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[ 18 F]JNJ-64413739 has been evaluated as PET-ligand for in vivo quantification of purinergic receptor subtype 7 receptor (P2X7R) using Logan graphical analysis with a metabolite-corrected arterial plasma input function. In the context of a P2X7R PET dose occupancy study, we evaluated a minimally invasive approach by limiting arterial sampling to baseline conditions. Meanwhile, post dose distribution volumes (V T ) under blocking conditions were estimated by combining baseline blood to plasma ratios and metabolite fractions with an MR angiography driven image derived input function (IDIF). Regional postdose V T,IDIF values were compared with corresponding V T,AIF estimates using a arterial input function (AIF), in terms of absolute values, test-retest reliability and receptor occupancy. Compared to an invasive AIF approach, postdose V T,IDIF values and corresponding receptor occupancies showed only limited bias (Bland-Altman analysis: 0.06 ± 0.27 and 3.1% ± 6.4%) while demonstrating a high correlation (Spearman ρ = 0.78 and ρ = 0.98 respectively). In terms of test-retest reliability, regional intraclass correlation coefficients were 0.98 ± 0.02 for V T,IDIF compared to 0.97 ± 0.01 for V T,AIF. These results confirmed that a postdose IDIF, guided by MR angiography and using baseline blood and metabolite data, can be considered for accurate [ 18 F]JNJ-64413739 PET quantification in a repeated PET study design, thus avoiding multiple invasive arterial sampling and increasing dosing flexibility., (© 2021. The Author(s).)

Preclinical and postmortem studies have suggested that regional synaptic density and glucose consumption (CMRGlc) are strongly related. However, the relation between synaptic density and cerebral glucose metabolism in the human brain has not directly been assessed in vivo. Using [ 11 C]UCB-J binding to synaptic vesicle glycoprotein 2 A (SV2A) as indicator for synaptic density and [ 18 F]FDG for measuring cerebral glucose consumption, we studied twenty healthy female subjects (age 29.6 ± 9.9 yrs) who underwent a single-day dual-tracer protocol (GE Signa PET-MR). Global measures of absolute and relative CMRGlc and specific binding of [ 11 C]UCB-J were indeed highly significantly correlated ( r  > 0.47, p  < 0.001). However, regional differences in relative [ 18 F]FDG and [ 11 C]UCB-J uptake were observed, with up to 19% higher [ 11 C]UCB-J uptake in the medial temporal lobe (MTL) and up to 17% higher glucose metabolism in frontal and motor-related areas and thalamus. This pattern has a considerable overlap with the brain regions showing different levels of aerobic glycolysis. Regionally varying energy demands of inhibitory and excitatory synapses at rest may also contribute to this difference. Being unaffected by astroglial and/or microglial energy demands, changes in synaptic density in the MTL may therefore be more sensitive to early detection of pathological conditions compared to changes in glucose metabolism.

Purpose: Histone deacetylase 6 (HDAC6) is a cytoplasmic enzyme that modulates intracellular transport and protein quality control. Inhibition of HDAC6 deacetylase activity has shown beneficial effects in disease models, including Alzheimer's disease and amyotrophic lateral sclerosis. This first-in-human positron emission tomography (PET) study evaluated the brain binding of [ 18 F]EKZ-001 ([ 18 F]Bavarostat), a radiotracer selective for HDAC6, in healthy adult subjects., Methods: Biodistribution and radiation dosimetry studies were performed in four healthy subjects (2M/2F, 23.5 ± 2.4 years) using sequential whole-body PET/CT. The most appropriate kinetic model to quantify brain uptake was determined in 12 healthy subjects (6M/6F, 57.6 ± 3.7 years) from 120-min dynamic PET/MR scans using a radiometabolite-corrected arterial plasma input function. Four subjects underwent retest scans (2M/2F, 57.3 ± 5.6 years) with a 1-day interscan interval to determine test-retest variability (TRV). Regional volume of distribution (V T ) was calculated using one-tissue and two-tissue compartment models (1-2TCM) and Logan graphical analysis (LGA), with time-stability assessed. V T differences between males and females were evaluated using volume of interest and whole-brain voxel-wise approaches., Results: The effective dose was 39.1 ± 7.0 μSv/MBq. Based on the Akaike information criterion, 2TCM was the preferred model compared to 1TCM. Regional LGA V T were in agreement with 2TCM V T , however demonstrated a lower absolute TRV of 7.7 ± 4.9%. Regional V T values were relatively homogeneous with highest values in the hippocampus and entorhinal cortex. Reduction of acquisition time was achieved with a 0 to 60-min scan followed by a 90 to 120-min scan. Males demonstrated significantly higher V T than females in the majority of cortical and subcortical brain regions. No relevant radiotracer related adverse events were reported., Conclusion: [ 18 F]EKZ-001 is safe and appropriate for quantifying HDAC6 expression in the human brain with Logan graphical analysis as the preferred quantitative approach. Males showed higher HDAC6 expression across the brain compared to females.

In the last two decades, it has been shown that anatomically-guided PET reconstruction can lead to improved bias-noise characteristics in brain PET imaging. However, despite promising results in simulations and first studies, anatomically-guided PET reconstructions are not yet available for use in routine clinical because of several reasons. In light of this, we investigate whether the improvements of anatomically-guided PET reconstruction methods can be achieved entirely in the image domain with a convolutional neural network (CNN). An entirely image-based CNN post-reconstruction approach has the advantage that no access to PET raw data is needed and, moreover, that the prediction times of trained CNNs are extremely fast on state of the art GPUs which will substantially facilitate the evaluation, fine-tuning and application of anatomically-guided PET reconstruction in real-world clinical settings. In this work, we demonstrate that anatomically-guided PET reconstruction using the asymmetric Bowsher prior can be well-approximated by a purely shift-invariant convolutional neural network in image space allowing the generation of anatomically-guided PET images in almost real-time. We show that by applying dedicated data augmentation techniques in the training phase, in which 16 [ 18 F]FDG and 10 [ 18 F]PE2I data sets were used, lead to a CNN that is robust against the used PET tracer, the noise level of the input PET images and the input MRI contrast. A detailed analysis of our CNN in 36 [ 18 F]FDG, 18 [ 18 F]PE2I, and 7 [ 18 F]FET test data sets demonstrates that the image quality of our trained CNN is very close to the one of the target reconstructions in terms of regional mean recovery and regional structural similarity., (Copyright © 2020 The Author(s). Published by Elsevier Inc. All rights reserved.)

., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Objective: To investigate in vivo whether synaptic loss and neurofibrillary tangle load spatially overlap and correlate with clinical symptoms in patients with amnestic mild cognitive impairment (aMCI)., Methods: In this cross-sectional study, 10 patients with aMCI and 10 healthy controls underwent triple PET-MRI with 11 C-UCB-J (synaptic vesicle protein 2A), 18 F-MK-6240 (tau deposition), and 11 C-Pittsburgh compound B (β-amyloid) and neuropsychological assessment. Gray matter atrophy was assessed by voxel-based morphometry with T1-weighted MRIs. Voxel-wise and volume-of-interest analyses were conducted on PET data. The interrelationship of synaptic density and tau deposition was investigated. We also investigated correlations of 18 F-MK-6240 and 11 C-UCB-J binding with cognitive performance., Results: Compared to controls, patients with aMCI showed a decreased 11 C-UCB-J binding mainly in substructures of the medial temporal lobe (MTL; 48%-51%, p cluster = 0.02). Increased 18 F-MK6240 binding in the same region was observed (42%-44%, p cluster = 0.0003), spreading to association cortices. In the MTL, higher 18 F-MK-6240 binding inversely related to lower 11 C-UCB-J binding ( p = 0.02, r = -0.76). Decreased performance on cognitive tests was associated with both increased 18 F-MK-6240 and decreased 11 C-UCB-J binding in the hippocampus ( p < 0.01, r > 0.7), although in a multivariate analysis only 18 F-MK-6240 binding was significantly related to cognitive performance., Conclusions: Patients with aMCI have high tau deposition and synaptic density loss mainly in key regions known to be involved in early cognitive impairment, indicating that these are interrelated in the MTL, while tau binding had already spread toward association cortices. Longitudinal data are needed to provide further insight into the temporal aspects of this relationship., (© 2020 American Academy of Neurology.)

Rationale: Endothelial cells (ECs) are highly glycolytic and generate the majority of their energy via the breakdown of glucose to lactate. At the same time, a main role of ECs is to allow the transport of glucose to the surrounding tissues. GLUT1 (glucose transporter isoform 1/ Slc2a1 ) is highly expressed in ECs of the central nervous system (CNS) and is often implicated in blood-brain barrier (BBB) dysfunction, but whether and how GLUT1 controls EC metabolism and function is poorly understood., Objective: We evaluated the role of GLUT1 in endothelial metabolism and function during postnatal CNS development as well as at the adult BBB., Methods and Results: Inhibition of GLUT1 decreases EC glucose uptake and glycolysis, leading to energy depletion and the activation of the cellular energy sensor AMPK (AMP-activated protein kinase), and decreases EC proliferation without affecting migration. Deletion of GLUT1 from the developing postnatal retinal endothelium reduces retinal EC proliferation and lowers vascular outgrowth, without affecting the number of tip cells. In contrast, in the brain, we observed a lower number of tip cells in addition to reduced brain EC proliferation, indicating that within the CNS, organotypic differences in EC metabolism exist. Interestingly, when ECs become quiescent, endothelial glycolysis is repressed, and GLUT1 expression increases in a Notch-dependent fashion. GLUT1 deletion from quiescent adult ECs leads to severe seizures, accompanied by neuronal loss and CNS inflammation. Strikingly, this does not coincide with BBB leakiness, altered expression of genes crucial for BBB barrier functioning nor reduced vascular function. Instead, we found a selective activation of inflammatory and extracellular matrix related gene sets., Conclusions: GLUT1 is the main glucose transporter in ECs and becomes uncoupled from glycolysis during quiescence in a Notch-dependent manner. It is crucial for developmental CNS angiogenesis and adult CNS homeostasis but does not affect BBB barrier function.

