Striatal and extrastriatal microPET imaging of D2/D3 dopamine receptors in rat brain with [¹⁸F]fallypride and [¹⁸F]desmethoxyfallypride

In this study, we compared two different D_2/3 receptor ligands, [¹⁸F]fallypride and [¹⁸F]desmethoxyfallypride ([¹⁸F]DMFP) with respect to the duration of the scan, visualization of extrastriatal receptors, and binding potentials (BP_ND) in the rat brain. In addition, we studied the feasibility of using these tracers following a period of awake tracer uptake, during which the animal may perform a behavioral task. Male Sprague–Dawley rats were imaged with [¹⁸F]fallypride and with [¹⁸F]DMFP in four different studies using microPET. All scans were performed under isoflurane anesthesia. The first (test) and second (retest) study were 150‐min baseline scans. No retest scans were performed with [¹⁸F]DMFP. A third study was a 60‐min awake uptake of radiotracer followed by a 90‐min scan. A fourth study was a 150‐min competition scan with haloperidol (0.2 mg/kg) administered via tail vein at 90‐min post‐[¹⁸F]fallypride injection and 60‐min post‐[¹⁸F]DMFP. For the test–retest studies, BP_ND was measured using both Logan noninvasive (LNI) method and the interval ratios (ITR) method. Cerebellum was used as a reference region. For the third study, the binding was measured only with the ITR method, and the results were compared to the baseline results. Studies showed that the average transient equilibrium time in the dorsal striatum (DSTR) was at 90 min for [¹⁸F]fallypride and 30 min for [¹⁸F]DMFP. The average BP_ND for [¹⁸F]fallypride was 14.4 in DSTR, 6.8 in ventral striatum (VSTR), 1.3 in substantia nigra/ventral tegmental area (SN/VTA), 1.4 in colliculi (COL), and 1.5 in central gray area. In the case of [¹⁸F]DMFP, the average BP_ND values were 2.2 in DSTR, 2.7 in VSTR, and 0.8 in SN/VTA. The haloperidol blockade showed detectable decrease in binding of both tracers in striatal regions with a faster displacement of [¹⁸F]DMFP. No significant changes in BP_ND of [¹⁸F]fallypride due to the initial awake state of the animal were found, whereas BP_ND of [¹⁸F]DMFP was significantly higher in the awake state compared to baseline. We were able to demonstrate that dynamic PET using MicroPET Inveon allows quantification of both striatal and extrastriatal [¹⁸F]fallypride binding in rats in vivo. Quantification of the striatal regions could be achieved with [¹⁸F]DMFP. Synapse 2011. © 2011 Wiley‐Liss, Inc.     

Relationship of self‐transcendence traits with in vivo dopamine D2/3 receptor availability and functional connectivity: An [18F]fallypride PET and fMRI study

Genetic research has implicated dopamine neurotransmission in the expression of the self‐transcendence trait in humans. However, molecular imaging of dopaminergic markers is undocumented in relation to this personality trait. In this multimodal imaging study, we first investigated the relationship between the self‐transcendence trait and in vivo dopamine D_2/3 receptor availability using [¹⁸F]fallypride positron emission tomography (PET). We next conducted seed‐based functional connectivity analyses using resting‐state functional magnetic resonance imaging (rs‐fMRI) data with regions derived from the PET analysis as seeds to explore the functional significance of D_2/3 receptor availability foci associated with the self‐transcendence trait. Twenty‐one healthy subjects underwent high‐resolution PET with [¹⁸F]fallypride and a subset of 18 subjects also completed 3‐Tesla rs‐fMRI. The Temperament and Character Inventory was used to measure the self‐transcendence trait. A voxel‐based whole brain analysis revealed that the [¹⁸F]fallypride binding potential (BP_ND) within the cluster of the left insula was significantly positively correlated with self‐transcendence trait scores. A region‐of‐interest analysis also showed a significant positive correlation between self‐transcendence and [¹⁸F]fallypride BP_ND in the left insula. The exploratory [¹⁸F]fallypride BP_ND seed‐based rs‐fMRI analysis showed that the functional connectivity from the left insula seed to the prefrontal cortices (including the inferior frontal region) was negatively associated with self‐transcendence trait scores. The results of the present study suggest that D_2/3 receptor‐mediated neurotransmission in the left insula may constitute a significant neurobiological factor in the self‐transcendence trait. The negative associations between BP_ND seed‐based functional connectivity and self‐transcendence trait scores may suggest reduced prefrontal control in this personality trait.     

