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Computed tomography angiography (CTA), magnetic resonance angiography (MRA) and 18F-FDG-PET have proven clinical value when evaluating patients with carotid atherosclerosis. In this systematic review, we will focus on the role of novel molecular imaging tracers in that assessment and their potential strengths to stratify stroke risk. We systematically searched PubMed, Embase, the Web of Science Core Collection, and Cochrane Library for articles reporting on molecular imaging to noninvasively detect or characterize inflammation in carotid atherosclerosis. As our focus was on nonclassical novel targets, we omitted reports solely on 18F-FDG and 18F-NaF. We summarized and mapped the selected studies to provide an overview of the current clinical development in molecular imaging in relation to risk factors, imaging and histological findings, diagnostic and prognostic performance. We identified 20 articles in which the utilized tracers to visualize carotid wall inflammation were somatostatin subtype-2- (SST2-) (n = 5), CXC-motif chemokine receptor 4- (CXCR4-) (n = 3), translocator protein- (TSPO-) (n = 2) and aVβ3 integrin-ligands (n = 2) and choline-tracers (n = 2). Tracer uptake correlated with traditional cardiovascular risk factors, that is, age, gender, diabetes, hypercholesterolemia, and hypertension as well as prior cardiovascular disease. We identified discrepancies between tracer uptake and grade of stenosis, plaque calcification, and 18F-FDG uptake, suggesting the importance of alternative characterization of atherosclerosis beyond classical neuroimaging features. Immunohistochemical analysis linked tracer uptake to markers of macrophage infiltration and neovascularization. Symptomatic carotid arteries showed higher uptake compared to asymptomatic (including contralateral, nonculprit) arteries. Some studies demonstrated a potential role of these novel molecular imaging as a specific intermediary (bio)marker for outcome. Several novel tracers show promise for identification of high-risk plaque inflammation. Based on the current evidence we cautiously propose the SST2-ligands and the choline radiotracers as viable candidates for larger prospective longitudinal outcome studies to evaluate their predictive use in clinical practice. [ABSTRACT FROM AUTHOR]

• PMR was observed in 45% of GCA patients. • These patients had a longer symptom duration before diagnosis and less pronounced inflammatory response. • GCA patients with PMR symptoms had more persistent disease with a higher risk of relapse and longer duration of GC treatment, requiring higher GC doses during follow-up. • GCA patients with PMR symptoms had a lower risk of developing thoracic aortic aneurysms during follow-up. To evaluate differences in presentation and outcome of giant cell arteritis (GCA) patients with and without polymyalgia rheumatica (PMR) symptoms. Consecutive patients diagnosed with GCA between 2000 and 2020 and followed for ≥12 months at the University Hospitals Leuven (Belgium), were included retrospectively. We included 398 GCA patients, of which 181 (45%) with PMR symptoms. Patients with PMR symptoms had a longer symptom duration (11 vs 6 weeks, p < 0.001). They less frequently reported fever (19% vs 28%, p = 0.030) and fatigue (52% vs 64%, p = 0.015) and tended to have less permanent vision loss (12% vs 19%, p = 0.052). There was no difference in the cumulative oral GC dose at 2 years (4.4 vs 4.3 g methylprednisolone, p = 0.571). However, those with PMR symptoms were treated with higher GC doses during subsequent follow-up (p < 0.05 from 38 months after diagnosis) and had a lower probability of stopping GC (62% vs 71%, HR 0.74 [95%CI 0.58–0.94], p = 0.018) with a longer median duration of GC treatment (29 vs 23 months, p = 0.021). In addition, presence of PMR symptoms was associated with an increased risk of relapse (64% vs 51%, HR 1.38 [95%CI 1.06–1.79], p = 0.017) with a higher number of relapses (1.47 [95%CI 1.30–1.65] vs 1.16 relapses [95%CI 1.02–1.31], p = 0.007). Patients with PMR symptoms less frequently developed thoracic aortic aneurysms during follow-up (3% vs 11%, p = 0.005). GCA patients with PMR symptoms had more recalcitrant disease with a higher risk of relapse and longer duration of GC treatment with need for higher GC doses. [ABSTRACT FROM AUTHOR]

Several lines of evidence point to alterations in glutamatergic signaling in Parkinson's disease (PD) and levodopa-induced dyskinesia (LID), involving the metabotropic glutamate receptor type 5 (mGluR5). Using small-animal positron emission tomography (PET) with [ 18 F]FPEB and proton magnetic resonance spectroscopy, we investigated cerebral changes in the mGluR5 and glutamate/glutamine availability in vivo in PD rats and following onset of LIDs. In parallel, behavioral tests were performed. Comparing PD to control rats, mGluR5 binding potential was decreased in a cluster comprising the bilateral caudate-putamen (CP), ipsilateral motor cortex and somatosensory cortex, and the contralateral somatosensory cortex and parietal association cortex, with the most pronounced reduction in the ipsilateral CP. mGluR5 binding potentials were not significantly altered upon levodopa (L-DOPA) treatment. However, following L-DOPA, an increase in relative mGluR5 uptake was present in the contralateral motor cortex and somatosensory cortex. Glutamate and glutamine concentrations did not differ between control and untreated PD rats or between hemispheres. Though, glutamine levels were higher in the contralateral CP of saline- and L-DOPA-treated rats as compared to the ipsilateral side. Relative mGluR5 uptake in the CP of levodopa-treated rats was also found positively correlated with abnormal involuntary movement scores. Conclusively, mGluR5 availability and glutamine concentrations in the CP are involved in PD, whereas mGluR5 availability in cortical regions may be involved in LID pathology. [ABSTRACT FROM AUTHOR]