With increasing improvements in the time of flight (TOF) resolution of positron emission tomography (PET) scanners, an accurate model of the TOF measurements is becoming increasingly important. This work considers two parameters of the TOF kernel; the relative positioning of the timing data-bins and the timing resolution along each line of response (LOR). Similar to an existing data-driven method, we assume that any shifts of data-bins along lines of response can be modelled as differences between crystal timing offsets. Inspired by this, timing resolutions of all LORs are modelled as the hypotenuse of timing resolutions of the crystal-pairs in coincidence. Furthermore, in order to mitigate the influence of potential inaccuracies of detector-pair sensitivities on crystal timing resolutions, relative LOR sensitivities are modelled as the product of efficiency factors for the two crystals in coincidence. We validate estimating maps of crystal timing offsets, timing resolutions and efficiencies from the emission data using noisy simulations of a brain phantom. Results are shown for phantom and patient data scanned on clinically available TOF-PET scanners. We find that the estimation of crystal timing resolutions is more sensitive to the data statistics than the estimation of crystal timing offsets. As a result, estimation of crystal timing properties could either be limited to high count emission data, or be obtained utilizing additional regularizations on the estimates. Using a more accurate model of the TOF acquisition, improvements are observed in standard activity reconstructions as well as joint reconstructions of activity and attenuation.

Histone deacetylase 6 (HDAC6) is a multifunctional cytoplasmic enzyme involved in diverse cellular processes such as intracellular transport and protein quality control. Inhibition of HDAC6 can alleviate defects in cell and rodent models of certain diseases, particularly neurodegenerative disorders, including Alzheimer's disease and amyotrophic lateral sclerosis. However, while HDAC6 represents a potentially powerful therapeutic target, development of effective brain-penetrant HDAC6 inhibitors remains challenging. Recently, [ 18 F]EKZ-001 ([ 18 F]Bavarostat), a brain-penetrant positron emission tomography (PET) radioligand with high affinity and selectivity toward HDAC6, was developed and evaluated preclinically for its ability to bind HDAC6. Herein, we describe the efficient and robust fully automated current Good Manufacturing Practices (cGMP) compliant production method. [ 18 F]EKZ-001 quantification methods were validated in nonhuman primates (NHP) using full kinetic modeling, and [ 18 F]EKZ-001 PET was applied to compare dose-occupancy relationships between two HDAC6 inhibitors, EKZ-317 and ACY-775. [ 18 F]EKZ-001 is cGMP produced with an average decay-corrected radiochemical yield of 14% and an average molar activity of 204 GBq/μmol. We demonstrate that a two-tissue compartmental model and Logan graphical analysis are appropriate for [ 18 F]EKZ-001 PET quantification in NHP brain. Blocking studies show that the novel compound EKZ-317 achieves higher target occupancy than ACY-775. This work supports the translation of [ 18 F]EKZ-001 PET for first-in-human studies.

Time-of-flight (TOF) PET data provide an effective means for attenuation correction (AC) when no (or incomplete or inaccurate) attenuation information is available. Since MR scanners provide little information on photon attenuation of different tissue types, AC in hybrid PET/MR scanners has always been challenging. In this contribution, we aim at validating the activity reconstructions of the maximum-likelihood ordered-subsets activity and attenuation (OSAA) reconstruction algorithm on a patient brain data set. We present a quantitative comparison of joint reconstructions with the current clinical gold standard-ordered-subsets expectation maximization-using CT-based AC in PET/CT, as well as the current state of the art in PET/MR, that is, zero time echo (ZTE)-based AC. Methods: The TOF PET emission data were initially used in a preprocessing stage to estimate crystal maps of efficiencies, timing offsets, and timing resolutions. Applying these additional corrections during reconstructions, OSAA, ZTE-based, and the vendor-provided atlas-based AC techniques were analyzed and compared with CT-based AC. In our initial study, we used the CT-based estimate of the expected scatter and later used the ZTE-based and OSAA attenuation estimates to compute the expected scatter contribution of the data during reconstructions. In all reconstructions, a maximum-likelihood scaling of the single-scatter simulation estimate to the emission data was used for scatter correction. The reconstruction results were analyzed in the 86 segmented regions of interest of the Hammers atlas. Results: Our quantitative analysis showed that, in practice, a tracer activity difference of +0.5% (±2.1%) and +0.1% (±2.3%) could be expected for the state-of-the-art ZTE-based and OSAA AC methods, respectively, in PET/MR compared with the clinical gold standard in PET/CT. Conclusion: Joint activity and attenuation estimation methods can provide an effective solution to the challenging AC problem for brain studies in hybrid TOF PET/MR scanners. With an accurate TOF-based (timing offsets and timing resolutions) calibration, and similar to the results of the state-of-the-art method in PET/MR, regional errors of joint TOF PET reconstructions are within a few percentage points., (© 2019 by the Society of Nuclear Medicine and Molecular Imaging.)

Rat models based on viral vector-mediated overexpression of α-synuclein are regarded as highly valuable models that closely mimic cardinal features of human Parkinson's disease (PD) such as L-DOPA-dependent motor impairment, dopaminergic neurodegeneration and α-synuclein inclusions. To date, the downstream effects of dopaminergic cell loss on brain glucose metabolism, including the neuroinflammation component, have not been phenotyped in detail for this model. Cerebral glucose metabolism was monitored throughout different stages of the disease using in vivo 2-[ 18 F]-fluoro-2-deoxy-d-glucose ([ 18 F]FDG) positron emission tomography (PET) and was combined with in vitro [ 18 F]DPA-714 autoradiography to assess concomitant inflammation. Rats were unilaterally injected with recombinant adeno-associated viral vector serotype 2/7 (rAAV2/7) encoding either A53T α-synuclein or eGFP. Brain [ 18 F]FDG microPET was performed at baseline, 1, 2, 3, 4, 6, and 9 weeks post-surgery, in combination with behavioral tests. As a second experiment, [ 18 F]DPA-714 autoradiography was executed across the same timeline. Voxel-based analysis of relative [ 18 F]FDG uptake showed a dynamic pattern of PD-related metabolic changes throughout the disease progression (weeks 2-9). Glucose hypermetabolism covering a large bilateral area reaching from the insular, motor- and somatosensory cortex to the striatum was observed at week 2. At week 4, hypermetabolism presented in a cluster covering the ipsilateral nigra-thalamic region, whereas hypometabolism was noted in the ipsilateral striatum at week 6. Elevated [ 18 F]FDG uptake was seen in a cluster extending across the contralateral striatum, motor- and somatosensory cortex at week 9. Increased [ 18 F]FDG in the region of the substantia nigra was associated with increased [ 18 F]DPA-714 binding, and correlated significantly with motor symptoms. These findings point to disease-associated metabolic and neuroinflammatory changes taking place in the primary area of dopaminergic neurodegeneration but also closely interconnected motor and somatosensory brain regions., (Copyright © 2019 Elsevier Inc. All rights reserved.)

We investigated the glucose metabolism in an adeno-associated viral vector based alpha-synuclein rat model for Parkinson's disease (PD) using longitudinal 18 F-FDG PET imaging, which resulted in an improved characterization of this animal model. We generated a PD specific pattern (PDSP) based on a multivariate classification approach to differentiate between a PD and control group at a late disease stage, where the neurodegeneration is considered nearly complete. In particular, we applied a principal component analysis prior to classification by a support vector machine (SVM). Moreover, by using a SVM for regression to predict corresponding motor scores, a PD motor pattern (PDMP) was derived as well. The PDSP mainly corresponds to the PDMP and overlaps to a large extent with the human pattern. We were able to quantify disease expression at previous time points by projecting onto the PDSP and PDMP. While a univariate analysis indicated metabolic changes which did not persist through time, both PDSP and PDMP were able to differentiate significantly (p-value < 0.05) between the PD and control group at week 4, 6 and 9 post injection, while no significant differences were obtained at baseline and at week 3, which is in accordance with the animal model.

Background: Gray matter volume decrease, white matter vascular pathology and amyloid accumulation are age-related brain changes that have been related to the pathogenesis of late life depression (LLD). Furthermore, lower hippocampal volume and more white matter hyperintensities (WMH) may contribute to poor response to electroconvulsive therapy (ECT) in severely depressed older adults. We hypothesized that the accumulation of age-related brain changes negatively affects outcome following ECT in LLD., Methods: 34 elderly patients with severe LLD were treated twice weekly with ECT until remission. All had both 3T structural magnetic resonance imaging (MRI) and β-amyloid positron emission tomography (PET) imaging using 18F-flutemetamol at baseline. MADRS and MMSE were obtained weekly which included 1 week prior to ECT (T0), after the sixth ECT (T1), and one week (T2) after the last ECT as well as at four weeks (T3) and 6 months (T4) after the last ECT. We conducted a multiple logistic regression analysis and a survival analysis with neuroimaging measures as predictors, and response, remission and relapse as outcome variable., Results: We did not find any association between baseline hippocampal volume, white matter hyperintensity volume and total amyloid load and response or remission at 1 and 4 weeks post ECT, nor with relapse at week 4., Limitations: The present exploratory study was conducted at a single center academic hospital, the sample size was small, the focus was on hippocampal volume and the predictive effect of structural and molecular changes associated with aging were used., Conclusions: Our study shows no evidence of relationship between response to ECT and age-related structural or molecular brain changes, implying that ECT can be applied effectively in depressed patients irrespective of accumulating age-related brain changes., (Copyright © 2019. Published by Elsevier B.V.)

