine. A cluster with significantly increased B/F tracer (+42%, P = 0.01) was seen in the right superior temporal gyrus with low-dose dexmedetomidine, but not after the high dose. Brain uptake of [(11)C]ORM-13070 has previously been shown to be reduced in conditions of increased synaptic noradrenaline concentrations. In this study, tracer binding in the thalamus tended to increase in accordance with reduced activity of noradrenergic projections from the locus coeruleus, but statistical significance was not reached., (© 2015 Wiley Periodicals, Inc.)

Rationale: No validated methods have been available for studying brain noradrenergic neurotransmission in vivo in humans. Positron emission tomography (PET) radiotracers are widely used in clinical drug development targeted to brain receptors and can also in some cases be employed to monitor extracellular (synaptic) neurotransmitter concentrations., Objectives: The objective of this study is to test the sensitivity of [(11)C]ORM-13070 uptake to increased concentrations of extracellular (synaptic) noradrenaline in the human brain., Methods: Eight subjects underwent a control PET scan with [(11)C]ORM-13070, a subtype-selective α2C-adrenoceptor antagonist radioligand, and two PET scans after two different noradrenaline challenges, i.e. during ketamine infusion and after a dose of atomoxetine combined with cold stimulation. Tracer uptake in the caudate nucleus and putamen was described with AUC values in scan time windows of 10-20 and 5-30 min post injection and quantified with the ratio method. Voxel-based analysis was performed with average bound per free (B/F) ratio images., Results: Both noradrenaline challenges were consistently associated with 10-20 % (p < 0.05) reductions in tracer uptake in the dorsal striatum, as determined with region-of-interest-based analysis. Voxel-based analysis revealed significant reductions in B/F ratios in the dorsal striatum, in the brain stem and in several cortical areas. Reductions of 24 and 23 % were detected in the peak putamen clusters with ketamine and atomoxetine + cold, respectively., Conclusion: Direct experimental support was gained for the suitability of [(11)C]ORM-13070 for imaging of brain noradrenergic neurotransmission.

This study explored the use of the α2C -adrenoceptor PET tracer [(11) C]ORM-13070 to monitor α2C -AR occupancy in the human brain. The subtype-nonselective α2 -AR antagonist atipamezole was administered to eight healthy volunteer subjects to determine its efficacy and potency (Emax and EC50 ) at inhibiting tracer uptake. We also explored whether the tracer could reveal changes in the synaptic concentrations of endogenous noradrenaline in the brain, in response to several pharmacological and sensory challenge conditions. We assessed occupancy from the bound-to-free ratio measured during 5-30 min post injection. Based on extrapolation of one-site binding, the maximal extent of inhibition of striatal [(11) C]ORM-13070 uptake (Emax ) achievable by atipamezole was 78% (95% CI 69-87%) in the caudate nucleus and 65% (53-77%) in the putamen. The EC50 estimates of atipamezole (1.6 and 2.5 ng/ml, respectively) were in agreement with the drug's affinity to α2C -ARs. These findings represent clear support for the use of [(11) C]ORM-13070 for monitoring drug occupancy of α2C -ARs in the living human brain. Three of the employed noradrenaline challenges were associated with small, approximately 10-16% average reductions in tracer uptake in the dorsal striatum (atomoxetine, ketamine, and the cold pressor test; P < 0.05 for all), but insulin-induced hypoglycemia did not affect tracer uptake. The tracer is suitable for studying central nervous system receptor occupancy by α2C -AR ligands in human subjects. [(11) C]ORM-13070 also holds potential as a tool for in vivo monitoring of synaptic concentrations of noradrenaline, but this remains to be further evaluated in future studies., (© 2014 Wiley Periodicals, Inc.)