Background & Aims: Differences in brain activity between health and functional dyspepsia (FD) have been reported; it is unclear whether this is influenced by gastric hypersensitivity or abuse history. Therefore, we aimed to determine the influence of gastric sensitivity and abuse history on gastric sensation scores and brain activity in homeostatic-afferent, emotional-arousal, and cortical-modulatory brain regions in FD. Methods: Abuse history was assessed using a validated self-report questionnaire. H2 15O positron emission tomography was performed in 25 FD patients (13 hypersensitive and 8 abused) during 3 conditions, that is, no distension, gastric distension at discomfort threshold, and sham distension. Data were analyzed in SPM2. Region of interest analysis was used to confirm differences in prehypothesized regions. Results: No association between hypersensitivity and abuse history was found. Gastric hypersensitivity was associated with significantly higher gastric sensation scores during baseline and sham. A condition-independent difference in ventral posterior cingulate activity was found between groups, as well as distension and sham-specific differences in brainstem and cingulate areas. Abuse history was associated with higher gastric sensation scores in all conditions and with differences in insular, prefrontal, and hippocampus/amygdala activity. Conclusions: Gastric sensitivity and abuse history independently influence gastric sensation as well as brain activity in FD. [Copyright &y& Elsevier]

Summary: Purpose: To unravel the mechanism of action of neurostimulation as a treatment for seizures, functional neuroimaging tools allow minimally invasive research in humans. We performed single-photon emission computed tomography (SPECT) in patients with epilepsy, treated with vagus nerve stimulation (VNS). Changes in regional cerebral blood flow (rCBF) at the time of initial stimulation as well as after chronic treatment were correlated with long-term clinical efficacy. Methods: In this pilot study, 27 patients (14 female and 13 male) who were treated with VNS at Ghent University Hospital for refractory epilepsy underwent a 99mTc-ECD (ethyl cystein dimer) SPECT activation study at the time the first stimulation train was administered. 12 patients underwent an additional 99mTc-ECD SPECT activation study 6 months later. Image acquisition was performed on a high-resolution triple-headed gamma camera. Significant rCBF changes were correlated with prospectively assessed clinical efficacy data. Results: Significant rCBF changes were found in the thalamus, the hippocampus and the parahippocampal gyrus. Acute limbic hyper-perfusion and chronic thalamic hypo-perfusion correlate with positive clinical efficacy. Conclusions: Acute and chronic electrical stimulation of the vagus nerve induces rCBF changes that can be measured by SPECT on a group-basis. The thalamus and the limbic system are thought to play a key role in the mechanism of action of VNS. [Copyright &y& Elsevier]

Background: A novel, high-affinity (.7–2.0 nmol) compound that selectively activates the α2, α3, and α5 (but not α1) γ-aminobutyric acid–A (GABAA) receptor subtypes, TPA023B (2′,6-difluoro-5′-[3-(1-hydroxy-1-methylethyl) imidazo[1,2-b][1,2,4]triazin-7-yl][1,1′-biphenyl]-2-carbonitrile) was pharmacologically characterized and studied by means of positron emission tomography (PET) to determine dynamic occupancies of the benzodiazepine binding site of human brain GABAA receptors after a single oral dose. Methods: Four healthy male volunteers were studied in a double-blind, randomized placebo-controlled study of which three were given a single dose of 1.5 mg TPA023B and the fourth received placebo. The time course of GABAA receptor occupancy was determined with multiple dynamic [11C]flumazenil PET studies at pre-dose baseline and 5 and 24 hours after dose. Arterial sampling and full kinetic modeling with a two-compartment model was used to calculate parametric maps of receptor availability (distribution volume VT) and of occupancy. Results: The GABAA receptor occupancy as determined from [11C]flumazenil VT values in all brain regions was reduced homogeneously, on average by 52.5 ± 1.2% after 5 hours and 46.4 ± 6.0% after 24 hours. No serious adverse events were encountered in humans. Conclusions: Single oral doses of 1.5 mg of TPA023B correspond to average receptor occupancies in neocortical regions of 52% and 46% after 5 and 24 hours, respectively. Provided suitable ligands and quantification methods are available for the appropriate target, quantitative PET offers a unique tool for dynamic in vivo measurement of relevant on-site receptor occupancy. [Copyright &y& Elsevier]