α2‐Adrenergic drugs modulate the binding of [18F]fallypride to dopamine D2/3 receptors in striatum of living mouse

Aim. To test for α₂ adrenergic modulation of dopamine D_2/3 receptor availability in striatum of living mice using the high‐affinity ligand [¹⁸F]fallypride and microPET. Methods. Groups of anesthetized mice were pretreated with saline, the α₂‐agonist clonidine (1 mg/kg), and the α₂‐antagonists RX821002 (1 mg/kg) and yohimbine (1 mg/kg). Dynamic microPET recordings lasting 120 min were then initiated upon i.v. tracer injection of [¹⁸F]fallypride. Parametric maps of [¹⁸F]fallypride binding potential (BP_ND) were calculated using the Logan method, with cerebellum serving as the reference region. Results. Mean striatal [¹⁸F]fallypride BP_ND was 10.6 ± 1.7 in the saline control animals, 8.9 ± 1.7 (?16%; P < 0.05) in the RX821002 group, 8.3 ± 2.6 (?22%; P < 0.05) in the yohimbine group and 10.3 ± 2.2 (n.s.) in the clonidine group. Conclusions. These findings are consistent with a tonic inhibition of dopamine release by α₂ adrenergic receptors, such that α₂ blockade increased the competition from endogenous dopamine at D_2/3 receptors, thus reducing the [¹⁸F]fallypride BP_ND by about 20%. Absent effects of clonidine suggest a ceiling effect in the tonic inhibition of dopamine release. This in vivo PET evidence for α₂/dopaminergic interaction may be relevant to putative actions of atypical antipsychotic medications via adrenergic receptors. Synapse, 2010. © 2010 Wiley‐Liss, Inc.     

The applicability of SRTM in [18F]fallypride PET investigations: impact of scan durations

The high-affinity radioligand [¹⁸F]fallypride (FP) is frequently used for quantification of striatal/extrastriatal D_2/3 receptors and the receptor occupancies of antipsychotics (APs). Its 110 minutes half-life allows long scan durations. However, the optimum scan duration is a matter of debate. This investigation focuses on scan-duration-related effects on simplified reference tissue model (SRTM) results and the time point of transient equilibrium in a large sample of dynamic FP positron emission tomography (PET) scans. Fifty drug-free and 50 AP-treated subjects underwent FP-PET scans (180 minutes scan duration). The binding potential (BP_ND) of the putamen, thalamus, and temporal cortex were calculated using the SRTM and the transient equilibrium model. Furthermore, receptor occupancies were calculated for AP-treated patients. Transient equilibrium in the unblocked putamen occurred after 121±29.6 minutes. The transient equilibrium occurred much earlier in the extrastriatal regions or under AP treatment. Stepwise scan shortening caused BP_ND underestimations of 0.58% for the first 10-minute reduction (putamen, SRTM), finally reaching 5.76% after 1 hour scan-time reduction. We observed preferential extrastriatal AP binding irrespective of the analytical method. [¹⁸F]fallypride scan durations of 180 minutes reliably reach equilibrium even in D_2/3-receptor-rich regions. Moderate reductions in FP scan durations only caused small changes to SRTM results even in receptor-rich regions. Apparently, the D_2/3 receptor occupancy results of APs, especially preferential extrastriatal binding observations, are not relevantly biased by inappropriate scan durations.     

Characterization of extrastriatal D2 in vivo specific binding of [¹⁸F](N-methyl)benperidol using PET

PET imaging studies of the role of the dopamine D2 receptor family in movement and neuropsychiatric disorders are limited by the use of radioligands that have near‐equal affinities for D2 and D3 receptor subtypes and are susceptible to competition with endogenous dopamine. By contrast, the radioligand [¹⁸F]N‐methylbenperidol ([¹⁸F]NMB) has high selectivity and affinity for the D2 receptor subtype (D2R) and is not sensitive to endogenous dopamine. Although [¹⁸F]NMB has high binding levels in striatum, its utility for measuring D2R in extrastriatal regions is unknown. A composite MR‐PET image was constructed across 14 healthy adult participants representing average NMB uptake 60 to 120 min after [¹⁸F]NMB injection. Regional peak radioactivity was identified using a peak‐finding algorithm. FreeSurfer and manual tracing identified a priori regions of interest (ROI) on each individual's MR image and tissue activity curves were extracted from coregistered PET images. [¹⁸F]NMB binding potentials (BP_NDs) were calculated using the Logan graphical method with cerebellum as reference region. In eight unique participants, extrastriatal BP_ND estimates were compared between Logan graphical methods and a three‐compartment kinetic tracer model. Radioactivity and BP_ND levels were highest in striatum, lower in extrastriatal subcortical regions, and lowest in cortical regions relative to cerebellum. Age negatively correlated with striatal BP_NDs. BP_ND estimates for extrastriatal ROIs were highly correlated across kinetic and graphical methods. Our findings indicate that PET with [¹⁸F]NMB measures specific binding in extrastriatal regions, making it a viable radioligand to study extrastriatal D2R levels in healthy and diseased states. Synapse 66:770–780, 2012. © 2012 Wiley Periodicals, Inc.     

