Change search
Refine search result
1 - 22 of 22
CiteExportLink to result list
Permanent link
Cite
Citation style
  • apa
  • ieee
  • modern-language-association-8th-edition
  • vancouver
  • Other style
More styles
Language
  • de-DE
  • en-GB
  • en-US
  • fi-FI
  • nn-NO
  • nn-NB
  • sv-SE
  • Other locale
More languages
Output format
  • html
  • text
  • asciidoc
  • rtf
Rows per page
  • 5
  • 10
  • 20
  • 50
  • 100
  • 250
Sort
  • Standard (Relevance)
  • Author A-Ö
  • Author Ö-A
  • Title A-Ö
  • Title Ö-A
  • Publication type A-Ö
  • Publication type Ö-A
  • Issued (Oldest first)
  • Issued (Newest first)
  • Created (Oldest first)
  • Created (Newest first)
  • Last updated (Oldest first)
  • Last updated (Newest first)
  • Disputation date (earliest first)
  • Disputation date (latest first)
  • Standard (Relevance)
  • Author A-Ö
  • Author Ö-A
  • Title A-Ö
  • Title Ö-A
  • Publication type A-Ö
  • Publication type Ö-A
  • Issued (Oldest first)
  • Issued (Newest first)
  • Created (Oldest first)
  • Created (Newest first)
  • Last updated (Oldest first)
  • Last updated (Newest first)
  • Disputation date (earliest first)
  • Disputation date (latest first)
Select
The maximal number of hits you can export is 250. When you want to export more records please use the Create feeds function.
  • 1.
    Burt, Tal
    et al.
    Burt Consultancy LLC, 2616 Erwin Rd 2405, Durham, NC 27705 USA.
    Vuong, Le Thuy
    Baker, Elizabeth
    Phys Comm Responsible Med, Washington, DC USA.
    Young, Graeme C.
    GSK, David Jack Ctr R&D, Translat Med, Res, Ware, Herts, England.
    McCartt, A. Daniel
    LLNL, Livermore, CA USA.
    Bergström, Mats
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Pharmacology. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Preclinical PET-MRI Platform.
    Sugiyama, Yuichi
    RIKEN, RIKEN Innovat Ctr, Sugiyama Lab, Yokohama, Kanagawa, Japan.
    Combes, Robert
    Phase 0, Including Microdosing Approaches: Applying the Three Rs and Increasing the Efficiency of Human Drug Development2018In: ATLA (Alternatives to Laboratory Animals), ISSN 0261-1929, Vol. 46, no 6, p. 335-346Article in journal (Refereed)
    Abstract [en]

    Phase 0 approaches, including microdosing, involve the use of sub-therapeutic exposures to the tested drugs, thus enabling safer, more-relevant, quicker and cheaper first-in-human (FIH) testing. These approaches also have considerable potential to limit the use of animals in human drug development. Recent years have witnessed progress in applications, methodology, operations, and drug development culture. Advances in applications saw an expansion in therapeutic areas, developmental scenarios and scientific objectives, in, for example, protein drug development and paediatric drug development. In the operational area, the increased sensitivity of Liquid Chromatography Tandem Mass Spectrometry (LC-MS/MS), expansion of the utility of Positron Emission Tomography (PET) imaging, and the introduction of Cavity Ring-Down Spectroscopy (CRDS), have led to the increased accessibility and utility of Phase 0 approaches, while reducing costs and exposure to radioactivity. PET has extended the application of microdosing, from its use as a predominant tool to record pharmacokinetics, to a method for recording target expression and target engagement, as well as cellular and tissue responses. Advances in methodology include adaptive Phase 0/Phase 1 designs, cassette and cocktail microdosing, and Intra-Target Microdosing (ITM), as well as novel modelling opportunities and simulations. Importantly, these methodologies increase the predictive power of extrapolation from microdose to therapeutic level exposures. However, possibly the most challenging domain in which progress has been made, is the culture of drug development. One of the main potential values of Phase 0 approaches is the opportunity to terminate development early, thus not only applying the principle of 'kill-early-kill-cheap' to enhance the efficiency of drug development, but also obviating the need for the full package of animal testing required for therapeutic level Phase 1 studies. Finally, we list developmental scenarios that utilised Phase 0 approaches in novel drug development.