Epilepsy is a common chronic neurological disorder that is controlled with medication in approximately 70% of cases. When partial seizures are recurrent despite the use of antiepileptic drugs, resection of the epileptogenic cortex may be considered. Nuclear medicine plays an important role in the presurgical assessment of patients with refractory epilepsy. Single-photon emission computed tomography (SPECT) and positron emission tomography (PET) techniques are used to determine the seizure onset zone, which needs to be resected to render a patient seizure free. Correct localization of the ictal onset zone with the use of SPECT or PET is associated with a better surgical outcome. Ictal perfusion SPECT imaging with 99mTc-ethyl cysteinate dimer (ECD) or 99mTc-hexamethylpropyleneamine oxime (HMPAO) enables one to detect the seizure onset zone in a majority of cases, especially in patients with temporal lobe epilepsy. Interictal SPECT imaging, which is more widely available, is unreliable to determine the ictal onset zone and is usually only used for comparison with ictal SPECT images. Assessment of the ictal onset zone using subtracted ictal and interictal studies, overlayed on structural imaging has proven to be more sensitive and more specific compared with visual assessment. Video-electroencephalography monitoring in combination with ictal SPECT imaging, however, is only available in specialized centers. It is important to inject the perfusion tracer as early as possible after the beginning of a seizure and to be aware of patterns of seizure propagation. Interictal 18F-fluorodeoxyglucose (FDG)-PET is routinely used to detect brain areas of hypometabolism, which usually encompass, but tend to be larger than, the seizure onset zone. Also, for assessment of FDG-PET, it is advisable to use an automated technique comparing the patient''s images to a normal database in addition to visual interpretation of the images, since automated techniques have proven to be more accurate. In view of the thickness of the cortical ribbon, which may be below the resolution of the PET camera, posthoc partial volume correction or PET reconstruction incorporating the anatomical information of magnetic resonance imaging (MRI), may be useful for optimal assessment of glucose metabolism. Perfusion SPECT and interictal FDG-PET are able to demonstrate areas of abnormal perfusion and metabolism at a distance from the ictal onset zone, which may be associated with cognitive and psychiatric comorbidities, and may represent the functional deficit zone in epilepsy. Part of the functional deficit zone is a dynamic seizure-related process, which may resolve with cessation of seizures. In recent years, novel PET tracers have been developed to visualize not only glucose metabolism but also a wide variety of specific receptor systems. In patients with epilepsy, changes in the γ-amino-butyric acidA receptor, opioid receptor, 5-HT1A serotonin receptor, nicotinic acetylcholine receptor systems, and others have been described. Because these tracers are not widely available and the superiority of studying these receptor systems over glucose metabolism in the presurgical evaluation of patients with refractory epilepsy remains to be proven, their use in clinical practice is limited at the moment. Finally, advances in small animal PET scanning allow the in vivo study of the process of epileptogenesis, starting from an initial brain insult to the development of seizures, in animal models of epilepsy. Potential new therapeutic targets may be discovered using this translational approach. [Copyright &y& Elsevier]

Summary: Cannabinoid 1 receptor (CB1R) inverse agonists are emerging as a potential obesity therapy. However, the physiological mechanisms by which these agents modulate human energy balance are incompletely elucidated. Here, we describe a comprehensive clinical research study of taranabant, a structurally novel acyclic CB1R inverse agonist. Positron emission tomography imaging using the selective CB1R tracer [18F]MK-9470 confirmed central nervous system receptor occupancy levels (∼10%–40%) associated with energy balance/weight-loss effects in animals. In a 12-week weight-loss study, taranabant induced statistically significant weight loss compared to placebo in obese subjects over the entire range of evaluated doses (0.5, 2, 4, and 6 mg once per day) (p < 0.001). Taranabant treatment was associated with dose-related increased incidence of clinical adverse events, including mild to moderate gastrointestinal and psychiatric effects. Mechanism-of-action studies suggest that engagement of the CB1R by taranabant leads to weight loss by reducing food intake and increasing energy expenditure and fat oxidation. [Copyright &y& Elsevier]

Abstract: The type 1 cannabinoid receptor (CB1) is a crucial modulator of synaptic transmission in brain and has been proposed as a potential therapeutic target in Parkinson''s disease (PD), especially for treatment of levodopa-induced dyskinesias (LID). Our aim was to measure CB1 levels in brains of PD patients in vivo and to investigate the relation between CB1 availability and LID. We studied 12 healthy controls and 29 PD patients (9 drug-naïve patients with early PD, 10 patients with advanced PD and LID, and 10 patients with advanced PD without LID). PD patients were examined using the Unified Parkinson''s Disease Rating Scale (UPDRS) and the modified Abnormal Involuntary Movement Scale (mAIMS). All subjects underwent positron emission tomography (PET) with the CB1-selective radioligand [18F] MK-9470 and magnetic resonance imaging (MRI). PD patients showed an absolute decrease in CB1 availability in the substantia nigra. By contrast, CB1 availability was relatively increased in nigrostriatal, mesolimbic, and mesocortical dopaminergic projection areas. CB1 availability did not differ significantly between advanced PD patients with and without LID. Within the group of PD patients with LID, there was no significant correlation between CB1 availability and LID severity. These data demonstrate regional changes in CB1 availability in PD in vivo, but do not support a role for dysregulation of CB1 levels in the pathogenesis of LID. [Copyright &y& Elsevier]