Stress‐induced dopamine release in human medial prefrontal cortex—18F‐Fallypride/PET study in healthy volunteers

Background: In laboratory animals, environmental stressors markedly activate the mesocortical dopamine system. The present study tested whether this occurs in humans. Methods: The effects of a laboratory psychological stressor (Montreal Imaging Stress Task, MIST) on mesocortical dopamine release in healthy young adults (11 males, mean age ± SD, 20.6 ± 2.4 years) was measured using positron emission tomography and [¹⁸F]fallypride. Each subject was scanned in two separate days in counterbalanced order: one with the MIST and one with the control task. Binding potential (BP_ND) maps of the whole brain were calculated for each scan, using a simplified reference tissue compartmental model. Then BP_ND was compared between subjects. Heart rate, galvanic skin response, and salivary cortisol level were measured during the scans. Results: The psychological stressor significantly decreased [¹⁸F]fallypride binding values in the dorsal part of the medial prefrontal cortex (dmPFC), corresponding to the rostal part of the cingulate motor zone. The greater the stress‐induced decrease in [¹⁸F]fallypride binding in the dmPFC, the greater the stress‐induced increases in heart rate. Conclusions: The present study provides evidence of stress‐induced dopamine release in the mPFC in humans, in vivo. Synapse 67:821–830, 2013 . © 2013 Wiley Periodicals, Inc.     

Impact of isoflurane anesthesia on D2 receptor occupancy by [18F]fallypride measured by microPET with a modified Logan plot

In the previous work, we reported a method that utilized imaging data collected from 60 to 120 min following [¹⁸F]fallypride administration to estimate the distribution volume ratio DVR′ (DVR′ ∝ DVR; DVR = 1 + BP_ND, where BP_ND is a measure of receptor density, DA D2 in this case). In this work, we use this method to assess the effects of isoflurane anesthesia on [¹⁸F]fallypride DVR′. Methods: Rats were injected with [¹⁸F]fallypride either unconsciously under ～1.5% isoflurane via the tail vein (Group 1) or consciously via a catheter inserted either in the jugular vein (Group 2) or the tail vein (Group 3). After about 1 h of free access to food and water the rats were anesthetized with 1.5% isoflurane and imaged in a microPET for 60 min. The rats that were injected consciously (Groups 2 and 3) were placed in a rat restrainer during [¹⁸F]fallypride injection. They were habituated in that restrainer for 3 days prior to the experiment day to minimize restraint‐related stress. For comparison, a control group of rats was imaged for 120 min simultaneously with the administration of [¹⁸F]fallypride i.v. while under 1.5% isoflurane. The DVR′ estimates from the 60 min acquisitions were compared with the DVR′ from the last 60 min of the 120 min acquisitions (after neglecting the first 60 min). In addition, the striatal time–activity curves were fit with a 2‐tissue + plasma compartment model using an arbitrary simulated plasma input function to obtain k₃/k₄ (≈ BP_ND) for the 60 and 120 min acquisitions. Results: Isoflurane anesthesia caused a significant reduction, up to 22%, in the DVR′ estimates, which were 15.7 ± 0.3 (mean ± SE) for the controls, 17.7 ± 0.3 for Group 1, 19.2 ± 0.4 for Group 2, and 18.8 ± 0.7 for Group 3. The compartmental model fit produced similar results, ～30% reduction in k₃/k₄ for the 120‐min acquisitions compared with the 60‐min acquisitions (initial conscious uptake of the radiotracer). Conclusion: The results of this study demonstrate that isoflurane anesthesia significantly decreases striatal [¹⁸F]fallypride BP_ND in rats. Of similar importance, this work demonstrates the effectiveness of delayed scans following radiotracer injection and the implication that different types of studies can be conducted simultaneously with this method, including studies of behavioral and environmental impact on brain receptors. Synapse, 2011. © 2011 Wiley‐Liss, Inc.     

Positron emission tomography imaging of amphetamine‐induced dopamine release in the human cortex: A comparative evaluation of the high affinity dopamine D2/3 radiotracers [11C]FLB 457 and [11C]fallypride

