Mirzaei N.,Imperial College London |
Tang S.P.,Imanova Ltd |
Ashworth S.,Imanova Ltd |
Coello C.,Imanova Ltd |
And 6 more authors.
GLIA | Year: 2016
Microglial activation has been linked with deficits in neuronal function and synaptic plasticity in Alzheimer's disease (AD). The mitochondrial translocator protein (TSPO) is known to be upregulated in reactive microglia. Accurate visualization and quantification of microglial density by PET imaging using the TSPO tracer [11C]-R-PK11195 has been challenging due to the limitations of the ligand. In this study, it was aimed to evaluate the new TSPO tracer [11C]PBR28 as a marker for microglial activation in the 5XFAD transgenic mouse model of AD. Dynamic PET scans were acquired following intravenous administration of [11C]PBR28 in 6-month-old 5XFAD mice and in wild-type controls. Autoradiography with [3H]PBR28 was carried out in the same brains to further confirm the distribution of the radioligand. In addition, immunohistochemistry was performed on adjacent brain sections of the same mice to evaluate the co-localization of TSPO with microglia. PET imaging revealed that brain uptake of [11C]PBR28 in 5XFAD mice was increased compared with control mice. Moreover, binding of [3H]PBR28, measured by autoradiography, was enriched in cortical and hippocampal brain regions, coinciding with the positive staining of the microglial marker Iba-1 and amyloid deposits in the same areas. Furthermore, double-staining using antibodies against TSPO demonstrated co-localization of TSPO with microglia and not with astrocytes in 5XFAD mice and human post-mortem AD brains. The data provided support of the suitability of [11C]PBR28 as a tool for in vivo monitoring of microglial activation and assessment of treatment response in future studies using animal models of AD. GLIA 2016;64:993-1006 Main points: [11C]PBR28 imaging shows increased uptake in brains of 5XFAD mice. Binding of [3H]PBR28 is enriched in cortex and hippocampus, which correlated with Iba-1 staining. TSPO co-localized with microglial staining but not with markers of astrocytes in 5XFAD mice. © 2016 Wiley Periodicals, Inc.
Gunn R.N.,Imperial College London |
Gunn R.N.,Imanova Ltd |
Gunn R.N.,University of Oxford |
Slifstein M.,Columbia University |
And 3 more authors.
Physics in Medicine and Biology | Year: 2015
PET imaging of proteins in the human brain with high affinity radiolabelled molecules has a history stretching back over 30 years. During this period the portfolio of protein targets that can be imaged has increased significantly through successes in radioligand discovery and development. This portfolio now spans six major categories of proteins; G-protein coupled receptors, membrane transporters, ligand gated ion channels, enzymes, misfolded proteins and tryptophan-rich sensory proteins. In parallel to these achievements in radiochemical sciences there have also been significant advances in the quantitative analysis and interpretation of the imaging data including the development of methods for image registration, image segmentation, tracer compartmental modeling, reference tissue kinetic analysis and partial volume correction. In this review, we analyze the activity of the field around each of the protein targets in order to give a perspective on the historical focus and the possible future trajectory of the field. The important neurobiology and pharmacology is introduced for each of the six protein classes and we present established radioligands for each that have successfully transitioned to quantitative imaging in humans. We present a standard quantitative analysis workflow for these radioligands which takes the dynamic PET data, associated blood and anatomical MRI data as the inputs to a series of image processing and bio-mathematical modeling steps before outputting the outcome measure of interest on either a regional or parametric image basis. The quantitative outcome measures are then used in a range of different imaging studies including tracer discovery and development studies, cross sectional studies, classification studies, intervention studies and longitudinal studies. Finally we consider some of the confounds, challenges and subtleties that arise in practice when trying to quantify and interpret PET neuroimaging data including motion artifacts, partial volume effects, age effects, image registration and normalization, input functions and metabolites, parametric imaging, receptor internalization and genetic factors. © 2015 Institute of Physics and Engineering in Medicine.
Kealey S.,King's College London |
Kealey S.,Imanova Ltd. |
Husbands S.M.,University of Bath |
Bennacef I.,Merck And Co. |
And 2 more authors.
Journal of Labelled Compounds and Radiopharmaceuticals | Year: 2014
Palladium(II)-mediated oxidative carbonylation reactions have been used to synthesize 11C-radiolabelled ureas via the coupling of amines with [11C]carbon monoxide, in a one-pot process. Following trapping of 11CO in a solution of copper(I) tris(3,5-dimethylpyrazolyl)borate, homocoupling reactions of primary aliphatic amines proceed in the presence of Pd(PPh3)2Cl2 to give the corresponding N,N-disubstituted [11C]ureas. Secondary amines do not produce the corresponding N,N,N,N-tetrasubsituted [11C]ureas under these conditions. This difference in reactivity allows for the formation of unsymmetrical N,N',N'-trisubstituted [11C]ureas using a mixture of a primary amine and a reactive secondary amine. The potential use of this method in positron emission tomography (PET) was demonstrated by the synthesis of the M1 muscarinic acetylcholine receptor radiotracer, [11C-carbonyl] GSK1034702. © 2013 John Wiley & Sons, Ltd.