Abstract: Background: Chronic neuropathic pain after injury to a peripheral nerve is known to be resistant to treatment. Peripheral nerve stimulation is one of the possible treatment options, which is, however, not performed frequently. In recent years we have witnessed a renewed interest for PNS. The aim of the present study was to evaluate the long-term clinical efficacy of PNS in a group of patients with peripheral neuropathic pain treated with PNS since the 1980s. Methods: Of an original series of 11 patients, 5 patients could be invited for clinical examination, detailed assessment of clinical pain and QST examination. The assessments were done both during habitual use of PNS and with the stimulator off. Results: Average pain intensity and pain unpleasantness ratings as assessed with visual analog and verbal rating scales showed significant beneficial effects of PNS. Quality of life measures (sleep and daily functioning) also showed positive effects. Quantitative Sensory Testing results did not show significant differences in cold pain and heat pain thresholds between the “ON” and “OFF” conditions. Conclusion: In selected patients with peripheral neuropathic pain PNS remains effective even after more than 20 years. [Copyright &y& Elsevier]

Abstract: Parkinson''s disease is a neurodegenerative disorder affecting the dopaminergic neurons in the substantia nigra. Aggregation of α-synuclein appears to play a central role in the pathogenesis. Novel animal models for neurodegeneration have been generated by lentiviral vector-mediated locoregional overexpression of disease-associated genes in the adult brain. We have used lentiviral vectors to overexpress a clinical mutant of α-synuclein, A30P, in the rat substantia nigra. This overexpression induced time-dependent cytoplasmic and neuritic accumulation of α-synuclein and neurodegeneration. A subgroup of the rats developed asymmetric rotational behavior after administration of amphetamine. In addition, these animals displayed reduced dopamine transporter binding visualized by 123I-FP-CIT microSPECT imaging. The behavioral and microSPECT data were validated by histological analysis. There was a strong correlation between the reduction of dopaminergic neurons in the substantia nigra and the reduction of dopamine transporter binding in the striatum. MicroSPECT imaging enables non-invasive imaging of the neurodegeneration allowing longitudinal follow-up in this new animal model for Parkinson''s disease and the evaluation of neuroprotective drugs. [Copyright &y& Elsevier]

Abstract: Serotonin (5-HT) has been implicated in the pathophysiology of depression. It is not known whether depression in post-myocardial infarction (MI) patients is also serotonin-mediated. In somatically healthy depressed persons, increased brain 5-HT2A receptor binding has been reported in some studies. In animal studies, decreased serotonin activity was found after induction of MI. In the present study, it was hypothesized that depressed post-MI patients would exhibit increased brain 5-HT2A receptor binding compared with non-depressed post-MI patients. Single photon emission computed tomography (SPECT) with the radioligand 123I-5-I-R91150, a 5-HT2A receptor antagonist, was used to study 5-HT2A receptor binding. SPECT scans were performed in nine depressed post-MI patients, 10 non-depressed post-MI patients and 10 healthy control subjects. Results were analysed using statistical parametric mapping. Depressed post-MI patients showed increased 5-HT2A receptor binding compared with non-depressed post-MI patients, and MI patients showed decreased 5-HT2A receptor binding compared with control persons. Both post-MI depression and MI seem to be associated with changes in 5-HT2A receptor binding. [Copyright &y& Elsevier]

Objective The goal of this study was to measure functional and structural aspects of local neuroinflammation induced by intracerebral injection of lipopolysaccharide (LPS) in rats using TSPO microPET imaging with [ 18 F]DPA-714, magnetic resonance imaging (MRI), in vitro autoradiography and immunohistochemistry (IHC) in order to characterize a small animal model for screening of new PET tracers targeting neuroinflammation. Methods Rats were injected stereotactically with LPS (50 μg) in the right striatum and with saline in the left striatum. [ 18 F]DPA-714 microPET, MRI, in vitro autoradiography and IHC studies were performed at different time points after LPS injection for 1 month. Results Analysis of the microPET data demonstrated high uptake of the tracer in the LPS injected site with an affected-to-non-affected side-binding potential ratio (BP right-to-left ) of 3.0 at 3 days after LPS injection. This BP ratio decreased gradually over time to 0.9 at 30 days after LPS injection. In vitro autoradiography ([ 18 F]DPA-714) and IHC (CD68, GFAP and TSPO) confirmed local neuroinflammation in this model. Dynamic contrast enhanced (DCE) MRI demonstrated BBB breakdown near the LPS injection site at day 1, which gradually resolved over time and was absent at 1 month after LPS injection. Conclusion The LPS model is useful for first screening of newly developed tracers because of the easy design and the robust, unilateral inflammatory reaction allowing the use of the contralateral region as control. Additionally, this model can be used to test and follow up the benefits of anti-inflammatory therapies by non-invasive imaging. [ABSTRACT FROM AUTHOR]