The use of PET and SPECT endogenous competition binding techniques has contributed to the understanding of the role of dopamine in several neuropsychiatric disorders. An important limitation of these imaging studies is the fact that measurements of acute changes in synaptic dopamine have been restricted to the striatum. The ligands previously used, such as [¹¹C]raclopride and [¹²³I]IBZM, do not provide sufficient signal to noise ratio to quantify D₂ receptors in extrastriatal areas, such as cortex, where the concentration of D₂ receptors is much lower than in the striatum. Given the importance of cortical DA function in cognition, a method to measure cortical dopamine function in humans would be highly desirable. The goal of this study was to compare the ability of two high affinity DA D₂ radioligands [¹¹C]FLB 457 and [¹¹C]fallypride to measure amphetamine‐induced changes in DA transmission in the human cortex. D₂ receptor availability was measured in the cortical regions of interest with PET in 12 healthy volunteers under control and postamphetamine conditions (0.5 mg kg^?1, oral), using both [¹¹C]FLB 457 and [¹¹C]fallypride (four scans per subjects). Kinetic modeling with an arterial input function was used to derive the binding potential (BP_ND) in eight cortical regions. Under controlled conditions, [¹¹C]FLB 457 BP_ND was 30–70% higher compared with [¹¹C]fallypride BP_ND in cortical regions. Amphetamine induced DA release led to a significant decrease in [¹¹C]FLB 457 BP_ND in five out the eight cortical regions evaluated. In contrast, no significant decrease in [¹¹C]fallypride BP_ND was detected in cortex following amphetamine. The difference between [¹¹C]FLB 457 and [¹¹C]fallypride ability to detect changes in the cortical D₂ receptor availability following amphetamine is related to the higher signal to noise ratio provided by [¹¹C]FLB 457. These findings suggest that [¹¹C]FLB 457 is superior to [¹¹C]fallypride for measurement of changes in cortical synaptic dopamine. Synapse 63:447–461, 2009. © 2009 Wiley‐Liss, Inc.     

Endogenous competition against binding of [18F]DMFP and [18F]fallypride to dopamine D2/3 receptors in brain of living mouse

Aim . Molecular imaging studies with benzamide radioligands can reveal competition from endogenous binding at D_2/3‐receptors in living brain. However, single photon emission computed tomography (SPECT) methods suffer from limited spatial resolution, and [¹¹C]‐labeled ligands are only available at positron emission tomography (PET) research sites with cyclotron‐radiochemistry facilities, whereas [¹⁸F] can be transported, due to its longer physical half‐life. Therefore, we endeavored to characterize the vulnerabilities of the benzamide antagonist [¹⁸F]desmethoxyfallypride (DMFP) and its high‐affinity congener [¹⁸F]fallypride (FP) to competition from endogenous dopamine in living mouse brain. Methods . Groups of awake mice were pretreated with saline, amphetamine (10 mg/kg), or reserpine (5 mg/kg), followed by i.v. tracer injections. Mice were killed at 2.5–90 min (DMFP) or 2.5–180 min (FP) circulation times. Brains were dissected and regional radioactivity concentration measured by gamma counting. Other groups of mice were anesthetized for dynamic microPET recordings with DMFP or FP. Binding potentials (BP_ND) were calculated using cerebellum as reference region. Results . With 90‐min circulation, DMFP BP_ND in striatum was 2.4 by dissection and 2.2 by microPET, which showed a 62% decrease in response to amphetamine‐evoked dopamine release and a 33% increase after reserpine‐evoked dopamine depletion. With 120‐min circulation, FP BP_ND in striatum was 24.1 by dissection and 9.2 by microPET, which showed a 31% decrease in the amphetamine group, but no effect of reserpine. Dissection showed similar sensitivities for FP binding, but only a 29% amphetamine‐evoked reduction for DMFP. Conclusions . Relative to gold standard ex vivo results, microPET estimates of DMFP BP_ND were unbiased, whereas FP BP_ND in striatum was substantially underestimated. Both tracers proved suitable for revealing pharmacologically evoked changes in competition at D_2/3‐receptors in striatum of living mice. Synapse 64:313–322, 2010. © 2009 Wiley‐Liss, Inc.     

Translational possibility of [18F]Mefway to image serotonin 1A receptors in humans: Comparison with [18F]FCWAY in rodents

Purpose: To compare the cerebral uptake and binding potential of [¹⁸F]FCWAY and [¹⁸F]Mefway in the rodent to assess their potential for imaging serotonin 1A (5‐HT_1A) receptors. Materials and Methods: In vitro liver microsomal studies were performed to evaluate the degree of defluorination. Dynamic positron emission tomography (PET) studies were then conducted for 2 h with or without an anti‐defluorination agent. The regions of interest were the hippocampus and frontal cortex (5‐HT_1A target regions) and the cerebellum (5‐HT_1A nontarget region). The in vivo kinetics of the radioligands were compared based on the brain uptake values and target‐to‐nontarget ratio. We also performed a comparison of binding potential (BP_ND) as a steady‐state binding parameter. Finally, binding affinities to 5‐HT_1A receptors were assessed in Chinese hamster ovary cells (CHO‐K1) cells expressing human recombinant 5‐HT_1A receptors. Results: The radiochemical yield of [¹⁸F]Mefway was slightly higher than that of [¹⁸F]FCWAY (19 vs. 15%). With regard to metabolic stability against defluorination, both compounds exhibited similar stability in rat liver microsomes, but [¹⁸F]Mefway displayed higher stability in the human microsome (defluorination ratio at 30 min: 32 vs. 29 in rat liver microsomes, 31 vs. 64 in human liver microsomes for [¹⁸F]Mefway and [¹⁸F]FCWAY, respectively). There were no significant differences in brain uptake, the target‐to‐nontarget ratios, and the BP_ND (at hippocampus, peak brain uptakes: 6.9 vs. 8.5, target‐to‐nontarget ratios: 6.9 vs. 8.5, BP_ND: 5.2 vs. 6.2 for [¹⁸F]Mefway and [¹⁸F]FCWAY). The binding affinity of [¹⁸F]Mefway was considerably higher than that of [¹⁸F]FCWAY (IC₅₀ : 1.5 nM vs. 2.2 nM). Conclusion: [¹⁸F]Mefway exhibits favorable characteristics compared to [¹⁸F]FCWAY in rodents, and may be a promising radioligand for use in human subjects. Synapse 68:595–603, 2014 . © 2014 Wiley Periodicals, Inc.     