Purpose: α2C-Adrenoceptors share inhibitory presynaptic functions with the more abundant α2A-adrenoceptor subtype, but they also have widespread postsynaptic modulatory functions in the brain. Research on the noradrenergic system of the human brain has been hampered by the lack of suitable PET tracers targeted to the α2-adrenoceptor subtypes., Methods: PET imaging with the specific α2C-adrenoceptor antagonist tracer [(11)C]ORM-13070 was performed twice in six healthy male subjects to investigate the test-retest reliability of tracer binding., Results: The bound/free ratio of tracer uptake relative to nonspecific uptake into the cerebellum during the time interval of 5 - 30 min was most prominent in the dorsal striatum: 0.77 in the putamen and 0.58 in the caudate nucleus. Absolute test-retest variability in bound/free ratios of tracer ranged from 4.3 % in the putamen to 29 % in the hippocampus. Variability was also <10 % in the caudate nucleus and thalamus. Intraclass correlation coefficients (ICC) ranged from 0.50 in the hippocampus to 0.89 in the thalamus (ICC >0.70 was also reached in the caudate nucleus, putamen, lateral frontal cortex and parietal cortex). The pattern of [(11)C]ORM-13070 binding, as determined by PET, was in good agreement with receptor density results previously derived from post-mortem autoradiography. PET data analysis results obtained with a compartmental model fit, the simplified reference tissue model and a graphical reference tissue analysis method were convergent with the tissue ratio method., Conclusion: The results of this study support the use of [(11)C]ORM-13070 PET in the quantitative assessment of α2C-adrenoceptors in the human brain in vivo. Reliable assessment of specific tracer binding in the dorsal striatum is possible with the help of reference tissue ratios.

[(11)C]TMSX ([7-N-methyl-(11)C]-(E)-8-(3,4,5-trimethoxystyryl)-1,3,7-trimethylxanthine) is a selective adenosine A2A receptor (A2AR) radioligand. In the central nervous system (CNS), A2AR are linked to dopamine D2 receptor function in striatum, but they are also important modulators of inflammation. The golden standard for kinetic modeling of brain [(11)C]TMSX positron emission tomography (PET) is to obtain arterial input function via arterial blood sampling. However, this method is laborious, prone to errors and unpleasant for study subjects. The aim of this work was to evaluate alternative input function acquisition methods for brain [(11)C]TMSX PET imaging. First, a noninvasive, automated method for the extraction of gray matter reference region using supervised clustering (SCgm) was developed. Second, a method for obtaining a population-based arterial input function (PBIF) was implemented. These methods were created using data from 28 study subjects (7 healthy controls, 12 multiple sclerosis patients, and 9 patients with Parkinson's disease). The results with PBIF correlated well with original plasma input, and the SCgm yielded similar results compared with cerebellum as a reference region. The clustering method for extracting reference region and the population-based approach for acquiring input for dynamic [(11)C]TMSX brain PET image analyses appear to be feasible and robust methods, that can be applied in patients with CNS pathology.

Background: The neurotransmitter norepinephrine has been implicated in psychiatric and neurodegenerative disorders. Examination of synaptic norepinephrine concentrations in the living brain may be possible with positron emission tomography (PET), but has been hampered by the lack of suitable radioligands., Methods: We explored the use of the novel α2C-adrenoceptor antagonist PET tracer [(11)C]ORM-13070 for measurement of amphetamine-induced changes in synaptic norepinephrine. The effect of amphetamine on [(11)C]ORM-13070 binding was evaluated ex vivo in rat brain sections and in vivo with PET imaging in monkeys., Results: Microdialysis experiments confirmed amphetamine-induced elevations in rat striatal norepinephrine and dopamine concentrations. Regional [(11)C]ORM-13070 receptor binding was high in the striatum and low in the cerebellum. After injection of [(11)C]ORM-13070 in rats, mean striatal specific binding ratios, determined using cerebellum as a reference region, were 1.4±0.3 after vehicle pretreatment and 1.2±0.2 after amphetamine administration (0.3mg/kg, subcutaneous). Injection of [(11)C]ORM-13070 in non-human primates resulted in mean striatal binding potential (BP ND) estimates of 0.65±0.12 at baseline. Intravenous administration of amphetamine (0.5 and 1.0mg/kg, i.v.) reduced BP ND values by 31-50%. Amphetamine (0.3mg/kg, subcutaneous) increased extracellular norepinephrine (by 400%) and dopamine (by 270%) in rat striata., Conclusions: Together, these results indicate that [(11)C]ORM-13070 may be a useful tool for evaluation of synaptic norepinephrine concentrations in vivo. Future studies are required to further understand a potential contribution of dopamine to the amphetamine-induced effect., (© The Author 2015. Published by Oxford University Press on behalf of CINP.)