Several lines of evidence imply early alterations in endocannabinoid and phosphodiesterase 10A (PDE10A) signaling in Huntington disease (HD). Using [ 18 F]MK-9470 and [ 18 F]JNJ42259152 small-animal positron emission tomography (PET), we investigated for the first time cerebral changes in type 1 cannabinoid (CB1) receptor binding and PDE10A levels in vivo in presymptomatic, early symptomatic, and late symptomatic HD (R6/2) mice, in relation to glucose metabolism ([ 18 F]FDG PET), brain morphology (magnetic resonance imaging) and motor function. Ten R6/2 and 16 wild-type (WT) mice were investigated at 3 different time points between the age of 4 and 13 weeks. Parametric CB1 receptor and PDE10A images were anatomically standardized to Paxinos space and analyzed voxelwise. Volumetric microMRI imaging was performed to assess HD pathology. In R6/2 mice, CB1 receptor binding was decreased in comparison with WT in a cluster comprising the bilateral caudate-putamen, globus pallidus, and thalamic nucleus at week 5 (−8.1% ± 2.6%, p = 1.7 × 10 −5 ). Longitudinal follow-up showed further progressive decline compared with controls in a cluster comprising the bilateral hippocampus, caudate-putamen, globus pallidus, superior colliculus, thalamic nucleus, and cerebellum (late vs. presymptomatic age: −13.7% ± 3.1% for R6/2 and +1.5% ± 4.0% for WT, p = 1.9 × 10 −5 ). In R6/2 mice, PDE10A binding potential also decreased over time to reach significance at early and late symptomatic HD (late vs. presymptomatic age: −79.1% ± 1.9% for R6/2 and +2.1% ± 2.7% for WT, p = 1.5 × 10 −4 ). The observed changes in CB1 receptor and PDE10A binding were correlated to anomalies exhibited by R6/2 animals in motor function, whereas no correlation was found with magnetic resonance imaging-based striatal volume. Our findings point to early regional dysfunctions in endocannabinoid and PDE10A signaling, involving the caudate-putamen and lateral globus pallidus, which may play a role in the progression of the disease in R6/2 animals. PET quantification of in vivo CB1 and/or PDE10A binding may thus be useful early biomarkers for HD. Our results also provide evidence of subtle motor deficits at earlier stages than previously described. [ABSTRACT FROM AUTHOR]

Objective: Recently, somatosensory cortex stimulation has been proposed as a possible treatment for neuropathic deafferentation pain, based on a simple 4-step concept: (1) pain is associated with increased activity in the somatosensory cortex, (2) allodynia-evoked blood-oxygen-level dependence functional magnetic resonance imaging (fMRI) activation depicts the area involved in the pain, (3) if fMRI-guided, neuronavigation-based transcranial magnetic stimulation can transiently suppress the pain, then (4) an extradural electrode can be implanted targeting the same area. Case Description: A patient who was successfully treated with this approach for over 6 years for trigeminal anesthesia dolorosa associated with a subjectively malpositioned eye after multiple recurrent facial skin tumor removals developed new pain after more extensive surgery. Reprogramming the implanted electrode was unsuccessful. The presence of the electrode yielded too many artifacts on a renewed fMRI, and therefore a positron emission tomography (PET) scan was performed under evoked allodynia. Fusing the previous fMRI with the new PET images depicted 2 novel targets for stimulation, 1 anterior and 1 posterior of the previous target and beyond the spatial configuration of the implant. After the addition of 2 new electrodes, the pain could again be controlled in a placebo-controlled way, but only when the 2 electrodes were activated. Conclusions: Combining fMRI and PET scanning can potentially demonstrate continuing map plasticity under progressive somatosensory deafferentation. The functional imaging data can be used as target for pathophysiology-based somatosensory cortex stimulation. [ABSTRACT FROM AUTHOR]