In vivo kinetics of [F-18]MEFWAY: a comparison with [C-11]WAY100635 and [F-18]MPPF in the nonhuman primate

[F‐18]Mefway was developed to provide an F‐18 labeled positron emission tomography (PET) neuroligand with high affinity for the serotonin 5‐HT_1A receptor to improve the in vivo assessment of the 5‐HT_1A system. The goal of this work was to compare the in vivo kinetics of [F‐18]mefway, [F‐18]MPPF, and [C‐11]WAY100635 in the rhesus monkey. Methods: Each of four monkeys were given bolus injections of [F‐18]mefway, [C‐11]WAY100635, and [F‐18]MPPF and scans were acquired with a microPET P4 scanner. Arterial blood was sampled to assay parent compound throughout the time course of the PET experiment. Time activity curves were extracted in the high 5‐HT_1A binding areas of the anterior cingulate cortex (ACG), mesial temporal cortex, raphe nuclei, and insula cortex. Time activity curves were also extracted in the cerebellum, which was used as a reference region. The in vivo kinetics of the radiotracers were compared based on the nondisplaceable distribution volume (V_ND) and binding potential (BP_ND). Results: At 30 min, the fraction of radioactivity in the plasma due to parent compound was 19%, 28%, and 29% and cleared from the arterial plasma at rates of 0.0031, 0.0078, and 0.0069 (min^?1) ([F‐18]mefway, [F‐18]MPPF, [C‐11]WAY100635). The BP_ND in the brain regions were mesial temporal cortex: 7.4 ± 0.6, 3.1 ± 0.4, 7.0 ± 1.2, ACG: 7.2 ± 1.2, 2.1 ± 0.2, 7.9 ± 1.2; raphe nuclei: 3.7 ± 0.6, 1.3 ± 0.3, 3.3 ± 0.7; and insula cortex: 4.2 ± 0.6, 1.2 ± 0.1, 4.7 ± 1.0 for [F‐18]mefway, [F‐18]MPPF, and [C‐11]WAY100635 respectively. Conclusions: In the rhesus monkey, [F‐18]mefway has similar in vivo kinetics to [C‐11]WAY100635 and yields greater than 2‐fold higher BP_ND than [F‐18]MPPF. These properties make [F‐18]mefway a promising radiotracer for 5‐HT_1A assay, providing higher counting statistics and a greater dynamic range in BP_ND. Synapse, 2011. © 2010 Wiley‐Liss, Inc.     

Interaction between serotonin transporter and dopamine D2/D3 receptor radioligand measures is associated with harm avoidant symptoms in anorexia and bulimia nervosa

Individuals with anorexia nervosa (AN) and bulimia nervosa (BN) have alterations of measures of serotonin (5-HT) and dopamine (DA) function, which persist after long-term recovery and are associated with elevated harm avoidance (HA), a measure of anxiety and behavioral inhibition. Based on theories that 5-HT is an aversive motivational system that may oppose a DA-related appetitive system, we explored interactions of positron emission tomography (PET) radioligand measures that reflect portions of these systems. Twenty-seven individuals recovered (REC) from eating disorders (EDs) (7 AN–BN, 11 AN, 9 BN) and nine control women (CW) were analyzed for correlations between [¹¹C]McN5652 and [¹¹C]raclopride binding. There was a significant positive correlation between [¹¹C]McN5652 binding potential (BP_{non displaceable(ND)}) and [¹¹C]Raclopride BP_ND for the dorsal caudate, antero-ventral striatum (AVS), middle caudate, and ventral and dorsal putamen. No significant correlations were found in CW. [¹¹C]Raclopride BP_ND, but not [¹¹C]McN5652 BP_ND, was significantly related to HA in REC EDs. A linear regression analysis showed that the interaction between [¹¹C]McN5652 BP_ND and [¹¹C]raclopride BP_ND in the dorsal putamen significantly predicted HA. This is the first study using PET and the radioligands [¹¹C]McN5652 and [¹¹C]raclopride to show a direct relationship between 5-HT transporter and striatal DA D2/D3 receptor binding in humans, supporting the possibility that 5-HT and DA interactions contribute to HA behaviors in EDs.     