18 F-MK-6240 ( 18 F-labeled 6-(fluoro)-3-(1H-pyrrolo[2,3-c]pyridin-1-yl)isoquinolin-5-amine) is a highly selective, subnanomolar-affinity PET tracer for imaging neurofibrillary tangles (NFTs). Plasma kinetics, brain uptake, and preliminary quantitative analysis of 18 F-MK-6240 in healthy elderly (HE) subjects, subjects with clinically probable Alzheimer disease (AD), and subjects with amnestic mild cognitive impairment were characterized in a study that is, to our knowledge, the first to be performed on humans. Methods: Dynamic PET scans of up to 150 min were performed on 4 cognitively normal HE subjects, 4 AD subjects, and 2 amnestic mild cognitive impairment subjects after a bolus injection of 152-169 MBq of 18 F-MK-6240 to evaluate tracer kinetics and distribution in brain. Regional SUV ratio (SUVR) and distribution volume ratio were determined using the cerebellar cortex as a reference region. Total distribution volume was assessed by compartmental modeling using radiometabolite-corrected input function in a subgroup of 6 subjects. Results: F-MK-6240 had rapid brain uptake with a peak SUV of 3-5, followed by a uniformly quick washout from all brain regions in HE subjects; slower clearance was observed in regions commonly associated with NFT deposition in AD subjects. In AD subjects, SUVR between 60 and 90 min after injection was high (approximately 2-4) in regions associated with NFT deposition, whereas in HE subjects, SUVR was approximately 1 across all brain regions, suggesting high tracer selectivity for binding NFTs in vivo. 18 F-MK-6240 total distribution volume was approximately 2- to 3-fold higher in neocortical and medial temporal brain regions of AD subjects than in HE subjects and stabilized by 60 min in both groups. Distribution volume ratio estimated by the Logan reference tissue model or compartmental modeling correlated well ( 18 F-MK-6240 total distribution volume was approximately 2- to 3-fold higher in neocortical and medial temporal brain regions of AD subjects than in HE subjects and stabilized by 60 min in both groups. Distribution volume ratio estimated by the Logan reference tissue model or compartmental modeling correlated well ( R F-MK-6240 exhibited favorable kinetics and high binding levels to brain regions with a plausible pattern for NFT deposition in AD subjects. In comparison, negligible tracer binding was observed in HE subjects. This pilot study suggests that simplified ratio methods such as SUVR can be used to quantify NFT binding. These results support further clinical development of 2 > 0.9) to SUVR from 60 to 90 min for AD subjects. Conclusion: 18 F-MK-6240 exhibited favorable kinetics and high binding levels to brain regions with a plausible pattern for NFT deposition in AD subjects. In comparison, negligible tracer binding was observed in HE subjects. This pilot study suggests that simplified ratio methods such as SUVR can be used to quantify NFT binding. These results support further clinical development of 18 F-MK-6240 for potential application in longitudinal studies., (© 2019 by the Society of Nuclear Medicine and Molecular Imaging.)

Objective: 18 F-Fluorodeoxyglucose ( 18 F-FDG) positron emission tomography (PET) single-center studies using support vector machine (SVM) approach to differentiate amyotrophic lateral sclerosis (ALS) from controls have shown high overall accuracy on an individual patient basis using local a priori defined classifiers. The aim of the study was to validate the SVM accuracy on a multicentric level., Methods: A previously defined Belgian (BE) group of 175 ALS patients (61.9 ± 12.2 years, 120M/55F) and 20 screened healthy controls (62.4 ± 6.4 years, 12M/8F) was used to classify another large dataset from Italy (IT), consisting of 195 patients (63.2 ± 11.6 years, 117M/78F) and 40 controls (62 ± 14.4 years; 29M/11F) free of any neurological and psychiatric disorder who underwent whole-body 18 F-FDG PET-CT for lung cancer without any evidence of paraneoplastic symptoms. 18 F-FDG within-center group comparisons based on statistical parametric mapping (SPM) were performed and SVM classifiers based on the local training sets were applied to differentiate ALS from controls from the other centers., Results: SPM group analysis showed only minor differences between both ALS groups, indicating pattern consistency. SVM using BE data set as training, classified 183/193 ALS-IT correctly (accuracy of 94.8%). However, 35/40 CON-IT were misclassified as ALS (accuracy 12.5%). Furthermore, using IT data as training, ALS-BE could not be distinguished from CON-BE. Within-center SPM group analysis confirmed prefrontal hypometabolism in CON-IT versus CON-BE, indicating subclinical brain changes in patients undergoing oncological scanning., Conclusion: This multicenter study confirms that the 18 F-FDG ALS pattern is stable across centers. Furthermore, it highlights the importance of carefully selected controls, as subclinical frontal changes might be present in patients in an oncological setting.

Inhibition of fatty acid amide hydrolase (FAAH) potentiates endocannabinoid activity and is hypothesized to have therapeutic potential for mood and anxiety disorders and pain. The clinical profile of JNJ-42165279, an oral selective FAAH inhibitor, was assessed by investigating the pharmacokinetics, pharmacodynamics, safety, and binding to FAAH in the brain of healthy human volunteers. Concentrations of JNJ-42165279 (plasma, cerebrospinal fluid (CSF), urine) and fatty acid amides (FAA; plasma, CSF), and FAAH activity in leukocytes was determined in a phase I multiple ascending dose study. A positron emission tomography study with the FAAH tracer [ 11 C]MK3168 was conducted to determine brain FAAH occupancy after single and multiple doses of JNJ-42165279. JNJ-42165279 administration resulted in an increase in plasma and CSF FAA. Significant blocking of brain FAAH binding of [ 11 C]MK3168 was observed after pretreatment with JNJ-42165279. JNJ-42165279 produces potent central and peripheral FAAH inhibition. Saturation of brain FAAH occupancy occurred with doses ≥10 mg of JNJ-42165279. No safety concerns were identified., (© 2018 The Authors. Clinical and Translational Science published by Wiley Periodicals, Inc. on behalf of American Society for Clinical Pharmacology and Therapeutics.)

Converging preclinical evidence links extrastriatal dopamine release and glutamatergic transmission via the metabotropic glutamate receptor 5 (mGluR5) to the rewarding properties of alcohol. To date, human evidence is lacking on how and where in the brain these processes occur. Mesocorticolimbic dopamine release upon intravenous alcohol administration and mGluR5 availability were measured in 11 moderate social drinkers by single-session [ 18 F]fallypride and [ 18 F]FPEB positron emission tomography, respectively. Additionally, baseline and postalcohol glutamate and glutamine levels in the anterior cingulate cortex (ACC) were measured by using proton-magnetic resonance spectroscopy. To investigate differences in reward domains linked to both neurotransmitters, regional imaging data were related to subjective alcohol responses. Alcohol induced significant [ 18 F]fallypride displacement in the prefrontal cortex (PFC), temporal and parietal cortices and thalamus (P < 0.05, corrected for multiple comparisons). Dopamine release in the ACC and orbitofrontal and ventromedial PFCs were correlated with subjective 'liking' and 'wanting' effects (P < 0.05). In contrast, baseline mGluR5 availability was positively correlated with the 'high' effect of alcohol in dorsolateral, ventrolateral and ventromedial PFCs and in the medial temporal lobe, thalamus and caudate nucleus (P < 0.05). Although neither proton-magnetic resonance spectroscopy glutamate nor glutamine levels were affected by alcohol, baseline ACC glutamate levels were negatively associated with the alcohol 'liking' effect (P < 0.003). These data reveal new mechanistic understanding and differential neurobiological underpinnings of the effects of acute alcohol consumption on human behavior. Specifically, prefrontal dopamine release may encode alcohol 'liking' and 'wanting' effects in specific areas underlying value processing and motivation, whereas mGluR5 availability in distinct prefrontal-temporal-subcortical regions is more related to the alcohol 'high' effect., (© 2017 Society for the Study of Addiction.)

Objective: We investigated changes in the endocannabinoid system and glucose metabolism during temporal lobe epileptogenesis., Methods: Because it is rarely possible to study epileptogenesis in humans, we applied the electrical amygdala kindling model in nonhuman primates to image longitudinal changes in type 1 cannabinoid receptor (CB1R) binding and cerebral glucose metabolism. Two rhesus monkeys received [ 18 F]-MK-9470 and fluorodeoxyglucose-positron emission tomography ([ 18 F]-FDG -PET) scans in each of the 4 kindling stages to quantify relative changes over time of CB1R binding and cerebral glucose metabolism in vivo. We constructed z-score images relative to a control group (n = 8), and considered only those changes measured in both kindled animals by calculating the binary conjunction image per kindling stage., Results: The seizure-onset zone exhibited an increased CB1R binding and a decreased glucose metabolism, which both aggravated gradually in extent and intensity throughout kindling. The ipsilateral thalamus and insula showed hypometabolism that coincided with an increase and a decrease in CB1R binding, respectively. These changes also became gradually more severe throughout kindling and overlapped with ictal perfusion changes during the final stage of amygdala kindling, with hyperperfusion in the ipsilateral thalamus and hypoperfusion in the ipsilateral insula., Significance: The observed changes in CB1R binding may reflect a combination of a protective mechanism of neurons against seizure activity that becomes stronger over time to combat more severe seizures, and on the other hand, a process of epileptogenesis that facilitates seizure activity and generalization, depending on the cell type involved in those specific regions. This study provides unique evidence that the CB1R is dynamically and progressively involved from the start of mesial temporal lobe epileptogenesis., (© 2018 The Authors. Epilepsia published by Wiley Periodicals, Inc. on behalf of International League Against Epilepsy.)

