Imperial College London

DrCorneliusDonat

Faculty of MedicineDepartment of Brain Sciences

Honorary Associate
 
 
 
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c.donat

 
 
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Burlington DanesHammersmith Campus

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Summary

 

Publications

Publication Type
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38 results found

Naseer S, Abelleira Hervas L, Savani D, De Burgh R, Aleksynas R, Donat C, Syed N, Sastre Met al., 2022, Traumatic brain injury leads to alterations in contusional cortical miRNAs involved in dementia, Biomolecules, Vol: 12, ISSN: 2218-273X

There is compelling evidence that head injury is a significant environmental risk factor for Alzheimer's disease (AD) and that a history of traumatic brain injury (TBI) accelerates the onset of AD. Amyloid-β plaques and tau aggregates have been observed in the post-mortem brains of TBI patients; however, the mechanisms leading to AD neuropathology in TBI are still unknown. In this study, we hypothesized that focal TBI induces changes in miRNA expression in and around affected areas, resulting in the altered expression of genes involved in neurodegeneration and AD pathology. For this purpose, we performed a miRNA array in extracts from rats subjected to experimental TBI, using the controlled cortical impact (CCI) model. In and around the contusion, we observed alterations of miRNAs associated with dementia/AD, compared to the contralateral side. Specifically, the expression of miR-9 was significantly upregulated, while miR-29b, miR-34a, miR-106b, miR-181a and miR-107 were downregulated. Via qPCR, we confirmed these results in an additional group of injured rats when compared to naïve animals. Interestingly, the changes in those miRNAs were concomitant with alterations in the gene expression of mRNAs involved in amyloid generation and tau pathology, such as β-APP cleaving enzyme (BACE1) and Glycogen synthase-3-β (GSK3β). In addition increased levels of neuroinflammatory markers (TNF-α), glial activation, neuronal loss, and tau phosphorylation were observed in pericontusional areas. Therefore, our results suggest that the secondary injury cascade in TBI affects miRNAs regulating the expression of genes involved in AD dementia.

Journal article

Graham NSN, Zimmerman KA, Moro F, Heslegrave A, Maillard SA, Bernini A, Miroz J-P, Donat CK, Lopez MY, Bourke N, Jolly AE, Mallas E-J, Soreq E, Wilson MH, Fatania G, Roi D, Patel MC, Garbero E, Nattino G, Baciu C, Fainardi E, Chieregato A, Gradisek P, Magnoni S, Oddo M, Zetterberg H, Bertolini G, Sharp DJet al., 2021, Axonal marker neurofilament light predicts long-term outcomes and progressive neurodegeneration after traumatic brain injury, Science Translational Medicine, Vol: 13, Pages: 1-15, ISSN: 1946-6234

Axonal injury is a key determinant of long-term outcomes after traumatic brain injury (TBI) but has been difficult to measure clinically. Fluid biomarker assays can now sensitively quantify neuronal proteins in blood. Axonal components such as neurofilament light (NfL) potentially provide a diagnostic measure of injury. In the multicenter BIO-AX-TBI study of moderate-severe TBI, we investigated relationships between fluid biomarkers, advanced neuroimaging, and clinical outcomes. Cerebral microdialysis was used to assess biomarker concentrations in brain extracellular fluid aligned with plasma measurement. An experimental injury model was used to validate biomarkers against histopathology. Plasma NfL increased after TBI, peaking at 10 days to 6 weeks but remaining abnormal at 1 year. Concentrations were around 10 times higher early after TBI than in controls (patients with extracranial injuries). NfL concentrations correlated with diffusion MRI measures of axonal injury and predicted white matter neurodegeneration. Plasma TAU predicted early gray matter atrophy. NfL was the strongest predictor of functional outcomes at 1 year. Cerebral microdialysis showed that NfL concentrations in plasma and brain extracellular fluid were highly correlated. An experimental injury model confirmed a dose-response relationship of histopathologically defined axonal injury to plasma NfL. In conclusion, plasma NfL provides a sensitive and clinically meaningful measure of axonal injury produced by TBI. This reflects the extent of underlying damage, validated using advanced MRI, cerebral microdialysis, and an experimental model. The results support the incorporation of NfL sampling subacutely after injury into clinical practice to assist with the diagnosis of axonal injury and to improve prognostication.