Agency: European Commission | Branch: FP7 | Program: CP-IP | Phase: HEALTH-2009-1.4-1 | Award Amount: 16.14M | Year: 2010
There are currently no cures for Parkinsons disease (PD) but one of the most effective reparative therapies in patients to date has been with allotransplants of dopamine (DA) neuroblasts obtained from fetal ventral mesencephalic (VM) tissue. However, this cell transplantation approach has given inconsistent results, with some patients doing extremely well and coming off anti-PD medication for years, whilst others have shown no or only modest clinical improvements, and in some cases also developed severe, off-state graft-induced dyskinesias (GIDs). The reasons behind this heterogeneity of outcomes, and the emergence of GIDs in particular, need to be better understood, not least in the perspective of the rapid advances that are now being made in the development of stem-cell based therapies. There is therefore an urgent need to revisit the trials that have already been done with fetal VM tissue in PD patients, with the expectation that a critical reassessment can form the basis for an optimised and more standardised procedure that will translate into more consistently efficacious transplants with minimal side-effects. Over the last two years a group of international experts, including the key investigators of the previous European and North American trials, has been re-examining the outcome of these trials as well as reviewing the results obtained from recent and ongoing animal experimental studies, and identified a number of weaknesses that may explain the inconsistent outcome in previous trials. As a result of these discussions, the group has agreed to join forces in a new round of experimental work and cell therapy trials in PD, based on a new jointly developed protocol where all these factors are taken into account. In the first instance fetal VM tissue containing mesencephalic DA neuroblasts will be used, with the expectation that this will pave the way for bigger trials using dopaminergic neurons derived from stem cells.
PubMed | Central and North West London NHS Trust, Imanova Ltd, Imperial College London, West London Mental Health NHS Trust and 2 more.
Type: Journal Article | Journal: Translational psychiatry | Year: 2017
Repeated withdrawal from alcohol is clinically associated with progressive cognitive impairment. Microglial activation occurring during pre-clinical models of alcohol withdrawal is associated with learning deficits. We investigated whether there was microglial activation in recently detoxified alcohol-dependent patients (ADP), using [
Agency: European Commission | Branch: H2020 | Program: MSCA-ITN-ETN | Phase: MSCA-ITN-2015-ETN | Award Amount: 3.91M | Year: 2016
The drug development strategy currently pursued by the pharmaceutical industry worldwide is inefficient and unsustainable for the health care system. To keep the latter affordable, drug development should become more efficient and drug treatment should become more personalized and rationalized. Molecular imaging can play a pivotal role in changing the landscape of drug design/development and improving the health care system. Positron Emission Tomography (PET) imaging, in particular, is the technology that has the potential to lead this fundamental innovation by providing at a much earlier stage reliable answers to key questions emerging during the care cycle: what and where is the disease? Is the disease accurately targeted by the therapy? Is the treatment effective? By answering the questions above, PET imaging has the capacity to render much more effectively the transition from pre-clinical to clinical phase, and to strongly facilitate the development of better drugs at an earlier stage and in a much more sustainable manner. The main obstacle to this change of paradigm in drug design and development is the lack of suitably trained translational scientists directly involved in PET imaging and imaging scientists with high-profile training in chemistry and PET-radiochemistry, which is particularly dramatic in Europe. This consortium is ideally suited to fill this gap, by providing top-quality training to the next generation of translational PET imaging scientists who will play a key role in shaping the future of drug design and development. The PET3D ETN will focus on 15 cutting-edge research projects in the 3 main therapeutic areas (oncology, cardiovascular, central nervous system) that will be conducted by 15 ESRs at 8 European beneficiary Institutions, 6 academic (all having a PET center on site) and 2 non-academic (one with a PET center on site and one big pharmaceutical company) representing the drug design and development terminus of the project.
Jones T.,PET Research Advisory Company |
Jones T.,University of Manchester |
Rabiner E.A.,Imanova Ltd |
Journal of Cerebral Blood Flow and Metabolism | Year: 2012
The early developments of brain positron emission tomography (PET), including the methodological advances that have driven progress, are outlined. The considerable past achievements of brain PET have been summarized in collaboration with contributing experts in specific clinical applications including cerebrovascular disease, movement disorders, dementia, epilepsy, schizophrenia, addiction, depression and anxiety, brain tumors, drug development, and the normal healthy brain. Despite a history of improving methodology and considerable achievements, brain PET research activity is not growing and appears to have diminished. Assessments of the reasons for decline are presented and strategies proposed for reinvigorating brain PET research. Central to this is widening the access to advanced PET procedures through the introduction of lower cost cyclotron and radiochemistry technologies. The support and expertize of the existing major PET centers, and the recruitment of new biologists, bio-mathematicians and chemists to the field would be important for such a revival. New future applications need to be identified, the scope of targets imaged broadened, and the developed expertize exploited in other areas of medical research. Such reinvigoration of the field would enable PET to continue making significant contributions to advance the understanding of the normal and diseased brain and support the development of advanced treatments. © 2012 ISCBFM All rights reserved.