Wide impairment of cerebral serotoninergic activity but inter-individual heterogeneity in bulimia nervosa patients: a pilot [18F]MPPF/PET study

Objectives. Bulimia nervosa (BN) is associated with abnormalities of serotoninergic system. Functional or ligand specific brain imaging studies revealed abnormalities in non-overlapping regions. [¹⁸F]MPPF (4-(2-methoxyphenyl)-1-[2-(N-2-pyridinyl)-p-fluorobenzamido]-ethylpiperazine) is a selective 5-HT_1A receptor antagonist with a serotonin-like affinity, capable to assess changes of brain serotoninergic activity in BN patients. Methods. [¹⁸F]MPPF cerebral binding potential (BP_ND) was measured by positron emission tomography scan in nine purging-type BN patients and eleven age-matched controls. Voxel-based statistical parametric mapping (SPM) analyses were performed to assess BP_ND differences between the two groups and between each BN patient and controls group. Results. Mean [¹⁸F]MPPF BP_ND was overall increased in BN patients. SPM analysis with revealed symmetrical large clusters of increased [¹⁸F]MPPF binding in insula, temporo-parietal cortex, prefrontal cortex, in limbic, paralimbic cortex and raphe nuclei. SPM individual analysis indicated significant heterogeneity of [¹⁸F]MPPF mapping within BN group, including cases with isolated up to widespread increased binding. [¹⁸F]MPPF BP_ND did not covariate with depression or eating behaviour-related scores. Conclusions. Large clusters of increased [¹⁸F]MPPF binding in severe BN overlap previous results, separately described within fMRI or PET studies. The relationship between the inter-individual [¹⁸F]MPPF binding heterogeneity and serotoninergic modulators efficacy in these patients remains to be assessed.     

Cocaine cue–induced dopamine release in the human prefrontal cortex

BackgroundAccumulating evidence indicates that drug-related cues can induce dopamine (DA) release in the striatum of substance abusers. Whether these same cues provoke DA release in the human prefrontal cortex remains unknown.MethodsWe used high-resolution positron emission tomography with [¹⁸F]fallypride to measure cortical and striatal DA D2/3 receptor availability in the presence versus absence of drug-related cues in volunteers with current cocaine dependence.ResultsTwelve individuals participated in our study. Among participants reporting a craving response (9 of 12), exposure to the cocaine cues significantly decreased [¹⁸F]fallypride binding potential (BP_ND) values in the medial orbitofrontal cortex and striatum. In all 12 participants, individual differences in the magnitude of craving correlated with BP_ND changes in the medial orbitofrontal cortex, dorsolateral prefrontal cortex, anterior cingulate, and striatum. Consistent with the presence of autoreceptors on mesostriatal but not mesocortical DA cell bodies, midbrain BP_ND values were significantly correlated with changes in BP_ND within the striatum but not the cortex. The lower the midbrain D2 receptor levels, the greater the striatal change in BP_ND and self-reported craving.LimitationsLimitations of this study include its modest sample size, with only 2 female participants. Newer tracers might have greater sensitivity to cortical DA release.ConclusionIn people with cocaine use disorders, the presentation of drug-related cues induces DA release within cortical and striatal regions. Both effects are associated with craving, but only the latter is regulated by midbrain autoreceptors. Together, the results suggest that cortical and subcortical DA responses might both influence drug-focused incentive motivational states, but with separate regulatory mechanisms.     

Compensation for cranial spill-in into the cerebellum improves quantitation of striatal dopamine D₂/₃ receptors in rats with prolonged [¹⁸F]-DMFP infusions

The condition of steady‐state receptor binding in positron emission tomography (PET) studies is best obtained through the use of a bolus plus steady‐infusion paradigm. This is a particularly important consideration in the context of in vivo competition studies, where a pharmacological challenge can be administered during the interval of steady‐state ligand binding, as in the case of [¹¹C]‐raclopride studies with amphetamine challenge. However, the short half‐life of ¹¹C imposes limits on the practical duration of constant infusions. Therefore, we chose to test [¹⁸F]‐DMFP as a tracer for dopamine D_2/3 receptors in rat striatum in the paradigm. Using a conventional bolus injection, the [¹⁸F]‐DMFP BP_ND was 3.8 in striatum of anesthetized rats. When followed by a constant infusion, we obtained quasi‐stable BP_ND estimates of 4.5 within an interval of 45 min. During infusions lasting up to 4 h, BP_ND declined progressively. This seemed due to the progressive spill‐in of radioactivity from the cranium to the cerebellum reference region, despite optimized iterative reconstruction of the images. Therefore, we propose a new concept of compensation for this spill‐in effect using pharmacokinetic considerations, without requiring high‐resolution anatomical images. Challenge with amphetamine (1 and 4 mg/kg) evoked an ～25% reduction in BP_ND. There was no clear evidence of dose‐dependence in the striatal‐binding changes, despite the considerably greater physiological effect, as documented by ECG. Thus, the general applicability of the bolus plus infusion method with [¹⁸F]‐DMFP for small animal studies is impeded by the substantial labeling of the cranium. The cranial uptake was linear, indicating first‐order kinetics for the enzymatic defluorination of the tracer. Based on this phenomenon, we developed an analytic method compensating for the effects of progressive cranial labeling on the estimation of specific binding in striatum. Synapse, 2012. © 2012 Wiley Periodicals, Inc.     