Importance: Cerebral amyloid-β aggregation is an early event in Alzheimer disease (AD). Understanding the association between amyloid aggregation and cognitive manifestation in persons without dementia is important for a better understanding of the course of AD and for the design of prevention trials., Objective: To investigate whether amyloid-β aggregation is associated with cognitive functioning in persons without dementia., Design, Setting, and Participants: This cross-sectional study included 2908 participants with normal cognition and 4133 with mild cognitive impairment (MCI) from 53 studies in the multicenter Amyloid Biomarker Study. Normal cognition was defined as having no cognitive concerns for which medical help was sought and scores within the normal range on cognitive tests. Mild cognitive impairment was diagnosed according to published criteria. Study inclusion began in 2013 and is ongoing. Data analysis was performed in January 2017., Main Outcomes and Measures: Global cognitive performance as assessed by the Mini-Mental State Examination (MMSE) and episodic memory performance as assessed by a verbal word learning test. Amyloid aggregation was measured with positron emission tomography or cerebrospinal fluid biomarkers and dichotomized as negative (normal) or positive (abnormal) according to study-specific cutoffs. Generalized estimating equations were used to examine the association between amyloid aggregation and low cognitive scores (MMSE score ≤27 or memory z score≤-1.28) and to assess whether this association was moderated by age, sex, educational level, or apolipoprotein E genotype., Results: Among 2908 persons with normal cognition (mean [SD] age, 67.4 [12.8] years), amyloid positivity was associated with low memory scores after age 70 years (mean difference in amyloid positive vs negative, 4% [95% CI, 0%-7%] at 72 years and 21% [95% CI, 10%-33%] at 90 years) but was not associated with low MMSE scores (mean difference, 3% [95% CI, -1% to 6%], P = .16). Among 4133 patients with MCI (mean [SD] age, 70.2 [8.5] years), amyloid positivity was associated with low memory (mean difference, 16% [95% CI, 12%-20%], P < .001) and low MMSE (mean difference, 14% [95% CI, 12%-17%], P < .001) scores, and this association decreased with age. Low cognitive scores had limited utility for screening of amyloid positivity in persons with normal cognition and those with MCI. In persons with normal cognition, the age-related increase in low memory score paralleled the age-related increase in amyloid positivity with an intervening period of 10 to 15 years., Conclusions and Relevance: Although low memory scores are an early marker of amyloid positivity, their value as a screening measure for early AD among persons without dementia is limited.

In this study, we have synthesized and evaluated 18 F-JNJ64349311, a tracer with high affinity for aggregated tau (inhibition constant value, 8 nM) and high (≥500×) in vitro selectivity for tau over β-amyloid, in comparison with the benchmark compound 18 F-AV1451 ( 18 F-T807) in mice, rats, and a rhesus monkey. Methods: In vitro binding characteristics were determined for Alzheimer's disease, progressive supranuclear palsy, and corticobasal degeneration patient brain tissue slices using autoradiography studies. Ex vivo biodistribution studies were performed in mice. Radiometabolites were quantified in the brain and plasma of mice and in the plasma of a rhesus monkey using high-performance liquid chromatography. Dynamic small-animal PET studies were performed in rats and a rhesus monkey to evaluate tracer pharmacokinetics in the brain. Results: Mouse biodistribution studies showed moderate initial brain uptake and rapid brain washout. Radiometabolite analyses after injection of 18 F-JNJ64349311 in mice showed the presence of a polar radiometabolite in plasma, but not in the brain. Semiquantitative autoradiography studies on postmortem tissue sections of human Alzheimer's disease brains showed highly displaceable binding to tau-rich regions. No specific binding was, however, found on human progressive supranuclear palsy and corticobasal degeneration brain slices. Small-animal PET scans of Wistar rats revealed moderate initial brain uptake (SUV, ∼1.5 at 1 min after injection) and rapid brain washout. Gradual bone uptake was, however, also observed. Blocking and displacement did not affect brain time-activity curves, suggesting no off-target specific binding of the tracer in the healthy rat brain. A small-animal PET scan of a rhesus monkey revealed moderate initial brain uptake (SUV, 1.9 at 1 min after injection) with a rapid washout. In the monkey, no bone uptake was detected during the 120-min scan. Conclusion: This biologic evaluation suggests that 18 F-JNJ64349311 is a promising tau PET tracer candidate, with a favorable pharmacokinetic profile, as compared with 18 F-AV1451., (© 2017 by the Society of Nuclear Medicine and Molecular Imaging.)

We have characterized both acute and long-term vascular and metabolic effects of unilateral common carotid artery occlusion in mice by in vivo magnetic resonance imaging and positron emission tomography. This common carotid artery occlusion model induces chronic cerebral hypoperfusion and is therefore relevant to both preclinical stroke studies, where it serves as a control condition for a commonly used mouse model of ischemic stroke, and neurodegeneration, as chronic hypoperfusion is causative to cognitive decline. By using perfusion magnetic resonance imaging, we demonstrate that under isoflurane anesthesia, cerebral perfusion levels recover gradually over one month. This recovery is paralleled by an increase in lumen diameter and altered tortuosity of the contralateral internal carotid artery at one year post-ligation as derived from magnetic resonance angiography data. Under urethane/α-chloralose anesthesia, no acute perfusion differences are observed, but the vascular response capacity to hypercapnia is found to be compromised. These hemispheric perfusion alterations are confirmed by water [ 15 O]-H 2 O positron emission tomography. Glucose metabolism ([ 18 F]-FDG positron emission tomography) or white matter organization (diffusion-weighted magnetic resonance imaging) did not show any significant alterations. In conclusion, permanent unilateral common carotid artery occlusion results in acute and long-term vascular remodeling, which may have immediate consequences for animal models of stroke but also vascular dementia.

Positive allosteric modulators (PAM) of metabotropic glutamate receptor 2 (mGluR2) are a potential therapy for anxiety, schizophrenia, and addiction. Aside from pathophysiologic imaging studies, an mGluR2 PET tracer would enable confirmation of sufficient central target engagement and assist dose selection for proof-of-concept studies of PAM compounds. 11 C-JNJ-42491293, a novel high-affinity radioligand (human 50% inhibitory concentration = 9.6 nM) for the PAM site of mGluR2, was evaluated as a selective mGluR2 PAM PET tracer., Methods: In vitro and ex vivo autoradiography binding experiments in Wistar and in mGluR2 knockout and wildtype rats as well as in vivo biodistribution and brain PET imaging studies in wildtype and mGluR2 knockout rats in a primate and in humans were performed., Results: In vitro binding studies and in vivo imaging studies in Wistar rats showed moderate brain uptake, with a distribution pattern fully consistent with the reported intracerebral distribution of mGluR2. Given these promising findings, biodistribution, dosimetry, and brain kinetic modeling of 11 C-JNJ-42491293 were determined in humans. Because of an unexpected high myocardial retention, additional 11 C-JNJ-42491293 imaging studies were performed in recently available mGluR2 knockout and wildtype rats and in a monkey using a structurally distinct mGluR2 PAM ligand with affinity for the same site, demonstrating off-target binding in vivo that could not have been anticipated from previous in vitro experiments. To date, the target of this non-mGluR2 tracer binding remains unknown., Conclusion: On the basis of in vivo selectivity issues suggested by human distribution and demonstrated in knockout rat models, 11 C-JNJ-42491293 was considered unsuitable as a specific PET ligand for in vivo imaging of mGluR2. These results emphasize the importance of elaborated in vitro/in vivo comparative studies and, when available, validation with knockout animal models or structurally distinct ligands with affinity for the same site, in radiotracer development., (© 2017 by the Society of Nuclear Medicine and Molecular Imaging.)

Purpose: The cannabinoid type 2 receptor (CB 2 R) is expressed by immune cells such as monocytes and macrophages. In the brain, CB 2 R is primarily found on microglia. CB 2 R upregulation has been reported in animal models of Alzheimer's disease, with a preferential localization near amyloid beta (Aβ) plaques, and in patients post mortem. We performed in vivo brain imaging and kinetic modelling of the CB 2 R tracer [ 11 C]NE40 in healthy controls (HC) and in patients with Alzheimer's disease (AD) to investigate whether higher CB 2 R availability regionally colocalized to Aβ deposits is present in vivo., Methods: Dynamic 90-min [ 11 C]NE40 PET scans were performed in eight HC and nine AD patients with full kinetic modelling using arterial sampling and metabolite correction and partial volume correction. All AD patients received a static [ 11 C]PIB scan 40 min after injection. In four HC, a retest scan with [ 11 C]NE40 PET was performed within 9 weeks to investigate test-retest characteristics., Results: [ 11 C]NE40 was metabolized quickly leading to 50 % of intact tracer 20 min after injection and 20 % at 90 min. A two-tissue kinetic model fitted most of the time-activity curves best; both binding potential (BP ND ) and distribution volume (V T ) parameters could be used. Brain uptake was generally low with an average K 1 value of 0.07 ml/min/ml tissue. V T and BP ND were in the range of 0.7 - 1.8 and 0.6 - 1.6, respectively. Test values in HC were about 30 % for V T and BP ND . AD patients showed overall significantly lower CB 2 R binding. No relationship was found between regional or global amyloid load and CB 2 R availability., Conclusion: Kinetic modelling of [ 11 C]NE40 is possible with a two-tissue reversible model. In contrast to preclinical and post-mortem data, [ 11 C]NE40 PET shows lower CB 2 R availability in vivo in AD patients, with no relationship to Aβ plaques. A possible explanation for these findings is that [ 11 C]NE40 binds to CB 2 R with lower affinity and/or selectivity than to CB 1 R.