Journal article

Calsolaro V, Matthews PM, Donat CK, Livingston NR, Femminella GD, Guedes SS, Myers J, Fan Z, Tyacke RJ, Venkataraman AV, Perneczky R, Gunn R, Rabiner EA, Gentleman S, Parker CA, Murphy PS, Wren PB, Hinz R, Sastre M, Nutt DJ, Edison Pet al., 2021, Astrocyte reactivity with late onset cognitive impairment assessed in-vivo using 11C-BU99008 PET and its relationship with amyloid load, Molecular Psychiatry, Vol: 26, Pages: 5848-5855, ISSN: 1359-4184

11C-BU99008 is a novel positron emission tomography (PET) tracer that enables selective imaging of astrocyte reactivity in vivo. To explore astrocyte reactivity associated with Alzheimer’s disease, 11 older, cognitively impaired (CI) subjects and 9 age-matched healthy controls (HC) underwent 3T magnetic resonance imaging (MRI), 18F-florbetaben and 11C-BU99008 PET. The 8 amyloid (Aβ)-positive CI subjects had higher 11C-BU99008 uptake relative to HC across the whole brain, but particularly in frontal, temporal, medial temporal and occipital lobes. Biological parametric mapping demonstrated a positive voxel-wise neuroanatomical correlation between 11C-BU99008 and 18F-florbetaben. Autoradiography using 3H-BU99008 with post-mortem Alzheimer’s brains confirmed through visual assessment that increased 3H-BU99008 binding localised with the astrocyte protein glial fibrillary acid protein and was not displaced by PiB or florbetaben. This proof-of-concept study provides direct evidence that 11C-BU99008 can measure in vivo astrocyte reactivity in people with late-life cognitive impairment and Alzheimer’s disease. Our results confirm that increased astrocyte reactivity is found particularly in cortical regions with high Aβ load. Future studies now can explore how clinical expression of disease varies with astrocyte reactivity.

Journal article

Farajzadeh Khosroshahi S, Yin X, Donat C, McGarry A, Yanez Lopez M, Baxan N, Sharp D, Sastre M, Ghajari Met al., 2021, Multiscale modelling of cerebrovascular injury reveals the role of vascular anatomy and parenchymal shear stresses, Scientific Reports, Vol: 11, ISSN: 2045-2322

Neurovascular injury is often observed in traumatic brain injury (TBI). However, the relationship between mechanical forces and vascular injury is still unclear. A key question is whether the complex anatomy of vasculature plays a role in increasing forces in cerebral vessels and producing damage. We developed a high-fidelity multiscale finite element model of the rat brain featuring a detailed definition of the angioarchitecture. Controlled cortical impacts were performed experimentally and in-silico. The model was able to predict the pattern of blood–brain barrier damage. We found strong correlation between the area of fibrinogen extravasation and the brain area where axial strain in vessels exceeds 0.14. Our results showed that adjacent vessels can sustain profoundly different axial stresses depending on their alignment with the principal direction of stress in parenchyma, with a better alignment leading to larger stresses in vessels. We also found a strong correlation between axial stress in vessels and the shearing component of the stress wave in parenchyma. Our multiscale computational approach explains the unrecognised role of the vascular anatomy and shear stresses in producing distinct distribution of large forces in vasculature. This new understanding can contribute to improving TBI diagnosis and prevention.

Journal article

Ries M, Watts H, Mota B, Yanez Lopez M, Donat C, Baxan N, Pickering J, Chau TSZ, Semmler A, Gurung B, Aleksynas R, Abelleira Hervas L, Iqbal S, Romero-Molina C, Hernandez Mir G, d'Amati A, Reutelingsperger C, Goldfinger M, Gentleman S, Van Leuven F, Solito E, Sastre Met al., 2021, Annexin-A1 restores cerebrovascular integrity concomitant with reduced amyloid-β and tau pathology, Brain: a journal of neurology, Vol: 144, Pages: 1526-1541, ISSN: 0006-8950