A graphical method to compare the in vivo binding potential of PET radioligands in the absence of a reference region: application to [11C]PBR28 and [18F]PBR111 for TSPO imaging

Positron emission tomography (PET) radioligands for a reversible central nervous system (CNS) demand a high specific to nonspecific signal characterized by the binding potential (BP_ND). The quantification of BP_ND requires the determination of the nondisplaceable binding usually derived from a reference region devoid of the target of interest. However, for many CNS targets, there is no valid reference region available. In such cases, the total volume of distribution (V_T) is often used as the outcome measure, which includes both the specific and nonspecific binding signals. Here we present a graphical method that allows for direct comparison of the binding potential of ligands using the regional V_T data alone via linear regression. The method was first validated using literature data for five serotonin transporter ligands, for which a reference region exists, and then applied to two second generation 18 kDa translocator protein radioligands, namely [¹¹C]PBR28 and [¹⁸F]PBR111. The analysis determined that [¹¹C]PBR28 had a higher BP_ND than [¹⁸F]PBR111.     

Comparing α7 nicotinic acetylcholine receptor binding,amyloid‐β deposition,and mitochondria complex‐I function in living brain: A PET study in aged monkeys

This study was aimed to assess the correlations among α7 nicotinic acetylcholine receptor (α7‐nAChR) binding, amyloid‐β (Aβ) deposition, and mitochondrial complex I (MC‐I) activity in the brain of aged monkeys (Macaca mulatta). Positron emission tomography (PET) measurements with [¹¹C](R)‐MeQAA, [¹¹C]PIB, and [¹⁸F]BCPP‐EF were conducted in monkeys in a conscious condition. [¹¹C](R)‐MeQAA binding was analyzed by a simplified reference tissue model to calculate nondisplaceable binding potential (BP_ND), [¹¹C]PIB uptake was calculated by standard uptake value ratio (SUVR), and [¹⁸F]BCPP‐EF binding was determined by Logan graphical analysis to calculate total distribution volume (V_T) with arterial blood sampling. Higher brain uptake was determined in the thalamus, hippocampus, striatum, and cortical regions for [¹¹C](R)‐MeQAA, while being lower in the cerebellum. Significant age‐related reduction of [¹¹C](R)‐MeQAA binding to α7‐nAChR was determined only in the occipital cortex. The plot of Vt of [¹⁸F]BCPP‐EF against BP_ND of [¹¹C](R)‐MeQAA indicated a significant negative correlation in the hippocampus and cortical regions in aged animals. Plotting of SUVR of [¹¹C]PIB against BP_ND of [¹¹C](R)‐MeQAA showed a positive correlation. The in vivo binding of [¹¹C](R)‐MeQAA could reflect the upregulation of α7‐nAChR induced by neurodegenerative damage determined by Aβ deposition as well as impaired MC‐I activity in living brain. Synapse 69:475–483, 2015. © 2015 Wiley Periodicals, Inc.     

A comparison of D2 receptor specific binding in obese and normal‐weight individuals using PET with (N‐[11C]methyl)benperidol

Previous PET imaging studies have demonstrated mixed findings regarding dopamine D2/D3 receptor availability in obese relative to nonobese humans. Nonspecific D2/D3 radioligands do not allow for separate estimation of D2 receptor (D2R) and D3 receptor (D3R) subtypes of the D2 receptor family, which may play different roles in behavior and are distributed differently throughout the brain. These radioligands are also displaceable by endogenous dopamine, confounding interpretation of differences in receptor availability with differing levels of dopamine release. The present study used PET imaging with the D2R‐selective radioligand (N‐[¹¹C] methyl)benperidol ([¹¹C]NMB), which is nondisplaceable by endogenous dopamine, to estimate D2R specific binding (BP_ND) and its relationship to body mass index (BMI) and age in 15 normal‐weight (mean BMI = 22.6 kg/m²) and 15 obese (mean BMI = 40.3 kg/m²) men and women. Subjects with illnesses or taking medications that interfere with dopamine signaling were excluded. Striatal D2R BP_ND was calculated using the Logan graphical method with cerebellum as a reference region. D2R BP_ND estimates were higher in putamen and caudate relative to nucleus accumbens, but did not differ between normal‐weight and obese groups. BMI values did not correlate with D2R BP_ND. Age was negatively correlated with putamen D2R BP_ND in both groups. These results suggest that altered D2R specific binding is not involved in the pathogenesis of obesity per se and underscore the need for additional studies evaluating the relationship between D3R, dopamine reuptake, or endogenous dopamine release and human obesity. Synapse 67:748–756, 2013. . © 2013 Wiley Periodicals, Inc.     