Purpose: (11)C-labelled 1-[(S)-1-(2,3-dihydrobenzo[1,2]dioxin-2-yl)methyl]-4-(3-methoxy-methylpyridin-2-yl)-piperazine ((11)C-ORM-13070) is a novel PET tracer for imaging of α2C-adrenoceptors in the human brain. Brain α2C-adrenoceptors may be therapeutic targets in several neuropsychiatric disorders, including depression, schizophrenia and Alzheimer's disease. To validate the use of (11)C-ORM-13070 in humans, we investigated its radiometabolism, pharmacokinetics, whole-body distribution and radiation dose., Methods: Radiometabolism was studied in a test-retest setting in six healthy men. After intravenous injection of (11)C-ORM-13070, blood samples were drawn over 60 min. Plasma samples were analysed by radio-HPLC for intact tracer and its radioactive metabolites. Metabolite-corrected plasma time-activity curves were used for calculation of pharmacokinetics. In a separate group of 12 healthy men, the whole-body distribution of (11)C-ORM-13070 and radiation exposure were investigated by dynamic PET/CT imaging without blood sampling., Results: Two radioactive metabolites of (11)C-ORM-13070 were detected in human arterial plasma. The proportion of unchanged (11)C-ORM-13070 decreased from 81 ± 4 % of total radioactivity at 4 min after tracer injection to 23 ± 4 % at 60 min. At least one of the radioactive metabolites penetrated into red blood cells, while the parent tracer remained in plasma. The apparent elimination rate constant and corresponding half-life of unchanged (11)C-ORM-13070 in arterial plasma were 0.0117 ± 0.0056 min(-1) and 73.6 ± 35.8 min, respectively. The organs with the highest absorbed doses were the liver (12 μSv/MBq), gallbladder wall (12 μSv/MBq) and pancreas (9.1 μSv/MBq). The mean effective dose was 3.9 μSv/MBq, with a range of 3.6 - 4.2 μSv/MBq., Conclusion: (11)C-ORM-13070 was rapidly metabolized in human subjects after intravenous injection. The effective radiation dose of (11)C-ORM-13070 was in the same range as that of other (11)C-labelled brain receptor tracers. An injection of 500 MBq of (11)C-ORM-13070 would expose a subject to 2.0 mSv of radiation. This supports the use of (11)C-ORM-13070 in repeated PET scans, for example, in receptor occupancy trials with novel drug candidates.

Unlabelled: We report the development of a PET tracer for α2C adrenoceptor imaging and its preliminary preclinical evaluation. α2C adrenoceptors in the human brain may be involved in various neuropsychiatric disorders, such as depression, schizophrenia, and neurodegenerative diseases. PET tracers are needed for imaging of this receptor system in vivo., Methods: High-specific-activity (11)C-ORM-13070 (1-[(S)-1-(2,3-dihydrobenzo[1,4]dioxin-2-yl)methyl]-4-(3-(11)C-methoxymethylpyridin-2-yl)-piperazine) was synthesized by (11)C-methylation of O-desmethyl-ORM-13070 with (11)C-methyl triflate, which was prepared from cyclotron-produced (11)C-methane via (11)C-methyl iodide. Rats and mice were investigated in vivo with PET and ex vivo with autoradiography. The specificity of (11)C-ORM-13070 binding to α2 adrenoceptors was demonstrated in rats pretreated with atipamezole, an α2 adrenoceptor antagonist. The α2C adrenoceptor selectivity of the tracer was determined by comparing tracer binding in wild-type and α2A- and α2AC adrenoceptor knockout (KO) mice. (11)C-ORM-13070 and its radioactive metabolites in rat plasma and brain tissue were analyzed with radio-high-performance liquid chromatography and mass spectroscopy. Human radiation dose estimates were extrapolated from rat biodistribution data., Results: The radiochemical yield, calculated from initial cyclotron-produced (11)C-methane, was 9.6% ± 2.7% (decay-corrected to end of bombardment). The specific activity of the product was 640 ± 390 GBq/μmol (decay-corrected to end of synthesis). The radiochemical purity exceeded 99% in all syntheses. The highest levels of tracer binding were observed in the striatum and olfactory tubercle of rats and control and α2A KO mice-that is, in the brain regions known to contain the highest densities of α2C adrenoceptors. In rats pretreated with atipamezole and in α2AC KO mice, (11)C tracer binding in the striatum and olfactory tubercle was low, similar to that of the frontal cortex and thalamus, regions with low densities of α2C adrenoceptors. Two radioactive metabolites were found in rat plasma, but only one of them was found in the brain; their identity was not revealed. The estimated effective radiation dose was comparable with the average exposure level in PET studies with (11)C tracers., Conclusion: An efficient method for the radiosynthesis of (11)C-ORM-13070 was developed. (11)C-ORM-13070 emerged as a potential novel radiotracer for in vivo imaging of brain α2C adrenoceptors., (© 2014 by the Society of Nuclear Medicine and Molecular Imaging, Inc.)