Unlabelled: The P2X7 receptor (P2X7R) orchestrates neuroinflammation, and this is the basis for an increased interest in the development of antagonists inhibiting P2X7R function in the brain. This study provides the preclinical evaluation of (11)C-JNJ-54173717, a PET tracer for P2X7R in both rats and nonhuman primates., Methods: (11)C-JNJ-54173717 is a high-affinity radiotracer for the human P2X7R (hP2X7R). Biodistribution and radiometabolite studies were performed. Viral vectors encoding either enhanced green fluorescent protein-hP2X7R or 3flag-hP2X7R were engineered and validated in cell culture. hP2X7R was regionally overexpressed in the rat striatum after stereotactic injection of viral vectors. Dynamic small-animal PET studies were performed in vector-injected rats and in healthy monkeys using (11)C-JNJ-54173717., Results: The affinity of JNJ-54173717 was 1.6 ± 0.1 nM in a rat cortex P2X7R membrane binding assay. In a functional assay at the recombinant human and rat P2X7R orthologs, the half maximal inhibitory concentration (IC50) of JNJ-54173717 was 4.2 ± 0.01 nM and 7.6 ± 0.01 nM, respectively. The rat biodistribution study showed that (11)C-JNJ-54173717 crossed the blood-brain barrier and was cleared from plasma mainly via the hepatobiliary pathway. A polar radiometabolite was found in rat plasma. No radiometabolites were detected in rat brain. Dynamic small-animal PET showed binding of (11)C-JNJ-54173717 in the striatum expressing hP2X7R, with rapid washout from the noninjected control striatum and other brain regions. Likewise, (11)C-JNJ-54173717 PET signal was blocked by a chemically distinct P2X7R ligand, indicating specific binding to P2X7R in the monkey brain., Conclusion: JNJ-54173717 is a high-affinity P2X7R antagonist. An animal rat model stably expressing hP2X7R was developed and validated, identifying favorable characteristics for (11)C-JNJ-54173717 as a PET radioligand for in vivo visualization of hP2X7R. (11)C-JNJ-54173717 selectively visualized P2X7R in the monkey brain, and this radioligand will be further evaluated in a clinical setting to study P2X7R expression levels in neurodegenerative disorders., (© 2016 by the Society of Nuclear Medicine and Molecular Imaging, Inc.)

Unlabelled: An objective biomarker for early identification and accurate differential diagnosis of amyotrophic lateral sclerosis (ALS) is lacking. (18)F-FDG PET brain imaging with advanced statistical analysis may provide a tool to facilitate this. The objective of this work was to validate volume-of-interest (VOI) and voxel-based (using a support vector machine [SVM] approach) (18)F-FDG PET analysis methods to differentiate ALS from controls in an independent prospective large cohort, using a priori-derived classifiers. Furthermore, the prognostic value of (18)F-FDG PET was evaluated., Methods: A prospective cohort of patients with a suspected diagnosis of a motor neuron disorder (n = 119; mean age ± SD, 61 ± 12 y; 81 men and 38 women) was recruited. One hundred five patients were diagnosed with ALS (mean age ± SD, 61.0 ± 12 y; 74 men and 31 women) (group 2), 10 patients with primary lateral sclerosis (mean age ± SD, 55.5 ± 12 y; 3 men and 7 women), and 4 patients with progressive muscular atrophy (mean age ± SD, 59.2 ± 5 y; 4 men). The mean disease duration of all patients was 15.0 ± 13.4 mo at diagnosis, with PET conducted 15.2 ± 13.3 mo after the first symptoms. Data were compared with a previously gathered dataset of 20 screened healthy subjects (mean age ± SD, 62.4 ± 6.4 y; 12 men and 8 women) and 70 ALS patients (mean age ± SD, 62.2 ± 12.5 y; 44 men and 26 women) (group 1). Data were spatially normalized and analyzed on a VOI basis (statistical software (using the Hammers atlas) and voxel basis using statistical parametric mapping. Discriminant analysis and SVM were used to classify new cases based on the classifiers derived from group 1., Results: Compared with controls, ALS patients showed a nearly identical pattern of hypo- and hypermetabolism in groups 1 and 2. VOI-based discriminant analysis resulted in an 88.8% accuracy in predicting the new ALS cases. For the SVM approach, this accuracy was 100%. Brain metabolism between ALS and primary lateral sclerosis patients was nearly identical and not separable on an individual basis. Extensive frontotemporal hypometabolism was predictive for a lower survival using a Kaplan-Meier survival analysis (P < 0.001)., Conclusion: On the basis of a previously acquired training set, (18)F-FDG PET with advanced discriminant analysis methods is able to accurately distinguish ALS from controls and aids in assessing individual prognosis. Further validation on multicenter datasets and ALS-mimicking disorders is needed to fully assess the general applicability of this approach., (© 2016 by the Society of Nuclear Medicine and Molecular Imaging, Inc.)

The aim of this study was to investigate the age-related changes in resting-state neurometabolic connectivity from childhood to adulthood (6-50 years old). Fifty-four healthy adult subjects and twenty-three pseudo-healthy children underwent [(18) F]-fluorodeoxyglucose positron emission tomography at rest. Using statistical parametric mapping (SPM8), age and age squared were first used as covariate of interest to identify linear and non-linear age effects on the regional distribution of glucose metabolism throughout the brain. Then, by selecting voxels of interest (VOI) within the regions showing significant age-related metabolic changes, a psychophysiological interaction (PPI) analysis was used to search for age-induced changes in the contribution of VOIs to the metabolic activity in other brain areas. Significant linear or non-linear age-related changes in regional glucose metabolism were found in prefrontal cortices (DMPFC/ACC), cerebellar lobules, and thalamo-hippocampal areas bilaterally. Decreases were found in the contribution of thalamic, hippocampal, and cerebellar regions to DMPFC/ACC metabolic activity as well as in the contribution of hippocampi to preSMA and right IFG metabolic activities. Increases were found in the contribution of the right hippocampus to insular cortex and of the cerebellar lobule IX to superior parietal cortex metabolic activities. This study evidences significant linear or non-linear age-related changes in regional glucose metabolism of mesial prefrontal, thalamic, mesiotemporal, and cerebellar areas, associated with significant modifications in neurometabolic connectivity involving fronto-thalamic, fronto-hippocampal, and fronto-cerebellar networks. These changes in functional brain integration likely represent a metabolic correlate of age-dependent effects on sensory, motor, and high-level cognitive functional networks. Hum Brain Mapp 37:3017-3030, 2016. © 2016 Wiley Periodicals, Inc., (© 2016 Wiley Periodicals, Inc.)

(18)F-FPEB is a promising PET tracer for studying the metabotropic glutamate subtype 5 receptor (mGluR5) expression in neuropsychiatric disorders. To assess the potential of (18)F-FPEB for longitudinal mGluR5 evaluation in patient studies, we evaluated the long-term test-retest reproducibility using various kinetic models in the human brain. Nine healthy volunteers underwent consecutive scans separated by a 6-month period. Dynamic PET was combined with arterial sampling and radiometabolite analysis. Total distribution volume (V(T)) and nondisplaceable binding potential (BP(ND)) were derived from a two-tissue compartment model without constraints (2TCM) and with constraining the K(1)/k(2) ratio to the value of either cerebellum (2TCM-CBL) or pons (2TCM-PONS). The effect of fitting different functions to the tracer parent fractions and reducing scan duration were assessed. Regional absolute test-retest variability (aTRV), coefficient of repeatability (CR) and intraclass correlation coefficient (ICC) were computed. The 2TCM-CBL showed best fits. The mean 6-month aTRV of V(T) ranged from 8 to 13% (CR < 25%) with ICC > 0.6 for all kinetic models. BPND from 2TCM-CBL with a sigmoid fit for the parent fractions showed the best reproducibility, with aTRV ≤ 7% (CR < 16%) and ICC > 0.9 in most regions. Reducing the scan duration from 90 to 60 min did not affect reproducibility. These results demonstrate for the first time that (18)F-FPEB brain PET has good long-term reproducibility, therefore validating its use to monitor mGluR5 expression in longitudinal clinical studies. We suggest a 2TCM-CBL with fitting a sigmoid function to the parent fractions to be optimal for this tracer., (© 2016 Wiley Periodicals, Inc.)

Single-photon emission computed tomography (SPECT) is a functional nuclear imaging technique that allows visualization and quantification of different in vivo physiologic and pathologic features of brain neurobiology. It has been used for many years in diagnosis of several neurologic and psychiatric disorders. In this chapter, we discuss the current state-of-the-art of SPECT imaging of brain perfusion and dopamine transporter (DAT) imaging. Brain perfusion SPECT imaging plays an important role in the localization of the seizure onset zone in patients with refractory epilepsy. In cerebrovascular disease, it can be useful in determining the cerebrovascular reserve. After traumatic brain injury, SPECT has shown perfusion abnormalities despite normal morphology. In the context of organ donation, the diagnosis of brain death can be made with high accuracy. In neurodegeneration, while amyloid or (18)F-fluorodeoxyglucose positron emission tomography (FDG-PET) are the nuclear diagnostic tools of preference for early and differential diagnosis of dementia, perfusion SPECT imaging can be useful, albeit with slightly lower accuracy. SPECT imaging of the dopamine transporter system is widely available in Europe and Asia, but since recently also in the USA, and has been accepted as an important diagnostic tool in the early and differential diagnosis of parkinsonism in patients with unclear clinical features. The combination of perfusion SPECT (or FDG-PET) and DAT imaging provides differential diagnosis between idiopathic Parkinson's disease, Parkinson-plus syndromes, dementia with Lewy bodies, and essential tremor., (© 2016 Elsevier B.V. All rights reserved.)

