Glia Imaging Differentiates Multiple System Atrophy from Parkinson's Disease: A Positron Emission Tomography Study with [C-11]PBR28 and Machine Learning Analysis

Background The clinical diagnosis of multiple system atrophy (MSA) is challenged by overlapping features with Parkinson's disease (PD) and late-onset ataxias. Additional biomarkers are needed to confirm MSA and to advance the understanding of pathophysiology. Positron emission tomography (PET) imaging of the translocator protein (TSPO), expressed by glia cells, has shown elevations in MSA. Objective In this multicenter PET study, we assess the performance of TSPO imaging as a diagnostic marker for MSA.Methods We analyzed [C-11]PBR28 binding to TSPO using imaging data of 66 patients with MSA and 24 patients with PD. Group comparisons were based on regional analysis of parametric images. The diagnostic readout included visual reading of PET images against clinical diagnosis and machine learning analyses. Sensitivity, specificity, and receiver operating curves were used to discriminate MSA from PD and cerebellar from parkinsonian variant MSA. Results We observed a conspicuous pattern of elevated regional [C-11]PBR28 binding to TSPO in MSA as compared with PD, with "hotspots" in the lentiform nucleus and cerebellar white matter. Visual reading discriminated MSA from PD with 100% specificity and 83% sensitivity. The machine learning approach improved sensitivity to 96%. We identified MSA subtype-specific TSPO binding patterns. Conclusions We found a pattern of significantly increased regional glial TSPO binding in patients with MSA. Intriguingly, our data are in line with severe neuroinflammation in MSA. Glia imaging may have potential to support clinical MSA diagnosis and patient stratification in clinical trials on novel drug therapies for an alpha-synucleinopathy that remains strikingly incurable. </p

Cohort Profile: COVIDMENT: COVID-19 cohorts on mental health across six nations

Why were the cohorts set up? With more than 218 million cases and 4.5 million deaths worldwide (Worldometers, 31 August 2021), the COVID-19 pandemic has had an unprecedented influence on the global economy and population health. As a potent global disaster, it is likely to significantly affect the incidence of adverse mental health symptoms and psychiatric disorders, particularly in vulnerable and highly affected populations. The World Health Organization and leading scientific journals have alerted concerning the potential adverse mental health impact of COVID-19 and emphasized the need for multinational research in this area, which additionally provides new insights into disease mechanisms

Synthesis and evaluation of new PET radioloigands for imaging central norepinephrine transporters

The noradrenergic (NE), serotonergic (5-HT) and dopaminergic (DA) neurotransmission systems all have specific proteins responsible for the regulation of synaptic concentrations of neurotransmitter in the central nervous system (CNS) and in the periphery. Several reports have shown that the expression of these proteins, the monoamine transporters, within the CNS, may be altered in patients with certain neurodegenerative or neuropsychiatric disorders. Positron emission tomography (PET) is an imaging technique that enables quantitative studies in high resolution of receptor or transporter proteins inside the living human brain. At the outset of research for this thesis, PET had been used successfully in the mapping of 5-HT and DA transporters, but not NE transporters (NETs). The aim of this thesis was to develop a radioligand suitable for imaging NETs in the human brain in vivo. This project focused on the screening of candidate NET radioligands by emission measurements in cynomolgus monkeys in vivo. Concomitant with these studies, radiometabolite analyses were performed on peripheral monkey plasma. To further characterise radioligands, in vitro autoradiography studies were performed on post mortem human brain tissue. During this screening process, nine of the most potent and selective NET inhibitors reported to date were prepared and labeled with carbon- 11 (t1/2 20.4 min) or fluorine- 18 (t1/2 109.8 min). Some improvements were also made with regards to the labelling of aryl fluoromethyl ethers and sulfides with fluorine- 18, with a view to potential application in preparing new candidate NET radioligands. Several candidate radioligands failed in the initial screening process. However, one lead compound was identified, namely (S,S)-[11C]MeNER. The regional distribution of (S,S)-[11C]MeNER in monkey brain was found to be in accord with known densities of NETs and was also shown to be specific to NET in a pre-treatment experiment. However, the binding kinetics of (S,S)-[11C]MeNER was found to be slow, which limited its utility in assessing regional NET densities in man. (S,S)-[18F]FMeNER was therefore developed as an improved analogue with a longer half-life that allowed the specific binding to reach equilibrium during the time-frame of the PET measurements. Its metabolic instability did however result in defluorination, which confounded the imaging of cortical regions. The di-deuterated analogue (S,S)-[18F]FMeNER-D2 was thus prepared, which showed a similar distribution in brain as the previously mentioned radioligands, but also displayed a reduced defluorination. In vitro autoradiography with (S,S)[18]FMeNER-D2 on post mortem human brain cryosections further demonstrated specific binding to NET. (S,S)18F]FMeNER-D2 has the potential to be the first useful radioligand for quantitative imaging of NETs in the living human brain