Background: Brain dopamine neurons code rewarding environmental stimuli by releasing endogenous dopamine, a transmission signal that is important for reinforcement learning. Human reward-seeking gambling behavior, and especially pathological gambling, has been presumed to be modulated by brain dopamine., Methods: Striatal dopamine release was studied with [(11)C]raclopride positron emission tomography (PET) during gambling with an ecologically valid slot machine gambling task. Twenty-four males with and without pathological gambling (DSM-IV) were scanned three times, and the effects of different gambling outcomes (high-reward and low-reward vs. control task) on dopamine release were evaluated., Results: Striatal dopamine was released in both groups during high-reward but also low-reward tasks. The dopamine release during the low-reward task was located in the associative part of the caudate nucleus. During the high-reward task, the effect was also seen in the ventral striatum and the magnitude of dopamine release was associated with parallel gambling "high". Furthermore, there was a positive correlation between dopamine release during the low-reward and the high-reward task. There was no general difference in the magnitude of dopamine release between pathological gamblers and controls. However, in pathological gamblers, dopamine release correlated positively with gambling symptom severity., Conclusions: Striatal dopamine is released during gambling irrespective of gambling outcome suggesting that the mere expectation/prediction of reward is sufficient to induce dopaminergic changes. Although dopamine release during slot machine gambling is comparable between healthy controls and pathological gamblers, greater gambling symptom severity is associated with greater dopaminergic responses. Thus, as the dopamine reward deficiency theory predicts blunted mesolimbic dopamine responses to gambling in addicted individuals, our results question the validity of the reward deficiency hypothesis in pathological gambling., (Copyright © 2012 Elsevier Inc. All rights reserved.)

Unlabelled: We assessed the ability of (11)C-acetate PET/CT, MRI, and proton MR spectroscopy ((1)H-MRS) to image localized prostate cancer and detect its aggressiveness, using qualitative and quantitative approaches., Methods: Twenty-one patients with untreated localized prostate cancer, diagnosed using transrectal ultrasound-guided biopsy, were prospectively enrolled. Cancer laterality was based on the percentage of cancer and the highest Gleason score determined from biopsies. In addition to PET/CT, 3-dimensional (1)H-MRS of the entire prostate volume using a quantitative approach was performed. The imaging and histologic findings of 8 patients undergoing subsequent prostatectomy were compared on a sextant level. For each lobe and sextant, standardized uptake values (SUVs) and (choline + creatine + polyamines)-to-citrate (CCP/C) ratios were obtained from (11)C-acetate PET/CT and (1)H-MRS, respectively. The visual and quantitative findings on PET/CT and MRI data were compared with cancer laterality and aggressiveness based on the Gleason score and with prostate-specific antigen (PSA) velocity and international risk group classification., Results: The sensitivity, specificity, and accuracy, on a lobar level using visual analysis, of (11)C-acetate PET/CT were 80%, 29%, 71%, respectively, and 89%, 29%, 79%, respectively, using contrast-enhanced MRI. The sensitivity and accuracy of (11)C-acetate PET/CT decreased to 64% and 63% and specificity increased to 62% when sextant analysis was performed. The agreement between prostate cancer laterality based on biopsy findings and visual interpretation of (11)C-acetate PET/CT and contrast-enhanced MRI was similar at 71%. The mean SUV maximum and CCP/C maximum for the dominant tumor lesion were 5.5 and 1.48, respectively, and did not differ significantly from values in the nondominant lobe. The dominant-lesion SUVs or CCP/C values were not associated with histologically determined prostate cancer aggressiveness, nor did PSA velocity correlate with the SUV or CCP/C values from the entire gland., Conclusion: (11)C-acetate PET/CT, MRI, and (1)H-MRS enable detection of localized prostate cancer with comparable and limited accuracy but fail to provide information on cancer aggressiveness.