Word finding symptoms are frequent early in the course of Alzheimer's disease and relate principally to functional changes in left posterior temporal cortex. In cognitively intact older adults, we examined whether amyloid load affects the network for language and associative-semantic processing. Fifty-six community-recruited subjects (52-74 years), stratified for apolipoprotein E and brain-derived neurotrophic factor genotype, received a neurolinguistic assessment, (18)F-flutemetamol positron emission tomography, and a functional MRI of the associative-semantic system. The primary measure of amyloid load was the cerebral-to-cerebellar gray matter standardized uptake value ratio in a composite cortical volume of interest (SUVR(comp)). The primary outcome analysis consisted of a whole-brain voxelwise linear regression between SUVR(comp) and fMRI response during associative-semantic versus visuoperceptual processing. Higher activity in one region, the posterior left middle temporal gyrus, correlated positively with increased amyloid load. The correlation remained significant when only the word conditions were contrasted but not for pictures. According to a stepwise linear regression analysis, offline naming reaction times correlated positively with SUVR(comp). A binary classification into amyloid-positive and amyloid-negative cases confirmed our findings. The left posterior temporal activity increase may reflect higher demands for semantic control in the presence of a higher amyloid burden., (© The Author 2014. Published by Oxford University Press. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.)

Purpose: [(18)F]DPA-714 is a radiotracer with high affinity for TSPO. We have characterized the kinetics of [(18)F]DPA-714 in rat brain and evaluated its ability to quantify TSPO expression with PET using a neuroinflammation model induced by unilateral intracerebral injection of lipopolysaccharide (LPS)., Methods: Dynamic small-animal PET scans with [(18)F]DPA-714 were performed in Wistar rats on a FOCUS-220 system for up to 3 h. Both plasma and perfused brain homogenates were analysed using HPLC to quantify radiometabolites. Full kinetic modelling of [(18)F]DPA-714 brain uptake was performed using a metabolite-corrected arterial plasma input function. Binding potential (BPND) calculated as the distribution volume ratio minus one (DVR-1) between affected and healthy brain tissue was used as the outcome measure and evaluated against reference tissue models., Results: The percentage of intact [(18)F]DPA-714 in arterial plasma samples was 92 ± 4 % at 10 min, 75 ± 8 % at 40 min and 52 ± 6 % at 180 min. The radiometabolite fraction in brain was negligible (<3 % at 30 min). Among the models investigated, the reversible two-tissue (2T) compartment model best described [(18)F]DPA-714 brain kinetics. BPND values obtained with a simplified and a multilinear reference tissue model (SRTM, MRTM) using the contralateral striatum as the reference region correlated well (Spearman's r = 0.96, p ≤ 0.003) with 2T BPND values calculated as DVR-1, and showed comparable bias (bias range 17.94 %, 20.32 %). Analysis of stability over time suggested that the acquisition time should be at least 90 min for SRTM and MRTM., Conclusion: Quantification of [(18)F]DPA-714 binding to TSPO with full kinetic modelling is feasible using a 2T model. SRTM and MRTM can be suggested as reasonable substitutes with the contralateral striatum as the reference region and a scan duration of at least 90 min. However, selection of the reference region depends on the disease model used.

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 (BPright-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., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Over the last several years, evidence has accumulated that the GABAA receptor is compromised in animal models for fragile X syndrome (FXS), a common hereditary form of intellectual disability. In mouse and fly models, agonists of the GABAA receptor were able to rescue specific consequences of the fragile X mutation. Here, we imaged and quantified GABAA receptors in vivo in brain of fragile X patients using Positron Emission Topography (PET) and [11C]flumazenil, a known high-affinity and specific ligand for the benzodiazepine site of GABAA receptors. We measured regional GABAA receptor availability in 10 fragile X patients and 10 control subjects. We found a significant reduction of on average 10% in GABAA receptor binding potential throughout the brain in fragile X patients. In the thalamus, the brain region showing the largest difference, the GABAA receptor availability was even reduced with 17%. This is one of the first reports of a PET study of human fragile X brain and directly demonstrates that the GABAA receptor availability is reduced in fragile X patients. The study reinforces previous hypotheses that the GABAA receptor is a potential target for rational pharmacological treatment of fragile X syndrome.

Importance: Amyloid-β positron emission tomography (PET) imaging allows in vivo detection of fibrillar plaques, a core neuropathological feature of Alzheimer disease (AD). Its diagnostic utility is still unclear because amyloid plaques also occur in patients with non-AD dementia., Objective: To use individual participant data meta-analysis to estimate the prevalence of amyloid positivity on PET in a wide variety of dementia syndromes., Data Sources: The MEDLINE and Web of Science databases were searched from January 2004 to April 2015 for amyloid PET studies., Study Selection: Case reports and studies on neurological or psychiatric diseases other than dementia were excluded. Corresponding authors of eligible cohorts were invited to provide individual participant data., Data Extraction and Synthesis: Data were provided for 1359 participants with clinically diagnosed AD and 538 participants with non-AD dementia. The reference groups were 1849 healthy control participants (based on amyloid PET) and an independent sample of 1369 AD participants (based on autopsy)., Main Outcomes and Measures: Estimated prevalence of positive amyloid PET scans according to diagnosis, age, and apolipoprotein E (APOE) ε4 status, using the generalized estimating equations method., Results: The likelihood of amyloid positivity was associated with age and APOE ε4 status. In AD dementia, the prevalence of amyloid positivity decreased from age 50 to 90 years in APOE ε4 noncarriers (86% [95% CI, 73%-94%] at 50 years to 68% [95% CI, 57%-77%] at 90 years; n = 377) and to a lesser degree in APOE ε4 carriers (97% [95% CI, 92%-99%] at 50 years to 90% [95% CI, 83%-94%] at 90 years; n = 593; P < .01). Similar associations of age and APOE ε4 with amyloid positivity were observed in participants with AD dementia at autopsy. In most non-AD dementias, amyloid positivity increased with both age (from 60 to 80 years) and APOE ε4 carriership (dementia with Lewy bodies: carriers [n = 16], 63% [95% CI, 48%-80%] at 60 years to 83% [95% CI, 67%-92%] at 80 years; noncarriers [n = 18], 29% [95% CI, 15%-50%] at 60 years to 54% [95% CI, 30%-77%] at 80 years; frontotemporal dementia: carriers [n = 48], 19% [95% CI, 12%-28%] at 60 years to 43% [95% CI, 35%-50%] at 80 years; noncarriers [n = 160], 5% [95% CI, 3%-8%] at 60 years to 14% [95% CI, 11%-18%] at 80 years; vascular dementia: carriers [n = 30], 25% [95% CI, 9%-52%] at 60 years to 64% [95% CI, 49%-77%] at 80 years; noncarriers [n = 77], 7% [95% CI, 3%-18%] at 60 years to 29% [95% CI, 17%-43%] at 80 years., Conclusions and Relevance: Among participants with dementia, the prevalence of amyloid positivity was associated with clinical diagnosis, age, and APOE genotype. These findings indicate the potential clinical utility of amyloid imaging for differential diagnosis in early-onset dementia and to support the clinical diagnosis of participants with AD dementia and noncarrier APOE ε4 status who are older than 70 years.

Importance: Cerebral amyloid-β aggregation is an early pathological event in Alzheimer disease (AD), starting decades before dementia onset. Estimates of the prevalence of amyloid pathology in persons without dementia are needed to understand the development of AD and to design prevention studies., Objective: To use individual participant data meta-analysis to estimate the prevalence of amyloid pathology as measured with biomarkers in participants with normal cognition, subjective cognitive impairment (SCI), or mild cognitive impairment (MCI)., Data Sources: Relevant biomarker studies identified by searching studies published before April 2015 using the MEDLINE and Web of Science databases and through personal communication with investigators., Study Selection: Studies were included if they provided individual participant data for participants without dementia and used an a priori defined cutoff for amyloid positivity., Data Extraction and Synthesis: Individual records were provided for 2914 participants with normal cognition, 697 with SCI, and 3972 with MCI aged 18 to 100 years from 55 studies., Main Outcomes and Measures: Prevalence of amyloid pathology on positron emission tomography or in cerebrospinal fluid according to AD risk factors (age, apolipoprotein E [APOE] genotype, sex, and education) estimated by generalized estimating equations., Results: The prevalence of amyloid pathology increased from age 50 to 90 years from 10% (95% CI, 8%-13%) to 44% (95% CI, 37%-51%) among participants with normal cognition; from 12% (95% CI, 8%-18%) to 43% (95% CI, 32%-55%) among patients with SCI; and from 27% (95% CI, 23%-32%) to 71% (95% CI, 66%-76%) among patients with MCI. APOE-ε4 carriers had 2 to 3 times higher prevalence estimates than noncarriers. The age at which 15% of the participants with normal cognition were amyloid positive was approximately 40 years for APOE ε4ε4 carriers, 50 years for ε2ε4 carriers, 55 years for ε3ε4 carriers, 65 years for ε3ε3 carriers, and 95 years for ε2ε3 carriers. Amyloid positivity was more common in highly educated participants but not associated with sex or biomarker modality., Conclusions and Relevance: Among persons without dementia, the prevalence of cerebral amyloid pathology as determined by positron emission tomography or cerebrospinal fluid findings was associated with age, APOE genotype, and presence of cognitive impairment. These findings suggest a 20- to 30-year interval between first development of amyloid positivity and onset of dementia.