Coordinated optimization of weekly reserve, day-ahead and balancing energy trade in hydropower

publishedVersio

Direct Plasma Metabolite Analysis of Positron Emission Tomography Radioligands by Micellar Liquid Chromatography with Radiometric Detection

Determination of radio-metabolites in plasma samples taken during a positron emission tomography (PET) study is an important component in the pharmacokinetic evaluation of PET radioligands. We have developed and validated a new analytical procedure for the plasma metabolite analysis of PET radioligands based on micellar liquid chromatography using an anionic surfactant mobile phase. Chromatographic separation was performed on an octadecyl semipreparative column (10 mm I.D. × 160 mm, 10 μm) using 100 mM sodium dodecyl sulfate (SDS) and 1-butanol in 10 mM sodium-phosphate (pH 7.2) at a flow rate of 5 mL/min. The samples taken from monkey or human plasma during PET measurements were directly injected into a liquid chromatographic (LC) system coupled to an online radiometric detector under micellar conditions using 1–2% (v/v) 1-butanol mobile phase to remove plasma proteins and concentrate the analytes at the column head. At 2 min, mobile phase was changed to elute and separate PET radioligand and its radiometabolites with high peak capacity under high submicellar conditions (10–25% 1-butanol). This procedure allowed direct plasma injection (up to 2 mL) into the LC column without any pretreatment with a short analysis-time of 8–10 min. Satisfactory reproducibility, linearity, sensitivity, accuracy and recovery were obtained in the validation study. The developed method was successfully applied to study the metabolism for diverse groups of PET radioligands and provided reliable determination of PET radioligands in human and monkey plasma. This method is advantageous in terms of simplifying and shortening the processes required to analyze short-lived radioligands as well as in providing a more accurate estimation of the metabolite corrected input function, especially for the radioligands with lower recoveries or degradation potential during the deproteination process in a conventional procedure

Direct Plasma Metabolite Analysis of Positron Emission Tomography Radioligands by Micellar Liquid Chromatography with Radiometric Detection

Determination of radio-metabolites in plasma samples taken during a positron emission tomography (PET) study is an important component in the pharmacokinetic evaluation of PET radioligands. We have developed and validated a new analytical procedure for the plasma metabolite analysis of PET radioligands based on micellar liquid chromatography using an anionic surfactant mobile phase. Chromatographic separation was performed on an octadecyl semipreparative column (10 mm I.D. × 160 mm, 10 μm) using 100 mM sodium dodecyl sulfate (SDS) and 1-butanol in 10 mM sodium-phosphate (pH 7.2) at a flow rate of 5 mL/min. The samples taken from monkey or human plasma during PET measurements were directly injected into a liquid chromatographic (LC) system coupled to an online radiometric detector under micellar conditions using 1–2% (v/v) 1-butanol mobile phase to remove plasma proteins and concentrate the analytes at the column head. At 2 min, mobile phase was changed to elute and separate PET radioligand and its radiometabolites with high peak capacity under high submicellar conditions (10–25% 1-butanol). This procedure allowed direct plasma injection (up to 2 mL) into the LC column without any pretreatment with a short analysis-time of 8–10 min. Satisfactory reproducibility, linearity, sensitivity, accuracy and recovery were obtained in the validation study. The developed method was successfully applied to study the metabolism for diverse groups of PET radioligands and provided reliable determination of PET radioligands in human and monkey plasma. This method is advantageous in terms of simplifying and shortening the processes required to analyze short-lived radioligands as well as in providing a more accurate estimation of the metabolite corrected input function, especially for the radioligands with lower recoveries or degradation potential during the deproteination process in a conventional procedure

Direct Plasma Metabolite Analysis of Positron Emission Tomography Radioligands by Micellar Liquid Chromatography with Radiometric Detection

Determination of radio-metabolites in plasma samples taken during a positron emission tomography (PET) study is an important component in the pharmacokinetic evaluation of PET radioligands. We have developed and validated a new analytical procedure for the plasma metabolite analysis of PET radioligands based on micellar liquid chromatography using an anionic surfactant mobile phase. Chromatographic separation was performed on an octadecyl semipreparative column (10 mm I.D. × 160 mm, 10 μm) using 100 mM sodium dodecyl sulfate (SDS) and 1-butanol in 10 mM sodium-phosphate (pH 7.2) at a flow rate of 5 mL/min. The samples taken from monkey or human plasma during PET measurements were directly injected into a liquid chromatographic (LC) system coupled to an online radiometric detector under micellar conditions using 1–2% (v/v) 1-butanol mobile phase to remove plasma proteins and concentrate the analytes at the column head. At 2 min, mobile phase was changed to elute and separate PET radioligand and its radiometabolites with high peak capacity under high submicellar conditions (10–25% 1-butanol). This procedure allowed direct plasma injection (up to 2 mL) into the LC column without any pretreatment with a short analysis-time of 8–10 min. Satisfactory reproducibility, linearity, sensitivity, accuracy and recovery were obtained in the validation study. The developed method was successfully applied to study the metabolism for diverse groups of PET radioligands and provided reliable determination of PET radioligands in human and monkey plasma. This method is advantageous in terms of simplifying and shortening the processes required to analyze short-lived radioligands as well as in providing a more accurate estimation of the metabolite corrected input function, especially for the radioligands with lower recoveries or degradation potential during the deproteination process in a conventional procedure