Alzheimer’s disease (AD), characterized by brain deposits of amyloid-β(Aβ) plaques and neurofibrillary tangles, is also linked to neurovascular dysfunction and blood-brain barrier (BBB) breakdown, affecting the passage of substances into and out of the brain. We hypothesized that treatment of neurovascular alterations could be beneficial in AD. Annexin A1 (ANXA1) is a mediator of glucocorticoids anti-inflammatory action that can suppress microglial activation and reduce BBB leakage. We have reported recently that treatment with recombinant human ANXA1 (hrANXA1) 2reduced Aβ levels by increased degradation in neuroblastoma cells and phagocytosis by microglia. Here, we show the beneficial effects of hrANXA1 in vivo by restoring efficient BBB function and decreasing Aβ and tau pathology in 5xFAD mice and Tau-P301L mice. We demonstrate that young 5xFAD mice already suffer cerebrovascular damage, while acute pre-administration of hrANXA1 rescued the vascular defects. Interestingly, the ameliorated BBB permeability in young 5xFAD mice by hrANXA1 correlated with reduced brain A load, due to increased clearance and degradation of Aβ by the insulin degrading enzyme (IDE). The systemic anti-inflammatory properties of hrANXA1 were also observed in 5XFAD mice, increasing IL-10 and reducing TNF-α expression. Additionally, the prolonged treatment with hrANXA1 reduced the memory deficits and increased synaptic density in young 5xFAD mice. Similarly, in Tau-P301L mice, acute hrANXA1 administration restored vascular architecture integrity, affecting the distribution of tight junctions, and reduced tau phosphorylation. The combined data support the hypothesis that the BBB breakdown early in AD can be restored by hrANXA1 as a potential therapeutic approach.

Journal article

Donat C, Yanez Lopez M, Sastre M, Baxan N, Goldfinger M, Seeamber R, Mueller F, Davies P, Hellyer P, Siegkas P, Gentleman S, Sharp D, Ghajari Met al., 2021, From biomechanics to pathology: predicting axonal injury from patterns of strain after traumatic brain injury., Brain: a journal of neurology, Vol: 144, Pages: 70-91, ISSN: 0006-8950

The relationship between biomechanical forces and neuropathology is key to understanding traumatic brain injury. White matter tracts are damaged by high shear forces during impact, resulting in axonal injury, a key determinant of long-term clinical outcomes. However, the relationship between biomechanical forces and patterns of white matter injuries, associated with persistent diffusion MRI abnormalities, is poorly understood. This limits the ability to predict the severity of head injuries and the design of appropriate protection. Our previously developed human finite element model of head injury predicted the location of post-traumatic neurodegeneration. A similar rat model now allows us to experimentally test whether strain patterns calculated by the model predicts in vivo MRI and histology changes. Using a Controlled Cortical Impact, mild and moderate injuries(1 and 2 mm) were performed. Focal and axonal injuries were quantified withvolumetric and diffusion 9.4T MRI two weeks post injury. Detailed analysis of the corpus callosum was conducted using multi-shell diffusion MRI and histopathology. Microglia and astrocyte density, including process parameters,along with white matter structural integrity and neurofilament expression were determined by quantitative immunohistochemistry. Linear mixed effects regression analyses for strain and strain rate with the employed outcome measures were used to ascertain how well immediate biomechanics could explain MRI and histology changes.The spatial pattern of mechanical strain and strain rate in the injured cortex shows good agreement with the probability maps of focal lesions derived from volumetric MRI. Diffusion metrics showed abnormalities in segments of the corpus callosum predicted to have a high strain, indicating white matter changes. The same segments also exhibited a severity-dependent increase in glia cell density, white matter thinning

Journal article

Brust P, Deuther-Conrad W, Donat C, Barthel H, Riss P, Paterson L, Hoepping A, Sabri O, Cumming Pet al., 2020, Preclinical and clinical aspects of nicotinic acetylcholine receptor imaging, PET and SPECT of Neurobiological Systems, Pages: 593-660, ISBN: 9783030531751