In vitro autoradiography and in vivo evaluation in cynomolgus monkey of [18F]FE‐PE2I,a new dopamine transporter PET radioligand

This study evaluated the in vitro and in vivo characteristics of a new dopamine transporter (DAT) radioligand, [¹⁸F]fluoroethyl(FE)PE2I, by autoradiography from postmortem human brain and by positron emission tomography (PET) in three cynomolgus monkeys. In the autoradiography experiments, high [¹⁸F]FE‐PE2I accumulation was observed in caudate and putamen that was selectively abolished by GBR12909 or β‐CIT but not by maprotiline. High doses of citalopram (>5 μM) also inhibited [¹⁸F]FE‐PE2I binding in the striatum. In vitro K_i of the radioligand was 12 nM at rodent dopamine transporter. [¹⁸F]FE‐PE2I brain uptake measured by PET was ～4–5% of the injected dose, with highest uptake in striatum followed by midbrain and thalamus, lower uptake in neocortex, and lowest in cerebellum. Peak specific binding in striatum was reached ～40 min and in midbrain 20–30 min postinjection. The ratio‐to‐cerebellum was 7–10 in striatum and 1.5–2.3 in midbrain. BP_ND measured with simplified reference tissue method using the cerebellum as reference region was 4.5 in striatum and 0.6 in midbrain. No displacement was shown after citalopram or maprotiline administration, while GBR12909 decreased the binding in striatum and midbrain to the level of cerebellum. [¹⁸F]FE‐PE2I showed relatively fast elimination and metabolism with the presence of two metabolite peaks with similar retention time as the labeled metabolites of [¹¹C]PE2I. [¹⁸F]FE‐PE2I showed in vivo selectivity for the DAT and compared with [¹¹C]PE2I, it showed faster kinetics and earlier peak equilibrium. The potential influence of the two radiometabolites on PET quantification requires further evaluation. Synapse 63:871–880, 2009. © 2009 Wiley‐Liss, Inc.     

Evaluation in monkey of two candidate PET radioligands, [11C]RX‐1 and [18F]RX‐2, for imaging brain 5‐HT4 receptors

The serotonin subtype‐4 (5‐HT₄) receptor, which is known to be involved physiologically in learning and memory, and pathologically in Alzheimer's disease, anxiety, and other neuropsychiatric disorders—has few radioligands readily available for imaging in vivo. We have previously reported two novel 5‐HT₄ receptor radioligands, namely [methoxy‐¹¹C](1‐butylpiperidin‐4‐yl)methyl 4‐amino‐3‐methoxybenzoate; [¹¹C]RX‐1), and the [¹⁸F]3‐fluoromethoxy analog ([¹⁸F]RX‐2), and in this study we evaluated them by PET in rhesus monkey. Brain scans were performed at baseline, receptor preblock or displacement conditions using SB 207710, a 5‐HT₄ receptor antagonist, on the same day for [¹¹C]RX‐1 and on different days for [¹⁸F]RX‐2. Specific‐to‐nondisplaceable ratio (BP_ND) was measured with the simplified reference tissue model from all baseline scans. To determine specific binding, total distribution volume (V_T) was also measured in some monkeys by radiometabolite‐corrected arterial input function after ex vivo inhibition of esterases from baseline and blocked scans. Both radioligands showed moderate to high peak brain uptake of radioactivity (2–6 SUV). Regional BP_ND values were in the rank order of known 5‐HT₄ receptor distribution with a trend for higher BP_ND values from [¹⁸F]RX‐2. One‐tissue compartmental model provided good fits with well identified V_T values for both radioligands. In the highest 5‐HT₄ receptor density region, striatum, 50–60% of total binding was specific. The V_T in receptor‐poor cerebellum reached stable values by about 60 min for both radioligands indicating little influence of radiometabolites on brain signal. In conclusion, both [¹¹C]RX‐1 and [¹⁸F]RX‐2 showed positive attributes for PET imaging of brain 5‐HT₄ receptors, validating the radioligand design strategy. Synapse 68:613–623, 2014 . © 2014 Wiley Periodicals, Inc.