Δ(9) -Tetrahydrocannabinol, the main psychoactive component of cannabis, exerts its central effects through activation of the cerebral type 1 cannabinoid (CB1 ) receptor. Pre-clinical studies have provided evidence that chronic cannabis exposure is linked to decreased CB1 receptor expression and this is thought to be a component underlying drug tolerance and dependence. In this study, we make first use of the selective high-affinity positron emission tomography (PET) ligand [(18) F]MK-9470 to obtain in vivo measurements of cerebral CB1 receptor availability in 10 chronic cannabis users (age = 26.0 ± 4.1 years). Each patient underwent [(18) F]MK-9470 PET within the first week following the last cannabis consumption. A population of 10 age-matched healthy subjects (age = 23.0 ± 2.9 years) was used as control group. Parametric modified standardized uptake value images, reflecting CB1 receptor availability, were calculated. Statistical parametric mapping and volume-of-interest (VOI) analyses of CB1 receptor availability were performed. Compared with controls, cannabis users showed a global decrease in CB1 receptor availability (-11.7 percent). VOI-based analysis demonstrated that the CB1 receptor decrease was significant in the temporal lobe (-12.7 percent), anterior (-12.6 percent) and posterior cingulate cortex (-13.5 percent) and nucleus accumbens (-11.2 percent). Voxel-based analysis confirmed this decrease and regional pattern in CB1 receptor availability in cannabis users. These findings revealed that chronic cannabis use may alter specific regional CB1 receptor expression through neuroadaptive changes in CB1 receptor availability, opening the way for the examination of specific CB1 -cannabis addiction interactions which may predict future cannabis-related treatment outcome., (© 2013 Society for the Study of Addiction.)

Background: Functional dyspepsia (FD) is a prevalent functional gastrointestinal disorder (FGID) defined by chronic epigastric symptoms in the absence of organic abnormalities likely to explain them. Comorbidity with mood and anxiety disorders as well as with other FGIDs and functional somatic syndrome (FSS) is high. FD is characterized by abnormal regional cerebral activity in cognitive/affective pain modulatory circuits, but it is unknown which neurotransmitter systems are involved. The authors aimed to assess and compare in vivo cerebral cannabinoid-1 (CB1) receptor availability between FD patients and age-, gender- and BMI-matched healthy controls (HC)., Methods: Twelve FD patients and 12 matched HC were investigated using positron emission tomography (PET) with the CB1 receptor radioligand [(18)F]MK-9470. Nine of the patients received a second PET scan after a naturalistic follow-up period of 36 ± 9.6 months (range: 25.2-50.4 months)., Results: FD patients had significantly higher CB1 receptor availability in the cerebral regions involved in (visceral) nociception (brainstem, insula, anterior cingulate cortex) as well as in the homeostatic and hedonic regulation of food intake [hypothalamus, (ventral) striatum] (p < 0.05 corrected for multiple testing, region of interest analysis), which persisted after a follow-up period of 36 ± 9.6 months., Conclusions: Although these findings need replication in larger samples, they suggest that the abnormal brain activity in several of these regions, previously demonstrated in FD, may be due to a sustained endocannabinoid system dysfunction, identifying it as a potential novel target for treatment and warranting further studies to elucidate whether it is also a feature of other FGIDs or FSSs.

Decreased glutamatergic neurotransmission is hypothesized to be involved in the pathophysiology of schizophrenia. Inhibition of glycine transporter Type-1 (GlyT1) reuptake is expected to increase the glutamatergic neurotransmission and may serve as treatment for cognitive and negative symptoms of schizophrenia. In this article, we present human data from a novel GlyT1 PET tracer, [(18) F]MK-6577. In the process of developing a GlyT1 inhibitor therapeutic, a PET tracer can assist in determining the dose with a high probability of sufficiently testing the mechanism of action. This article reports the human PET studies with [(18) F]MK-6577 for measuring GlyT1 receptor availability at baseline in normal human subjects and occupancy with a GlyT1 inhibitor, MK-2637. Studies were also performed to measure radiation burden and the baseline test-retest (T-RT) variability of the tracer. The effective dose from sequential whole-body dosimetry scans in three male subjects was estimated to be 24.5 ± 2.9 µSV/MBq (mean ± SD). The time-activity curves from T-RT scans modeled satisfactorily using a two tissue compartmental model. The tracer uptake was highest in the pons (VT  = 6.7 ± 0.9, BPND  = 4.1 ± 0.43) and lowest in the cortex (VT  = 2.1 ± 0.5, BPND  = 0.60 ± 0.23). VT T-RT variability measured in three subjects was <12% on average. The occupancy scans performed in a cohort of 15 subjects indicated absence of a reference region. The in vivo potency (Occ50 ) of MK-2637 was determined using two methods: A: Lassen plot with a population input function (Occ50  = 106 nM, SE = 20 nM) and B: pseudo reference tissue model using cortex as the pseudo reference region (Occ50  = 141 nM, SE = 21 nM)., (© 2014 Wiley Periodicals, Inc.)

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., (Copyright © 2014 Elsevier Inc. All rights reserved.)

Brain injury following stroke affects neurogenesis in the adult mammalian brain. However, a complete understanding of the origin and fate of the endogenous neural stem cells (eNSCs) in vivo is missing. Tools and technology that allow non-invasive imaging and tracking of eNSCs in living animals will help to overcome this hurdle. In this study, we aimed to monitor eNSCs in a photothrombotic (PT) stroke model using in vivo bioluminescence imaging (BLI). In a first strategy, inducible transgenic mice expressing firefly luciferase (Fluc) in the eNSCs were generated. In animals that received stroke, an increased BLI signal originating from the infarct region was observed. However, due to histological limitations, the identity and exact origin of cells contributing to the increased BLI signal could not be revealed. To overcome this limitation, we developed an alternative strategy employing stereotactic injection of conditional lentiviral vectors (Cre-Flex LVs) encoding Fluc and eGFP in the subventricular zone (SVZ) of Nestin-Cre transgenic mice, thereby specifically labeling the eNSCs. Upon induction of stroke, increased eNSC proliferation resulted in a significant increase in BLI signal between 2days and 2weeks after stroke, decreasing after 3months. Additionally, the BLI signal relocalized from the SVZ towards the infarct region during the 2weeks following stroke. Histological analysis at 90days post stroke showed that in the peri-infarct area, 36% of labeled eNSC progeny differentiated into astrocytes, while 21% differentiated into mature neurons. In conclusion, we developed and validated a novel imaging technique that unequivocally demonstrates that nestin(+) eNSCs originating from the SVZ respond to stroke injury by increased proliferation, migration towards the infarct region and differentiation into both astrocytes and neurons. In addition, this new approach allows non-invasive and specific monitoring of eNSCs over time, opening perspectives for preclinical evaluation of candidate stroke therapeutics., (Copyright © 2014 Elsevier Inc. All rights reserved.)

Unlabelled: Serotonin-mediated mechanisms, in particular via the serotonin transporter (SERT), are thought to have an effect on food intake and play an important role in the pathophysiology of obesity. However, imaging studies that examined the correlation between body mass index (BMI) and SERT are sparse and provided contradictory results. The aim of this study was to further test the association between SERT and BMI in a large cohort of healthy subjects., Methods: 127 subjects of the ENC DAT database (58 females, age 52 ± 18 years, range 20-83, BMI 25.2 ± 3.8 kg/m(2), range 18.2-41.1) were analysed using region-of-interest (ROI) and voxel-based approaches to calculate [(123)I]FP-CIT specific-to-nonspecific binding ratios (SBR) in the hypothalamus/thalamus and midbrain/brainstem as SERT-specific target regions., Results: In the voxel-based analysis, SERT availability and BMI were positively associated in the thalamus, but not in the midbrain. In the ROI-analysis, the interaction between gender and BMI showed a trend with higher correlation coefficient for men in the midbrain albeit not significant (0.033SBRm(2)/kg, p=0.1)., Conclusions: The data are in agreement with previous PET findings of an altered central serotonergic tone depending on BMI, as a probable pathophysiologic mechanism in obesity, and should encourage further clinical studies in obesity targeting the serotonergic system., (Copyright © 2014 Elsevier B.V. and ECNP. All rights reserved.)

The endocannabinoid system (ECS) is an important modulatory and potentially neuroprotective homeostatic system in the brain. In Alzheimer's disease (AD), the role of type 1 cannabinoid receptor (CB₁R) is unclear, with contradictory findings in post-mortem studies showing upregulation, downregulation or unchanged CB₁R status. We have investigated CB₁R availability in vivo in patients with AD, in relation to amyloid deposition, cognitive functioning and apolipoprotein E (ApoE) genotype. Eleven AD patients and 7 healthy volunteers (HV) underwent combined [¹⁸F]MK-9470 PET and [¹¹C]PIB PET scans to assess CB₁R availability and amyloid deposition, respectively, and T1 volumetric MRI for partial volume correction. We found no difference in CB₁R availability between AD and HV, VOI-based fractional uptake values (FUR) were 0.043±0.01 for AD and 0.045±0.01 for controls (p=0.9). CB₁R availability did not correlate with neuropsychological test scores and was not modulated by ApoE genotype. As expected, global [¹¹C]PIB SUVR (standardized uptake value ratio) was increased in AD (SUVR 1.9±0.3) compared to HV (1.2±0.1) with p<0.001, but no correlation was found between amyloid β (Aβ) deposition and CB₁R availability. In conclusion, we found no in vivo evidence for a difference in CB₁R availability in AD compared to age-matched controls. Taken together with recently reported in vivo CB₁R changes in Parkinson's and Huntington's disease, these data suggest that the CB₁R is differentially involved in neurodegenerative disorders., (© 2013 Published by Elsevier B.V. and ECNP.)