Innovations in radiochemistry and pharmacology are opening new vistas for studies of nicotinic acetylcholine receptors (nAChRs) in human brain by positron emission tomography (PET) and by single-photon emission computed tomography (SPECT). In parallel, instrumentation optimized for molecular imaging in rodents facilitates preclinical studies in models of human diseases with perturbed nAChR signalling, notably Alzheimer's disease and other neurodegenerative conditions, schizophrenia and other neuropsychiatric disorders, substance abuse and traumatic brain injury. The nAChRs are ligand-gated ion channels composed of five subunits forming a central pore for cation flux. The most abundant nAChRs in the central nervous system are heteropentamers (designated α4β2), followed by the α7 homopentamer. We present a systematic review of published findings with the various nAChR ligands using imaging techniques in vivo, emphasizing preclinical models and human studies. Molecular PET imaging of the α4β2 nAChR subtype with the antagonist 2-[18F]fluoro-A-85380 is hampered by the long acquisition times. Newer agents such as (-)-[18F]flubatine, [18F]XTRA or [18F]nifene permit quantitation of α4β2 receptors with PET recordings lasting 90 min or less and without the toxicity risk of earlier epibatidine derivatives. The early PET studies of α7 nAChRs suffered from low pharmacological specificity, further hampered by low natural abundance of the receptor. However, several good α7 nAChR ligands such as [18F]ASEM and [18F]DBT10 have emerged in the past few years. There are still no ligands selective for α6-containing nAChRs, despite their importance for nicotine-induced dopamine release in striatum. Selective α3β4 nAChR radioligands are under development but remain untested in clinical studies of depression and addiction. Several nAChR ligands find use for pharmacological occupancy studies, and competition from endogenous

Book chapter

Donat CK, Hansen HH, Hansen HD, Mease RC, Horti AG, Pomper MG, L'Estrade ET, Herth MM, Peters D, Knudsen GM, Mikkelsen JDet al., 2020, In Vitro and In Vivo Characterization of Dibenzothiophene Derivatives [<SUP>125</SUP>I]Iodo-ASEM and [<SUP>18</SUP>F]ASEM as Radiotracers of Homo- and Heteromeric α7 Nicotinic Acetylcholine Receptors, MOLECULES, Vol: 25

Journal article

Nutma E, Stephenson JA, Gorter RP, de Bruin J, Boucherie DM, Donat CK, Breur M, van der Valk P, Matthews P, Owen D, Amor Set al., 2019, A quantitative neuropathological assessment of translocator protein expression in multiple sclerosis, Brain, Vol: 142, Pages: 3440-3455, ISSN: 1460-2156

The 18kDa translocator protein (TSPO) is increasingly used to study brain and spinal cord inflammation in degenerative diseases of the CNS such as multiple sclerosis. The enhanced TSPO PET signal that arises during disease is widely-considered to reflect activated pathogenicmicroglia, although quantitative neuropathological data to support this interpretation has not been available. With the increasing interest in the role of chronic microglial activation in multiple sclerosis, characterising the cellular neuropathology associated with TSPO expression is of clear importance for understanding the cellular and pathological processes on which TSPO PET imaging is reporting.Here we have studied the cellular expression of TSPO and specific binding of two TSPO targeting radioligands ([3H]PK11195 and [3H]PBR28) in tissue sections from 42 multiple sclerosis cases and 12 age-matched controls. Markers of homeostatic and reactive microglia, astrocytes, and lymphocytes were used to investigate the phenotypes of cells expressing TSPO. There was an approximate 20-fold increase in cells double positive for TSPO and human leukocyte antigen -DR in active lesions and in the rim of chronic active lesion, relative to normal appearing white matter. TSPO was uniformly expressed across myeloid cells irrespective of their phenotype, rather than being preferentially associated with pro-inflammatory microglia or macrophages. TSPO+astrocytes were increased up to 7-fold compared to normal appearing white matter across all lesion sub-types and accounted for 25% of the TSPO+ cells in these lesions. To relate TSPO protein expression to ligand binding, specific binding of the TSPO ligands [3H]PK11195 and [3H]PBR28was determined in the same lesions. TSPO radioligand binding was increased up to seven times for [3H]PBR28 and up to two times for [3H]PK11195 in active lesions and the centre of chronic ac

Journal article

Sastre M, Edison P, Donat C, 2018, In vivo imaging of Glial activation in Alzheimer's disease, Frontiers in Neurology, Vol: 9, ISSN: 1664-2295