Veronese M.,University of Padua |
Gunn R.N.,Imanova Ltd |
Gunn R.N.,Imperial College London |
Gunn R.N.,University of Oxford |
And 2 more authors.
NeuroImage | Year: 2013
Quantitative PET studies with arterial blood sampling usually require the correction of the measured total plasma activity for the presence of metabolites. In particular, if labelled metabolites are found in the plasma in significant amounts their presence has to be accounted for, because it is the concentration of the parent tracer which is required for data quantification. This is achieved by fitting a Parent Plasma fraction (PPf) model to discrete metabolite measurements. The commonly used method is based on an individual approach, i.e. for each subject the PPf model parameters are estimated from its own metabolite samples, which are, in general, sparse and noisy. This fact can compromise the quality of the reconstructed arterial input functions, and, consequently, affect the quantification of tissue kinetic parameters.In this study, we proposed a Non-Linear Mixed Effect Modelling (NLMEM) approach to describe metabolite kinetics. Since NLMEM has been developed to provide robust parameter estimates in the case of sparse and/or noisy data, it has the potential to be a reliable method for plasma metabolite correction.Three different PET datasets were considered: [11C]-(+)-PHNO (54 scans), [11C]-PIB (22 scans) and [11C]-DASB (30 scans). For each tracer both simulated and measured data were considered and NLMEM performance was compared with that provided by individual analysis.Results showed that NLMEM provided improved estimates of the plasma parent input function over the individual approach when the metabolite data were sparse or contained outliers. © 2012 Elsevier Inc.
Agency: GTR | Branch: EPSRC | Program: | Phase: Research Grant | Award Amount: 261.18K | Year: 2015
Magnetic Resonance (MR) and radionuclide imaging using Positron Emission Tomography (PET) have established roles in medical diagnosis, clinical research and drug development. In recognition of the complementary nature of these two modalities, which have historically been used separately, integrated PET-MR scanners have been designed and marketed by manufacturers. These devices open-up exciting avenues to exploit the synergy between these two modalities in many areas, including dementia, cardiology, and investigation of dynamic processes such as the uptake of contrast agents by tumours. Both modalities are tomographic: from the measured data, (stacks of) slices or volumes representing anatomical and functional properties of the patient can be reconstructed using sophisticated algorithms. Image quality is critically dependent on image reconstruction methods. Development and testing of novel algorithms on patient data requires considerable expertise and effort in software implementation. We will establish a new Collaborative Computational Project (CCP) to connect researchers working at different sites and on the different modalities of PET and/or MR in the area of image reconstruction, concentrating on the logistical and computational aspects of integrated PET-MR. The platform to be provided by this CCP will be an enabling technology which removes the frequent obstacles encountered when working with the raw medical imaging datasets acquired by PET and MR scanners. It will be straightforward to work with data in a standardized format, massively aiding and accelerating innovative developments in image reconstruction and processing for PET-MR, and ultimately enabling the possibility of synergistic image reconstruction.
Jiao J.,University of Oxford |
Jiao J.,Imanova Ltd |
Searle G.E.,Imanova Ltd |
Tziortzi A.C.,Imanova Ltd |
And 6 more authors.
NeuroImage | Year: 2014
In dynamic positron emission tomography (PET) neuroimaging studies, where scan durations often exceed 1h, registration of motion-corrupted dynamic PET images is necessary in order to maintain the integrity of the physiological, pharmacological, or biochemical information derived from the tracer kinetic analysis of the scan. In this work, we incorporate a pharmacokinetic model, which is traditionally used to analyse PET data following any registration, into the registration process itself in order to allow for a groupwise registration of the temporal time frames. The new method is shown to achieve smaller registration errors and improved kinetic parameter estimates on validation data sets when compared with image similarity based registration approaches. When applied to measured clinical data from 10 healthy subjects scanned with [11C]-(+)-PHNO (a dopamine D3/D2 receptor tracer), it reduces the intra-class variability on the receptor binding outcome measure, further supporting the improvements in registration accuracy. Our method incorporates a generic tracer kinetic model which makes it applicable to different PET radiotracers to remove motion artefacts and increase the integrity of dynamic PET studies. © 2013 Elsevier Inc.