  • 2.
    Elgland, Mathias
    et al.
    Linkoping Univ, Dept Phys Chem & Biol IFM, Linkoping, Sweden.
    Nordeman, Patrik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Preparative Medicinal Chemistry. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Preclinical PET-MRI Platform.
    Fyrner, Timmy
    Linkoping Univ, Dept Phys Chem & Biol IFM, Linkoping, Sweden.
    Konradsson, Peter
    Linkoping Univ, Dept Phys Chem & Biol IFM, Linkoping, Sweden.
    Antoni, Gunnar
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Preclinical PET-MRI Platform. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Preparative Medicinal Chemistry.
    Nilsson, Peter
    Linkoping Univ, Dept Phys Chem & Biol IFM, Linkoping, Sweden.
    Synthesis of beta-configured clickable [18F]FDGs as novel 18F-fluoroglycosylation tools for PET in vivo imaging2017In: Abstract of Papers of the American Chemical Society, ISSN 0065-7727, Vol. 253Article in journal (Other academic)
  • 3.
    Eriksson, Jonas
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Preparative Medicinal Chemistry.
    Roy, Tamal
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Preparative Medicinal Chemistry.
    Sawadjoon, Supaporn
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Preparative Medicinal Chemistry.
    Bachmann, Kim
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Preparative Medicinal Chemistry.
    Sköld, Christian
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Preparative Medicinal Chemistry.
    Larhed, Mats
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Preparative Medicinal Chemistry.
    Weis, Jan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences.
    Selvaraju, Ram
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Preclinical PET-MRI Platform.
    Korsgren, Olle
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Hematology and Immunology.
    Eriksson, Olof
    Uppsala University, Science for Life Laboratory, SciLifeLab.
    Synthesis and initial preclinical evaluation of the CRTH2 antagonist [C-11] MK-72462019In: Journal of Labelled Compounds and Pharmaceuticals, WILEY 111 RIVER ST, HOBOKEN 07030-5774, NJ USA , 2019, Vol. 62, p. S544-S545Conference paper (Refereed)
  • 4.
    Eriksson, Jonas
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry.
    Roy, Tamal
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry.
    Sawadjoon, Supaporn
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry.
    Bachmann, Kim
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry.
    Sköld, Christian
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry.
    Larhed, Mats
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Preparative Medicinal Chemistry.
    Weis, Jan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Radiology.
    Selvaraju, Ramkumar
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Preclinical PET-MRI Platform.
    Korsgren, Olle
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Eriksson, Olof
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry.
    Odell, Luke R.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry.
    Synthesis and preclinical evaluation of the CRTH2 antagonist [11C]MK-7246 as a novel PET tracer and potential surrogate marker for pancreatic beta-cell mass2019In: Nuclear Medicine and Biology, ISSN 0969-8051, E-ISSN 1872-9614, Vol. 71, p. 1-10Article in journal (Refereed)
    Abstract [en]

    Introduction: MK-7246 is a potent and selective antagonist for chemoattractant receptor-homologous molecule expressed on Th2 cells (CRTH2). Within the pancreas CRTH2 is selectively expressed in pancreatic β-cells where it is believed to play a role in insulin release. Reduction in β-cell mass and insufficient insulin secretion in response to elevated blood glucose levels is a hallmark for type 1 and type 2 diabetes. Reported here is the synthesis of [11C]MK-7246 and initial preclinical evaluation towards CRTH2 imaging. The aim is to develop a method to quantify β-cell mass with PET and facilitate non-invasive studies of disease progression in individuals with type 2 diabetes.

    Methods: The precursor N-desmethyl-O-methyl MK-7246 was synthesized in seven steps and subjected to methylation with [11C]methyl iodide followed by hydrolysis to obtain [11C]MK-7246 labelled in the N-methyl position. Preclinical evaluation included in vitro radiography and immune-staining performed in human pancreatic biopsies. Biodistribution studies were performed in rat by PET-MRI and in pig by PET-CT imaging. The specific tracer uptake was examined in pig by scanning before and after administration of MK-7246 (1 mg/kg). Predicted dosimetry of [11C]MK-7246 in human males was estimated based on the biodistribution in rat.