Alzheimer's disease (AD) is characterized by memory loss and decline of cognitive function, associated with progressive neurodegeneration. While neuropathological processes like amyloid plaques and tau neurofibrillary tangles have been linked to neuronal death in AD, the precise role of glial activation on disease progression is still debated. It was suggested that neuroinflammation could occur well ahead of amyloid deposition and may be responsible for clearing amyloid, having a neuroprotective effect; however, later in the disease, glial activation could become deleterious, contributing to neuronal toxicity. Recent genetic and preclinical studies suggest that the different activation states of microglia and astrocytes are complex, not as polarized as previously thought, and that the heterogeneity in their phenotype can switch during disease progression. In the last few years, novel imaging techniques e.g., new radiotracers for assessing glia activation using positron emission tomography and advanced magnetic resonance imaging technologies have emerged, allowing the correlation of neuro-inflammatory markers with cognitive decline, brain function and brain pathology in vivo. Here we review all new imaging technology in AD patients and animal models that has the potential to serve for early diagnosis of the disease, to monitor disease progression and to test the efficacy and the most effective time window for potential anti-inflammatory treatments.

Journal article

Donat CK, Mirzaei N, Tang S-P, Edison P, Sastre Met al., 2018, Erratum to: Imaging of Microglial Activation in Alzheimer's Disease by [11C]PBR28 PET., Methods Mol Biol, Vol: 1750, Pages: E1-E1

Journal article

Donat C, Mirzaei N, Tang S-P, Edison P, Sastre Met al., 2018, Imaging of Microglial Activation in Alzheimer's Disease by [11C]PBR28 PET, Biomarkers for Alzheimer's disease drug development, Editors: Perneczky, Publisher: Humana Press, Pages: 323-339

Book chapter

Donat CK, Mirzaei N, Tang S-P, Edison P, Sastre Met al., 2018, Imaging of Microglial Activation in Alzheimer's Disease by [11C]PBR28 PET., Methods Mol Biol, Vol: 1750, Pages: 323-339

Deficits in neuronal function and synaptic plasticity in Alzheimer's disease (AD) are believed to be linked to microglial activation. A hallmark of reactive microglia is the upregulation of mitochondrial translocator protein (TSPO) expression. Positron emission tomography (PET) is a nuclear imaging technique that measures the distribution of trace doses of radiolabeled compounds in the body over time. PET imaging using the 2nd generation TSPO tracer [11C]PBR28 provides an opportunity for accurate visualization and quantification of changes in microglial density in transgenic mouse models of Alzheimer's disease (AD). Here, we describe the methodology for the in vivo use of [11C]PBR28 in AD patients and the 5XFAD transgenic mouse model of AD and compare the results against healthy individuals and wild-type controls. To confirm the results, autoradiography with [3H]PBR28 and immunochemistry was carried out in the same mouse brains. Our data shows that [11C]PBR28 is suitable as a tool for in vivo monitoring of microglial activation and may be useful to assess treatment response in future studies.

Journal article

Donat CK, Scott G, Gentleman S, Sastre Met al., 2017, Microglial activation in traumatic brain injury, Frontiers in Aging Neuroscience, Vol: 9, ISSN: 1663-4365

Microglia have a variety of functions in the brain, including synaptic pruning, CNS repair and mediating the immune response against peripheral infection. Microglia rapidly become activated in response to CNS damage. Depending on the nature of the stimulus, microglia can take a number of activation states, which correspond to altered microglia morphology, gene expression and function. It has been reported that early microglia activation following traumatic brain injury (TBI) may contribute to the restoration of homeostasis in the brain. On the other hand, if they remain chronically activated, such cells display a classically activated phenotype, releasing pro-inflammatory molecules, resulting in further tissue damage and contributing potentially to neurodegeneration. However, new evidence suggests that this classification is over-simplistic and the balance of activation states can vary at different points. In this article, we review the role of microglia in TBI, analyzing their distribution, morphology and functional phenotype over time in animal models and in humans. Animal studies have allowed genetic and pharmacological manipulations of microglia activation, in order to define their role. In addition, we describe investigations on the in vivo imaging of microglia using translocator protein (TSPO) PET and autoradiography, showing that microglial activation can occur in regions far remote from sites of focal injuries, in humans and animal models of TBI. Finally, we outline some novel potential therapeutic approaches that prime microglia/macrophages toward the beneficial restorative microglial phenotype after TBI.