Unlabelled: Vesicular monoamine transporter 2 (VMAT2) is a putative molecular target for the quantitative imaging of pancreatic beta-cell mass by PET. The VMAT2 PET tracer (11)C-dihydrotetrabenazine ((11)C-DTBZ) exhibits high pancreatic uptake that is reduced in type 1 diabetes. The aim of this study was to assess the islet and VMAT2 specificity of DTBZ binding in the pancreas., Methods: The biodistribution of (11)C-DTBZ in rats was determined 10 and 60 min after injection. The localization of DTBZ radioactivity in rat and human pancreatic tissue sections was investigated by autoradiography. Saturation and competition binding assays were performed with (3)H-DTBZ and sections of rat pancreatic and control tissues. The binding of (11)C-DTBZ in pancreatic sections from rats with streptozotocin-induced diabetes was compared with that in control rats., Results: The values for the pancreatic uptake of (11)C-DTBZ (percentage injected dose per gram of tissue) were 3.0 at 10 min and 2.7 at 60 min. At 10 min, pancreatic radioactivity was heterogeneously distributed, with higher levels toward the head of the pancreas (head-to-tail ratio, 1.7). No such gradient was observed in pancreatic sections incubated with (11)C-DTBZ and (3)H-DTBZ in vitro. In rats, (11)C-DTBZ and (3)H-DTBZ binding in pancreatic islets did not exceed binding in the exocrine pancreas. Saturable (3)H-DTBZ binding was observed in the rat brain striatum (dissociation constant [K(d)], 1.3 nM) and the bovine adrenal medulla (K(d), 3.3 nM), whereas in the rat pancreas, (3)H-DTBZ binding was nonsaturable. Competition binding with (3)H-DTBZ and VMAT2 antagonists also indicated that DTBZ binding in the rat pancreas was nonspecific and did not represent binding to VMAT2. Nonspecific pancreatic (11)C-DTBZ binding was lower in rats with streptozotocin-induced diabetes than in control rats. In sections of human pancreas, a subset of pancreatic islets were weakly but VMAT2-specifically labeled with (3)H-DTBZ., Conclusion: The results showed that the pancreatic uptake of (11)C-DTBZ is mainly due to nonspecific binding in the exocrine pancreas and suggested that the reduction in pancreatic (11)C-DTBZ binding observed in type 1 diabetes is not specific for the loss of beta-cell mass.

Purpose: The aim of this study was to evaluate the visual assessment of positron emission tomography images of N-[methyl-11C]2-(4'-methylaminophenyl)-6-hydroxybenzothiazole ([11C]PIB) in a patient population with mild to moderate memory impairment or dementia., Methods: We compared the visual ratings of two readers using kappa statistics and correlated the results of visual and quantitative region of interest (ROI) analyses. The one reader had good experience in evaluating PIB images and the other had little previous experience. The sensitivity and specificity of the visual assessment was determined using quantitative data from 18 healthy controls previously examined: [11C]PIB uptake was considered as abnormal if it was more than 2 SD above the mean of the healthy subjects., Results: The evaluation of visual classification as "normal" or "abnormal" showed good interobserver agreement (kappa = 0.90). There was a clear correlation between visual and quantitative analysis (r = 0.47-0.79, p < 0.001). The most difficult visually assessed brain area was the putamen (kappa = 0.11; correlation with quantitative analysis: reader A r = 0.22; reader B r = 0.60)., Conclusion: Our study shows that visual evaluation of [(11)C]PIB images conforms with quantitative analyses also in a clinical patient population supporting the feasibility of visual evaluation in clinical settings.

Purpose: To demonstrate the theoretical feasibility of [(11)C]acetate PET/CT in delineating the malignant intraprostatic lesions (IPL's) in prostate cancer and to use the data in external beam radiotherapy to boost the biologically defined target volume (BTV)., Methods and Materials: Twelve men with intracapsular prostate carcinoma were imaged with [(11)C]acetate PET/CT and the data were used to delineate the BTV. Six dynamic IMRT plans were generated to each patient: a standard IMRT (sIMRT) plan with a 77.9 Gy dose to PTV (prostate gland with a 6-mm margin) and a simultaneous integrated boost IMRT (SIB(IMRT)) plan to deliver 77.9 Gy, 81 Gy, 84 Gy, 87 Gy and 90 Gy to the BTV and 72 Gy to the rest of PTV. To study the theoretical dose escalation based on the delineation of BTV, tumor control probabilities (TCPs) and normal tissue complication probabilities (NTCPs) of bladder and rectum were calculated and compared between the treatment plans., Results: [(11)C]Acetate was used to delineate the IPL's of all 12 patients. With every patient the TCP was increased with SIB(IMRT) without increasing the NTCP of the bladder or rectum. The probability of uncomplicated control (PUC) was increased on average by 28% with the SIB(IMRT) treatment plans. The highest PUC was achieved with an average dose of 82.1 Gy to the BTV., Conclusions: Our study indicates that [(11)C]acetate can be used to define the IPL's and in combination with SIB(IMRT) the defined areas can theoretically be treated to ultra high doses without increasing the treatment toxicity. These results motivate the formal validation of [(11)C]acetate PET for biological dose planning in prostate cancer.