Introduction In vivo visualization of PDE10A using PET provides a tool to evaluate the role of PDE10A in various neuropsychiatric diseases and can also be useful in the clinical evaluation of PDE10A inhibitor drug candidates. We evaluated several carbon-11 and fluorine-18 labeled PDE10A inhibitors as potential PDE10A PET radioligands. Materials & Methods [ 11 C]MP10, [ 11 C]JNJ42071965 and four other tracers were developed. Their biodistribution was evaluated in rats. Rat plasma and brain radiometabolites were quantified. Baseline microPET imaging was performed in normal rats and PDE10A knockout (KO) and wild-type (WT) mice. Blocking and displacement studies were conducted. The selectivity of the tracer binding was further studied in an ex vivo autoradiography experiment in PDE10A KO and WT mice. Results Biodistribution showed brain uptake for all tracers in the striatum and wash-out from the cerebellum. [ 11 C] 1 ( 11 C-MP10) had the highest specific uptake index (striatum (S) vs. cerebellum (C) ratios (S/C)-1) at 60 min (7.4). [ 11 C] 5 ([ 11 C]JNJ42071965) had a high index at the early time points (1.0 and 3.7 at 2 and 30 min p.i., respectively). The affinity of [ 11 C] 4 , [ 18 F] 3 and [ 18 F] 6 was too low to visualize PDE10A using microPET. [ 11 C] 2 showed a specific binding, while kinetics of [ 11 C] 1 were too slow. [ 11 C] 5 reached equilibrium after 10 min (uptake index = 1.2). Blocking and displacement experiments in rats and baseline imaging in PDE10A KO mice showed specific and reversible binding of [ 11 C] 5 to PDE10A. Conclusions We successfully radiolabeled and evaluated six radiotracers for their potential to visualize PDE10A in vivo. While [ 11 C] 1 had the highest striatal specific uptake index, its slow kinetics likely compromise clinical use of this tracer. [ 11 C] 5 has a relatively high striatum-to-background ratio and fast kinetic profile, which makes it a valuable carbon-11 alternative. [ABSTRACT FROM AUTHOR]

Abstract: Introduction: The transient receptor potential vanilloid subfamily member 1 (TRPV1) receptor, a non-selective cation channel, is known for its key role in pain nociception and neurogenic inflammation. TRPV1 expression has been demonstrated in diverse tissues and an essential role for TRPV1 in various disorders has been suggested. A TRPV1-specific PET-radioligand can serve as a useful tool for further in vivo research in animals and directly in humans. In this study, we report the synthesis and biological evaluation of a carbon-11 labelled analogue of N-(3-methoxyphenyl)-4-chlorocinnamide (SB366791) which was reported as a specific high-affinity antagonist for TRPV1. Methods: The new tracer was evaluated with respect to log D and biodistribution in control, pretreated and TRPV1−/− mice. The percentage of radiometabolites of [11C]SB366791 was determined in mouse plasma and brain. Results: [11C] SB366791 was obtained in good yield (69%±11%; isolated amounts 3034–5032MBq) and high specific activity (390±215GBq/μmol). The tracer was efficiently cleared from blood and all major organs via hepatobiliary and renal pathways. Initial brain uptake was high (1.6% ID) and wash-out from brain was rapid. The retention of [11C] SB366791 in the trigeminal nerve of control mice was prominent. The in vitro binding affinity of SB366791 was determined to be 280±56 nM and 780±140 nM for human and rat TRPV1, respectively. Conclusions: [11C] SB366791 has favourable biodistribution characteristics in mice. However the obtained low binding affinity for TRPV1 may not be sufficient to use the current compound as PET tracer. [Copyright &y& Elsevier]

Abstract: Introduction: Up-regulation of the type 2 cannabinoid receptor (CB2R) has been reported in (neuro)inflammatory diseases. In this study, we report the preclinical evaluation of [11C]NE40 as positron emission tomography (PET) radioligand for visualization of the CB2R. Methods: The selectivity of NE40 for CB2R and its toxicity and mutagenicity were determined. [11C]NE40 was evaluated by biodistribution and autoradiography studies in normal rats and a microPET study in normal mice, rats and a rhesus monkey. Specific in vivo binding of [11C]NE40 to human CB2R (hCB2R) was studied in a rat model with hCB2R overexpression. Results: [11C]NE40 shows specific CB2R binding in the spleen and blood of normal rats and high brain uptake in rhesus monkey. [11C]NE40 showed specific and reversible binding to hCB2R in vivo in a rat model with local hCB2R overexpression. Conclusions: [11C]NE40 shows favorable characteristics as radioligand for in vivo visualization of the CB2R and is a promising candidate for hCB2R PET imaging. [Copyright &y& Elsevier]

Background: The endocannabinoid system is a possible target in the treatment of eating disorders. We used positron emission tomography to investigate the type 1 cannabinoid receptor (CB1R) in bulimic and anorectic patients. Methods: We investigated 16 female bulimia nervosa patients (BN) (age = 23.8 ± 7.1 years) and 14 female anorexia nervosa patients (AN) (age = 20.5 ± 3.6 years) using the selective CB1R ligand [18F]MK-9470. The control group consisted of 19 age-matched women (age = 25.2 ± 8.5 years). Statistical parametric mapping (p family-wise error < .05) and volume-of-interest analyses of CB1R availability were performed. Results: Global CB1R availability was significantly increased in cortical and subcortical brain areas in AN patients compared with healthy control subjects (+24.5%, p = .0003). Regionally, CB1R availability was increased in the insula in both AN and BN patients (p = .01 and p = .0004) and the inferior frontal and temporal cortex in AN patients only (p = .02). Conclusions: Global CB1R upregulation in AN patients is a possible long-term compensatory mechanism to an underactive endocannabinoid system in anorectic conditions. There is a similarity in CB1R dysregulation both in AN and BN in the insular cortex, which is involved in the integration of interoceptive information, gustatory information, reward, and emotion processing. [ABSTRACT FROM AUTHOR]