Journal article

Kranz M, Sattler B, Tiepolt S, Wilke S, Deuther-Conrad W, Donat CK, Fischer S, Patt M, Schildan A, Patt J, Smits R, Hoepping A, Steinbach J, Sabri O, Brust Pet al., 2016, Radiation dosimetry of the alpha(4)beta(2) nicotinic receptor ligand (+)-[F-18]flubatine, comparing preclinical PET/MRI and PET/CT to first-in-human PET/CT results, EJNMMI Physics, Vol: 3, ISSN: 2197-7364

BackgroundBoth enantiomers of [18F]flubatine are new radioligands for neuroimaging of α4β2 nicotinic acetylcholine receptors with positron emission tomography (PET) exhibiting promising pharmacokinetics which makes them attractive for different clinical questions. In a previous preclinical study, the main advantage of (+)-[18F]flubatine compared to (−)-[18F]flubatine was its higher binding affinity suggesting that (+)-[18F]flubatine might be able to detect also slight reductions of α4β2 nAChRs and could be more sensitive than (−)-[18F]flubatine in early stages of Alzheimer’s disease. To support the clinical translation, we investigated a fully image-based internal dosimetry approach for (+)-[18F]flubatine, comparing mouse data collected on a preclinical PET/MRI system to piglet and first-in-human data acquired on a clinical PET/CT system. Time-activity curves (TACs) were obtained from the three species, the animal data extrapolated to human scale, exponentially fitted and the organ doses (OD), and effective dose (ED) calculated with OLINDA.ResultsThe excreting organs (urinary bladder, kidneys, and liver) receive the highest organ doses in all species. Hence, a renal/hepatobiliary excretion pathway can be assumed. In addition, the ED conversion factors of 12.1 μSv/MBq (mice), 14.3 μSv/MBq (piglets), and 23.0 μSv/MBq (humans) were calculated which are well within the order of magnitude as known from other 18F-labeled radiotracers.ConclusionsAlthough both enantiomers of [18F]flubatine exhibit different binding kinetics in the brain due to the respective affinities, the effective dose revealed no enantiomer-specific differences among the investigated species. The preclinical dosimetry and biodistribution of (+)-[18F]flubatine was shown and the feasibility of a dose assessment based on image data acquired on a small animal PET/MR and a clinical PET/CT was demonstrated. Additionally, the first-in-human study confirmed the t

Journal article

Ludwig FA, Smits R, Fischer S, Donat CK, Hoepping A, Brust P, Steinbach Jet al., 2016, LC-MS Supported Studies on the in Vitro Metabolism of both Enantiomers of Flubatine and the in Vivo Metabolism of (+)-[(18)F]Flubatine-A Positron Emission Tomography Radioligand for Imaging alpha4beta2 Nicotinic Acetylcholine Receptors, Molecules, Vol: 21, ISSN: 1420-3049

Both enantiomers of [18F]flubatine are promising radioligands for neuroimaging of α4β2 nicotinic acetylcholine receptors (nAChRs) by positron emission tomography (PET). To support clinical studies in patients with early Alzheimer’s disease, a detailed examination of the metabolism in vitro and in vivo has been performed. (+)- and (−)-flubatine, respectively, were incubated with liver microsomes from mouse and human in the presence of NADPH (β-nicotinamide adenine dinucleotide 2′-phosphate reduced tetrasodium salt). Phase I in vitro metabolites were detected and their structures elucidated by LC-MS/MS (liquid chromatography-tandem mass spectrometry). Selected metabolite candidates were synthesized and investigated for structural confirmation. Besides a high level of in vitro stability, the microsomal incubations revealed some species differences as well as enantiomer discrimination with regard to the formation of monohydroxylated products, which was identified as the main metabolic pathway in this assay. Furthermore, after injection of 250 MBq (+)-[18F]flubatine (specific activity > 350 GBq/μmol) into mouse, samples were prepared from brain, liver, plasma, and urine after 30 min and investigated by radio-HPLC (high performance liquid chromatography with radioactivity detection). For structure elucidation of the radiometabolites of (+)-[18F]flubatine formed in vivo, identical chromatographic conditions were applied to LC-MS/MS and radio-HPLC to compare samples obtained in vitro and in vivo. By this correlation approach, we assigned three of four main in vivo radiometabolites to products that are exclusively C- or N-hydroxylated at the azabicyclic ring system of the parent molecule.