Purpose of Review: This review evaluates the potential clinical utility of amyloid imaging., Recent Findings: Amyloid PET is a valid in-vivo marker of neuritic plaque load and correlates with amyloid plaque surface area. Abundant diffuse plaques, however, with scant neuritic plaques can also give rise to a positive scan, most often reported in association with Lewy body disease. Specificity of amyloid PET for discriminating Alzheimer's disease from healthy controls is higher than that of structural MRI. Sensitivity for discriminating Alzheimer's disease from healthy controls or from frontotemporal lobar degeneration is also higher than that of fluorodeoxyglucose-PET, with higher interreader reliability. Within a same center there is high concordance between dichotomization of cases based on amyloid PET versus cerebrospinal fluid Aβ42. In a tentative algorithm, we restrict clinical-diagnostic use to dementia with age of onset before 60 years, primary progressive aphasia and corticobasal syndrome, cases with objective cognitive deficits that could be due to a neurodegenerative cause but also have significant cerebrovascular or psychiatric comorbidity, and rapidly progressive dementia., Summary: Empirical studies that evaluate how amyloid PET can change clinical-diagnostic thinking are starting to emerge. Key questions to be resolved are its role compared with cerebrospinal fluid markers and its impact on patient outcome.

Calcitonin gene-related peptide (CGRP) is a potent neuropeptide whose agonist interaction with the CGRP receptor (CGRP-R) in the periphery promotes vasodilation, neurogenic inflammation and trigeminovascular sensory activation. This process is implicated in the cause of migraine headaches, and CGRP-R antagonists in clinical development have proven effective in treating migraine-related pain in humans. CGRP-R is expressed on blood vessel smooth muscle and sensory trigeminal neurons and fibers in the periphery as well as in the central nervous system. However, it is not clear what role the inhibition of central CGRP-R plays in migraine pain relief. To this end, the CGRP-R positron emission tomography (PET) tracer [(11)C]MK-4232 (2-[(8R)-8-(3,5-difluorophenyl)-6,8-[6-(11)C]dimethyl-10-oxo-6,9-diazaspiro[4.5]decan-9-yl]-N-[(2R)-2'-oxospiro[1,3-dihydroindene-2,3'-1H-pyrrolo[2,3-b]pyridine]-5-yl]acetamide) was discovered and developed for use in clinical PET studies. In rhesus monkeys and humans, [(11)C]MK-4232 displayed rapid brain uptake and a regional brain distribution consistent with the known distribution of CGRP-R. Monkey PET studies with [(11)C]MK-4232 after intravenous dosing with CGRP-R antagonists validated the ability of [(11)C]MK-4232 to detect changes in CGRP-R occupancy in proportion to drug plasma concentration. Application of [(11)C]MK-4232 in human PET studies revealed that telcagepant achieved only low receptor occupancy at an efficacious dose (140 mg PO). Therefore, it is unlikely that antagonism of central CGRP-R is required for migraine efficacy. However, it is not known whether high central CGRP-R antagonism may provide additional therapeutic benefit.

Unlabelled: Phosphodiesterase 10A (PDE10A) plays a central role in striatal signaling and is implicated in several neuropsychiatric disorders, such as movement disorders and schizophrenia. We performed initial brain kinetic modeling of the novel PDE10A tracer (18)F-JNJ-42259152 (2-[[4-[1-(2-(18)F-fluoroethyl)-4-(4-pyridinyl)-1H-pyrazol-3-yl]phenoxy]methyl]-3,5-dimethyl-pyridine) and studied test-retest reproducibility in healthy volunteers., Methods: Twelve healthy volunteers (5 men, 7 women; age range, 42-77 y) were scanned dynamically up to 135 min after bolus injection of 172.5 ± 10.3 MBq of (18)F-JNJ42259152. Four volunteers (2 men, 2 women) underwent retest scanning, with a mean interscan interval of 37 d. Input functions and tracer parent fractions were determined using arterial sampling and high-performance liquid chromatography analysis. Volumes of interest for the putamen, caudate nucleus, ventral striatum, substantia nigra, thalamus, frontal cortex, and cerebellum were delineated using individual volumetric T1 MR imaging scans. One-tissue (1T) and 2-tissue (2T) models were evaluated to calculate total distribution volume (VT). Simplified models were also tested to calculate binding potential (BPND), including the simplified reference tissue model (SRTM) and multilinear reference tissue model, using the frontal cortex as the optimal reference tissue. The stability of VT and BPND was assessed down to a 60-min scan time., Results: The average intact tracer half-life in blood was 90 min. The 2T model VT values for the putamen, caudate nucleus, ventral striatum, substantia nigra, thalamus, frontal cortex, and cerebellum were 1.54 ± 0.37, 0.90 ± 0.24, 0.64 ± 0.18, 0.42 ± 0.09, 0.35 ± 0.09, 0.30 ± 0.07, and 0.36 ± 0.12, respectively. The 1T model provided significantly lower VT values, which were well correlated to the 2T VT. SRTM BPND values referenced to the frontal cortex were 3.45 ± 0.43, 1.78 ± 0.35, 1.10 ± 0.31, and 0.44 ± 0.09 for the respective target regions putamen, caudate nucleus, ventral striatum, and substantia nigra, with similar values for the multilinear reference tissue model. Good correlations were found for the target regions putamen, caudate nucleus, ventral striatum, and substantia nigra between the 2T-compartment model BPND and the SRTM BPND (r = 0.57, 0.82, 0.70, and 0.64, respectively). SRTM BPND using a 90- and 60-min acquisition interval showed low bias. Test-retest variability was 5%-19% for 2T VT and 5%-12% for BPND SRTM., Conclusion: Kinetic modeling of (18)F-JNJ-42259152 shows that PDE10A activity can be reliably quantified and simplified using a reference tissue model with the frontal cortex as reference and a 60-min acquisition period.

Antagonism of the central opioid receptor like-1 receptor (ORL1) has been implicated in cognition, and has been a focus of drug discovery efforts to ameliorate the cognitive deficits that remain during the stable treatment of schizophrenia with current antipsychotics. In order to facilitate dose selection for phase II clinical testing an ORL1-specific PET tracer was developed to determine drug plasma concentration versus occupancy relationships in order to ensure that the doses selected and the degree of target engagement were sufficient to ensure adequate proof of concept testing. MK-0911 is a selective, high affinity antagonist for the ORL1 receptor radiolabeled with high specific activity (18)F for positron emission tomography (PET) studies. Evaluation of [(18)F]MK-0911 in rhesus monkey PET studies showed a pattern of brain uptake which was consistent with the known distribution of ORL1. In vitro autoradiography with [(18)F]MK-0911 in rhesus monkey and human brain tissue slices showed a regional distribution that was consistent with in vivo imaging results in monkey. Pre-treatment of rhesus monkeys with high doses of structurally diverse ORL1 antagonists MK-0584, MK-0337, or MK-5757 achieved blockade of [(18)F]MK-0911 in all gray matter regions. Baseline PET studies with [(18)F]MK-0911 in healthy human subjects showed tracer distribution and kinetics similar to that observed in rhesus monkey. Quantification of [(18)F]MK-0911 uptake in repeat human baseline PET studies showed a test-retest variability in volume of distribution (V(T)) averaging 3% across brain regions. Humans dosed orally with MK-5757 showed reduced [(18)F]MK-0911 tracer concentration in brain proportional with MK-5757 dose and plasma level. [(18)F]MK-0911 was useful for determining MK-5757-induced receptor occupancy of ORL1 to guide MK-5757 dose-selection for clinical proof-of-concept studies. Additionally, [(18)F]MK-0911 may be a useful tool for studying the pharmacology of ORL1 in various human populations and disease states., (Copyright © 2012 Elsevier Inc. All rights reserved.)

Purpose: Dopamine transporter (DAT) imaging with [(123)I]FP-CIT (DaTSCAN) is an established diagnostic tool in parkinsonism and dementia. Although qualitative assessment criteria are available, DAT quantification is important for research and for completion of a diagnostic evaluation. One critical aspect of quantification is the availability of normative data, considering possible age and gender effects on DAT availability. The aim of the European Normal Control Database of DaTSCAN (ENC-DAT) study was to generate a large database of [(123)I]FP-CIT SPECT scans in healthy controls., Methods: SPECT data from 139 healthy controls (74 men, 65 women; age range 20-83 years, mean 53 years) acquired in 13 different centres were included. Images were reconstructed using the ordered-subset expectation-maximization algorithm without correction (NOACSC), with attenuation correction (AC), and with both attenuation and scatter correction using the triple-energy window method (ACSC). Region-of-interest analysis was performed using the BRASS software (caudate and putamen), and the Southampton method (striatum). The outcome measure was the specific binding ratio (SBR)., Results: A significant effect of age on SBR was found for all data. Gender had a significant effect on SBR in the caudate and putamen for the NOACSC and AC data, and only in the left caudate for the ACSC data (BRASS method). Significant effects of age and gender on striatal SBR were observed for all data analysed with the Southampton method. Overall, there was a significant age-related decline in SBR of between 4 % and 6.7 % per decade., Conclusion: This study provides a large database of [(123)I]FP-CIT SPECT scans in healthy controls across a wide age range and with balanced gender representation. Higher DAT availability was found in women than in men. An average age-related decline in DAT availability of 5.5 % per decade was found for both genders, in agreement with previous reports. The data collected in this study may serve as a reference database for nuclear medicine centres and for clinical trials using [(123)I]FP-CIT SPECT as the imaging marker.