Abstract: The type 2 cannabinoid receptor (CB2R) is part of the endocannabinoid system and is expressed in tissues related to the immune system. As the CB2R has a very low brain expression in non-pathological conditions, but is upregulated in activated microglia, it is an interesting target for visualization of neuroinflammation using positron emission tomography with a suitable radiolabeled CB2R ligand. In this study, we radiolabelled a fluoroethyl derivative of GW405833, a well known CB2R partial agonist, with fluorine-18 (half-life 109.8min) by alkylation of the phenol precursor with 1-bromo-2-[18F]fluoroethane. In vitro studies showed that FE-GW405833 behaved as a selective high affinity (27nM) inverse agonist for hCB2R. [18F]FE-GW405833 showed moderate initial brain uptake in mice and rats, but a slow washout from brain and plasma due to retention of a radiometabolite. Specific binding of the tracer to human CB2R was demonstrated in vivo in a rat model with local CB2R overexpression in the brain. Optimized derivatives of GW405833 that are less susceptible to metabolism will need to be developed in order to provide a useful tracer for CB2R quantification with PET. [Copyright &y& Elsevier]

Abstract: Type 1 cannabinoid (CB1) receptors are expressed in high concentrations in the central nervous system, including the basal ganglia, and could have direct or indirect effects on motor behavior through modulation of dopaminergic, glutamatergic and GABA-ergic neurotransmission. Using the CB1 receptor radioligand [18F]MK-9470 and small-animal PET, we investigated for the first time in vivo cerebral changes in [18F]MK-9470 binding in the 6-hydroxydopamine (6-OHDA) rat model of Parkinson''s disease (PD), parallel to dopamine transporter (DAT) imaging, tyrosine hydroxylase (TH) staining, and behavioral measurements. In the 6-OHDA model, relative [18F]MK-9470 PET binding decreased in the contralateral cerebellum (−9%, p<0.0004) and caudate-putamen bilaterally (ipsilateral −8%, contralateral −7%; p=0.001 and p<0.0003, respectively). The number of TH+ neurons in the substantia nigra was inversely correlated to CB1 receptor binding in the ipsilateral cerebellum (p=1.10−6). The behavioral outcome was positively related to regional CB1 receptor binding in the contralateral somatosensory cortex (p=4.10−6). In vivo [18F]MK-9470 PET imaging points to changes in endocannabinoid transmission, specifically for CB1 receptors in the 6-OHDA model of PD, with mainly involvement of the caudate-putamen, but also distant regions of the motor circuitry, including the cerebellum and somatosensory cortex. [Copyright &y& Elsevier]

Abstract: Introduction: The type 2 cannabinoid (CB2) receptor is part of the endocannabinoid system and has been suggested as a mediator of several central and peripheral inflammatory processes. Imaging of the CB2 receptor has been unsuccessful so far. We synthesized and evaluated a carbon-11- and a fluorine-18-labeled 2-oxoquinoline derivative as new PET tracers with high specificity and affinity for the CB2 receptor. Methods: Two 2-oxoquinoline derivatives were synthesized and radiolabeled with either carbon-11 or fluorine-18. Their affinity and selectivity for the human CB2 receptor were determined. Biological evaluation was done by biodistribution, radiometabolite and autoradiography studies in mice. Results: In vitro studies showed that both compounds are high affinity CB2-specific inverse agonists. Biodistribution study of the tracers in mice showed a high in vivo initial brain uptake and fast brain washout, in accordance with the low CB2 receptor expression levels in normal brain. A persistently high in vivo binding to the spleen was observed, which was inhibited by pretreatment with two structurally unrelated CB2 selective inverse agonists. In vitro autoradiography studies with the radioligands confirmed CB2-specific binding to the mouse spleen. Conclusion: We synthesized two novel CB2 receptor PET tracers that show high affinity/selectivity for CB2 receptors. Both tracers show favourable characteristics as radioligands for central and peripheral in vivo visualization of the CB2 receptor and are promising candidates for primate and human CB2 PET imaging. [Copyright &y& Elsevier]