Journal article

Donat CK, Gaber K, Meixensberger J, Brust P, Pinborg LH, Hansen HH, Mikkelsen JDet al., 2016, Changes in Binding of [(123)I]CLINDE, a High-Affinity Translocator Protein 18 kDa (TSPO) Selective Radioligand in a Rat Model of Traumatic Brain Injury, Neuromolecular Medicine, Vol: 18, Pages: 158-169, ISSN: 1559-1174

After traumatic brain injury (TBI), secondaryinjuries develop, including neuroinflammatory processesthat contribute to long-lasting impairments. These secondaryinjuries represent potential targets for treatment anddiagnostics. The translocator protein 18 kDa (TSPO) isexpressed in activated microglia cells and upregulated inresponse to brain injury and therefore a potential biomarkerof the neuroinflammatory processes. Second-generationradioligands of TSPO, such as [123I]CLINDE, have ahigher signal-to-noise ratio as the prototype ligandPK11195. [123I]CLINDE has been employed in humanstudies using single-photon emission computed tomographyto image the neuroinflammatory response after stroke.In this study, we used the same tracer in a rat model of TBIto determine changes in TSPO expression. Adult Sprague–Dawley rats were subjected to moderate controlled corticalimpact injury and sacrificed at 6, 24, 72 h and 28 days postsurgery. TSPO expression was assessed in brain sectionsemploying [123I]CLINDE in vitro autoradiography. From24 h to 28 days post surgery, injured animals exhibited amarked and time-dependent increase in [123I]CLINDEbinding in the ipsilateral motor, somatosensory and parietalcortex, as well as in the hippocampus and thalamus.Interestingly, binding was also significantly elevated in thecontralateral M1 motor cortex following TBI. Craniotomywithout TBI caused a less marked increase in [123I]CLINDE binding, restricted to the ipsilateral hemisphere.Radioligand binding was consistent with an increase inTSPO mRNA expression and CD11b immunoreactivity atthe contusion site. This study demonstrates the applicabilityof [123I]CLINDE for detailed regional and quantitativeassessment of glial activity in experimental models ofTBI.

Journal article

Wenzel B, Mollitor J, Deuther-Conrad W, Dukic-Stefanovic S, Kranz M, Vraka C, Teodoro R, Gunther R, Donat CK, Ludwig FA, Fischer S, Smits R, Wadsak W, Mitterhauser M, Steinbach J, Hoepping A, Brust Pet al., 2016, Development of a Novel Nonpeptidic (18)F-Labeled Radiotracer for in Vivo Imaging of Oxytocin Receptors with Positron Emission Tomography, Journal of Medicinal Chemistry, Vol: 59, Pages: 1800-1817, ISSN: 0022-2623

With the aim of imaging and quantification of oxytocin receptors (OTRs) in living brain using positron emission tomography (PET), we developed a 18F-labeled small molecule radiotracer and investigated its in vivo pharmacokinetics in mice and pig. [18F]6b (KD = 12.3 nM) was radiolabeled by a two-step procedure using a microwave system with radiochemical yields of 26.9 ± 4.7%. Both organ distribution and small animal PET studies revealed limited brain uptake of [18F]6b in mouse (mean SUV of 0.04 at 30 min pi). Besides, significant radioactivity uptake in the pituitary gland was observed (SUV of 0.7 at 30 min pi). In a dynamic PET study in one piglet, we detected a higher uptake of [18F]6b in the olfactory bulb (SUV of 0.34 at 30 min pi) accompanied by a low uptake in the whole brain. In vitro autoradiographic studies on porcine brain sections indicated interaction of [18F]6b with several off-target receptors.