Simplified and accessible [18F]F-AraG synthesis procedure for preclinical PET

The PET tracer [18F]F-AraG, an arabinosyl guanine analog, has shown promise for visualizing activated T cells in multiple diseases. Herein, a practitioner's protocol is described, in which the PET tracer is prepared using minimal equipment and manual actions, making it widely accessible for preclinical applications

Pulmonary PET imaging confirms preferential lung target occupancy of an inhaled bronchodilator

Background: Positron emission tomography (PET) is a non-invasive molecular imaging technique that traces the distribution of radiolabeled molecules in experimental animals and human subjects. We hypothesized that PET could be used to visualize the binding of the bronchodilator drug ipratropium to muscarinic receptors (MR) in the lungs of living non-human primates (NHP). The objectives of this study were two-fold: (i) to develop a methodology for quantitative imaging of muscarinic receptors in NHP lung and (ii) to estimate and compare ipratropium-induced MR occupancy following drug administration via intravenous injection and inhalation, respectively. Methods: A series of PET measurements (n=18) was performed after intravenous injection of the selective muscarinic radioligand C-11-VC-002 in NHP (n=5). The lungs and pituitary gland (both rich in MR) were kept in the field of view. Each PET measurement was followed by a PET measurement preceded by treatment with ipratropium (intravenous or inhaled). Results: Radioligand binding was quantified using the Logan graphical analysis method providing the total volume of distribution (V-T). Ipratropium reduced the V-T in the lung and pituitary in a dose-dependent fashion. At similar plasma ipratropium concentrations, administration by inhalation produced larger reductions in V-T for the lungs. The plasma-derived apparent affinity for ipratropium binding in the lung was one order of magnitude higher after inhalation (K-iih=1.01nM) than after intravenous infusion (K-iiv=10.84nM). Conclusion: Quantitative muscarinic receptor occupancy imaging by PET articulates and quantifies the therapeutic advantage of the inhaled route of delivery and provides a tool for future developments of improved inhaled drugs

Synthesis, Biodistribution, and Radiation Dosimetry of a Novel mGluR5 Radioligand : F-18-AZD9272

The metabotropic glutamate receptor subtype mGluR5 has been proposed as a potential drug target for CNS disorders such as anxiety, depression, Parkinson's disease, and epilepsy. The AstraZeneca compound AZD9272 has previously been labeled with carbon-11 and used as a PET radioligand for mGluR5 receptor binding. The molecular structure of AZD9272 allows one to label the molecule with fluorine-18 without altering the structure. The aim of this study was to develop a fluorine-18 analogue of AZD9272 and to examine its binding distribution in the nonhuman primate brain in vivo as well as to obtain whole body radiation dosimetry. F-18-AZD9272 was successfully synthesized from a nitro precursor. The radioligand was stable, with a radiochemical purity of &gt;99% at 2 h after formulation in a sterile phosphate buffered solution (pH = 7.4). After injection of F-18-AZD9272 in two cynomolgus monkeys, the maximum whole brain radioactivity concentration was 4.9-6.7% of the injected dose (n = 2) and PET images showed a pattern of regional radioactivity consistent with that previously obtained for C-11-AZD9272. The percentage of parent radioligand in plasma was 59 and 64% (n = 2) at 120 min after injection of F-18-AZD9272, consistent with high metabolic stability. Two whole body PET scans were performed in nonhuman primates for a total of 231 min after injection of F-18-AZD9272. Highest uptakes were seen in liver and small intestine, followed by brain and kidney. The estimated effective dose was around 0.017 mSv/MBq. F-18-AZD9272 shows suitable properties as a PET radioligand for in vivo imaging of binding in the primate brain. F-18-labeled AZD9272 offers advantages over C-11-AZD9272 in terms of higher image resolution, combined with a longer half-life. Moreover, based on the distribution and the estimated radiation burden, imaging of F-18-AZD9272 could be used as an improved tool for quantitative assessment and characterization of AZD9272 binding sites in the human brain by using PET