Abstract: Introduction: The cannabinoid type 2 receptor (CB2 receptor) is part of the endocannabinoid system and has been suggested as mediator of a number of central and peripheral inflammatory processes. In the present study, we have synthesized N-[(1s)-1-[4-[[4-methoxy-2-[(4-[11C]methoxyphenyl)sulfonyl)-phenyl]sulfonyl] phenyl]ethyl]methanesulfonamide ([11C]methoxy-Sch225336) and evaluated this new tracer agent as a potential positron emission tomography radioligand for the in vivo visualization of CB2 receptors. Methods: Sch225336 was demethylated and the resulting phenol precursor was radiolabelled with a carbon-11 methyl group by methylation using [11C]methyl iodide, followed by purification by high-performance liquid chromatography. The log P of [11C]methoxy-Sch225336 and its biodistribution in normal mice were determined. Enhancement of brain uptake by inhibition of blood-brain barrier (BBB) efflux transporters was studied. Mouse plasma was analysed to quantify the formation of radiometabolites. The affinity of Sch225336 for the human cannabinoid type 1 and type 2 receptor was determined. Results: [11C]methoxy-Sch225336 was obtained with a decay corrected radiochemical yield of about 30% and a specific activity of 88.8 GBq/μmol (end of synthesis). After intravenous injection in mice, the compound is rapidly cleared from the blood through the hepatobiliary pathway and does not show particular retention in any of the major organs. Polar metabolites were found in mouse plasma. Brain uptake was low despite the favourable log P value of 2.15, which is partly due to efflux by BBB pumps. Conclusion: [11C]methoxy-Sch225336 is a good candidate for in vivo imaging of the CB2 receptor, although the low blood-brain barrier penetration limits its potential for central nervous system imaging. [Copyright &y& Elsevier]

Abstract: There is substantial evidence that the endocannabinoid system and in particular the type 1 cannabinoid receptor (CB1R) is involved in epilepsy. We evaluated the in vivo effect of chronic administration of the anti-epileptic drugs valproate (VPA) and levetiracetam (LEV) on rat brain CB1 receptors using the positron emission tomography (PET) tracer [18F]MK-9470. Six Wistar rats were treated with VPA (200mg/kg) or LEV (50mg/kg) IP daily for 2weeks. Dynamic imaging after intravenous injection of 18MBq [18F]MK-9470 was performed on a FOCUS 220 microPET at baseline and after chronic treatment. Six animals were used as controls and were injected with saline, using the same protocol. Parametric images based on standardized uptake values (SUV) were generated and were spatially normalized to Paxinos space. These CB1R images were analyzed using a predefined volume of interest (VOI)-based analysis. Differences in SUV values between chronic and baseline scans in each condition (saline, VPA and LEV treatment) were calculated in each VOI. Direct binding affinity of the drugs at CB1R was assessed by competitive binding assay in Chinese hamster ovarian cells expressing human CB1R. Chronic injections of saline did not produce significant changes in global [18F]MK-9470 binding (p =0.43), nor in tracer binding in individual VOIs. We found a significant increase in global cerebral [18F]MK-9470 binding after chronic VPA administration compared to sham treated animals (+32.5%, p <0.001), as well as in tracer binding in all individual VOIs. After chronic administration of LEV, there was no significant change in global cerebral CB1R binding (+6.9%, p =0.81), nor in tracer binding in individual VOIs. As VPA does not exhibit high affinity for CB1R (displacement of [3H]-SR141716A 1.3±14.0%), such upregulation is most likely caused by an indirect effect on the endocannabinoid system. This increase in CB1R tracer binding and possibly signaling may represent a supplementary and new mechanism of VPA, but not LEV, since activation of CB1Rs has been shown to decrease excitability and excitotoxicity on-demand. [Copyright &y& Elsevier]

Abstract: Introduction: [2′-[18F]Fluoroethyl (lR-2-exo-3-exe)-8-methyl-3-(4-chlorophenyl)-8-azabicyclo[3.2.1]-octane-2-carboxylate] ([18F]FECT) is a positron emission tomography (PET) tracer for imaging the dopamine transporter (DAT) in vivo. We report an improved radiosynthesis procedure and affinity data and have analyzed both brain tissue and plasma samples for the presence of radiometabolites as a function of time post intravenous injection of [18F]FECT to rats. Methods: The radiosynthesis of [18F]FECT was carried out using [18F]fluoroethyltriflate ([18F]FEtOTf) as a labeling agent. The affinity of FECT for DAT was determined in vitro by binding experiments on rat striatal membranes. Three rats were injected with [18F]FECT and blood samples were collected at 1 or 3 h post injection (p.i.). Plasma was separated and analyzed using reversed-phase high-performance liquid chromatography (RP-HPLC). Similarly, cerebrum and cerebellum were isolated after sacrifice of the animals at 3 h p.i. of the tracer and homogenized. HPLC analysis was performed on extracts of both samples to examine the presence of metabolites. Results: The radiochemical yield for [18F]FECT was 85% relative to the starting activity of [18F]FEtOTf. The inhibitory constant (K i) of FECT for DAT was found to be 6 nM. The fraction of radioactivity corresponding to intact [18F]FECT was 93% in plasma at both 1 and 3 h p.i. and 96% in cerebrum as well as cerebellum samples at 3 h p.i. Conclusions: FECT has a high affinity for the dopamine transporter. [18F]FECT was found to be stable in vivo and the amount of radiolabeled metabolites in plasma and brain at 3 h p.i. is negligible. Hence, [18F]FECT can be used for the in vivo quantification of DAT using PET. [Copyright &y& Elsevier]