Journal article

Kranz M, Sattler B, Wust N, Deuther-Conrad W, Patt M, Meyer PM, Fischer S, Donat CK, Wunsch B, Hesse S, Steinbach J, Brust P, Sabri Oet al., 2016, Evaluation of the Enantiomer Specific Biokinetics and Radiation Doses of [(18)F]Fluspidine-A New Tracer in Clinical Translation for Imaging of sigma(1) Receptors, Molecules, Vol: 21

Journal article

Richter N, Donat CK, 2015, Of mice and men, ephemera: theory & politics in organization, Vol: 15, Pages: 307-318

Journal article

Holzhausen C, Groger D, Mundhenk L, Donat CK, Schnorr J, Haag R, Gruber ADet al., 2015, Biodistribution, cellular localization, and in vivo tolerability of S-35-labeled antiinflammatory dendritic polyglycerol sulfate amine, Journal of Nanoparticle Research, Vol: 17, ISSN: 1388-0764

Journal article

Magnussen JH, Ettrup A, Donat CK, Peters D, Pedersen MH, Knudsen GM, Mikkelsen JDet al., 2015, Radiosynthesis and in vitro validation of (3)H-NS14492 as a novel high affinity alpha7 nicotinic receptor radioligand, Eur J Pharmacol, Vol: 762, Pages: 35-41

Journal article

Teodoro R, Scheunemann M, Deuther-Conrad W, Wenzel B, Fasoli FM, Gotti C, Kranz M, Donat CK, Patt M, Hillmer A, Zheng MQ, Peters D, Steinbach J, Sabri O, Huang Y, Brust Pet al., 2015, A Promising PET Tracer for Imaging of alpha(7) Nicotinic Acetylcholine Receptors in the Brain: Design, Synthesis, and in Vivo Evaluation of a Dibenzothiophene-Based Radioligand, Molecules, Vol: 20, Pages: 18387-421

Journal article

Holl K, Schepmann D, Fischer S, Ludwig FA, Hiller A, Donat CK, Deuther-Conrad W, Brust P, Wunsch Bet al., 2014, Asymmetric Synthesis of Spirocyclic 2-Benzopyrans for Positron Emission Tomography of sigma1 Receptors in the Brain, Pharmaceuticals (Basel), Vol: 7, Pages: 78-112

Journal article

Sattler B, Kranz M, Starke A, Wilke S, Donat CK, Deuther-Conrad W, Patt M, Schildan A, Patt J, Smits R, Hoepping A, Schoenknecht P, Steinbach J, Brust P, Sabri Oet al., 2014, Internal dose assessment of (-)-18F-flubatine, comparing animal model datasets of mice and piglets with first-in-human results, J Nucl Med, Vol: 55, Pages: 1885-92

Journal article

Rotering S, Deuther-Conrad W, Cumming P, Donat CK, Scheunemann M, Fischer S, Xiong G, Steinbach J, Peters D, Sabri O, Bucerius J, Brust Pet al., 2014, Imaging of alpha7 nicotinic acetylcholine receptors in brain and cerebral vasculature of juvenile pigs with [(18)F]NS14490, EJNMMI Res, Vol: 4, Pages: 43-43

Journal article

Rötering S, Deuther-Conrad W, Cumming P, Donat CK, Scheunemann M, Fischer S, Xiong G, Steinbach J, Peters D, Sabri O, Bucerius J, Brust Pet al., 2014, Imaging of alpha7 nicotinic acetylcholine receptors in brain and cerebral vasculature of juvenile pigs with [(18)F]NS14490, EJNMMI Res, Vol: 4, Pages: 43-43

Journal article

Brust P, Deuther-Conrad W, Becker G, Patt M, Donat CK, Stittsworth S, Fischer S, Hiller A, Wenzel B, Dukic-Stefanovic S, Hesse S, Steinbach J, Wunsch B, Lever SZ, Sabri Oet al., 2014, Distinctive in vivo kinetics of the new sigma1 receptor ligands (R)-(+)- and (S)-(-)-18F-fluspidine in porcine brain, J Nucl Med, Vol: 55, Pages: 1730-6

Journal article

Brust P, Deuther-Conrad W, Donat CK, Barthel H, Riss P, Paterson L, Hoepping A, Sabri O, Cumming Pet al., 2014, Preclinical aspects of nicotinic acetylcholine receptor imaging., PET and SPECT of Neurobiological Systems, Editors: Dierckx, Otte, de Vries, van Waarde, Luiten, Publisher: Springer-Verlag Berlin Heidelberg

Book chapter

Donat CK, Fischer F, Walter B, Deuther-Conrad W, Brodhun M, Bauer R, Brust Pet al., 2014, Early increase of cannabinoid receptor density after experimental traumatic brain injury in the newborn piglet, Acta Neurobiol Exp (Wars), Vol: 74, Pages: 197-210

Journal article

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