    Results: [11C]MK-7246 was obtained with activities sufficient for the current investigations (270±120 MBq) and a radiochemical purity of 93±2%. The tracer displayed focal binding in areas with insulin positive islet of Langerhans in human pancreas sections. Baseline uptake in pig was significantly reduced in CRTH2-rich areas after administration of MK-7246; pancreas (66% reduction) and spleen (88% reduction). [11C]MK-7246 exhibited a safe human predicted dosimetry profile as extrapolated from the rat biodistribution data.

    Conclusions: Initial preclinical in vitro and in vivo evaluation of [11C]MK-7246 show binding and biodistribution properties suitable for PET imaging of CRTH2. Further studies are warranted to assess its potential in β-cell mass imaging and CRTH2 drug development.

  • 5.
    Eriksson, Olof
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Theranostics.
    Johnström, Peter
    Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden.
    Cselenyi, Zsolt
    Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden.
    Jahan, Mahabuba
    Karolinska Institutet and Stockholm County Council, Stockholm, Sweden.
    Selvaraju, Ram kumar
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Preclinical PET-MRI Platform.
    Jensen-Waern, Marianne
    Swedish University of Agricultural Sciences, Uppsala, Sweden.
    Takano, Akihiro
    Karolinska Institutet and Stockholm County Council, Stockholm, Sweden.
    Sörhede Winzell, Maria
    AstraZeneca R&D, Mölndal, Sweden.
    Halldin, Christer
    6Lee Kong Chian School of Medicine, Nanyang Technological University, Singapore.
    Skrtic, Stanko
    Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden .
    Korsgren, Olle
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    In Vivo Visualization of beta-Cells by Targeting of GPR442018In: Diabetes, ISSN 0012-1797, E-ISSN 1939-327X, Vol. 67, no 2, p. 182-192Article in journal (Refereed)
    Abstract [en]

    GPR44 expression has recently been described as highly beta-cell selective in the human pancreas and constitutes a tentative surrogate imaging biomarker in diabetes. A radiolabeled small-molecule GPR44 antagonist, [C-11]AZ12204657, was evaluated for visualization of beta-cells in pigs and non-human primates by positron emission tomography as well as in immunodeficient mice transplanted with human islets under the kidney capsule. In vitro autoradiography of human and animal pancreatic sections from subjects without and with diabetes, in combination with insulin staining, was performed to assess beta-cell selectivity of the radiotracer. Proof of principle of in vivo targeting of human islets by [C-11]AZ12204657 was shown in the immunodeficient mouse transplantation model. Furthermore, [C-11]AZ12204657 bound by a GPR44-mediated mechanism in pancreatic sections from humans and pigs without diabetes, but not those with diabetes. In vivo [C-11]AZ12204657 bound specifically to GPR44 in pancreas and spleen and could be competed away dose-dependently in nondiabetic pigs and nonhuman primates. [C-11]AZ12204657 is a first-in-class surrogate imaging biomarker for pancreatic beta-cells by targeting the protein GPR44.

  • 6.
    Eriksson, Olof
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Theranostics.
    Rosenström, Ulrika
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Preparative Medicinal Chemistry.
    Selvaraju, Ram Kumar
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Preclinical PET-MRI Platform.
    Eriksson, Barbro
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Endocrine Tumor Biology.
    Velikyan, Irina
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Preparative Medicinal Chemistry.
    Species differences in pancreatic binding of DO3A-VS-Cys40-Exendin42017In: Acta Diabetologica, ISSN 0940-5429, E-ISSN 1432-5233, Vol. 54, no 11, p. 1039-1045Article in journal (Refereed)
    Abstract [en]

    AIMS: Radiolabeled Exendin-4 has been proposed as suitable imaging marker for pancreatic beta cell mass quantification mediated by Glucagon-like peptide-1 receptor (GLP-1R). However, noticeable species variations in basal pancreatic uptake as well as uptake reduction degree due to selective beta cell ablation were observed.

    METHODS: -Exendin4 Positron Emission Tomography (PET) in the same species. In vitro, ex vivo, and in vivo data formed the basis for calculating the theoretical in vivo contribution of each pancreatic compartment.

    RESULTS: -Exendin4.

    CONCLUSIONS: IPR as well as the exocrine GLP-1R density is the main determinants of the species variability in pancreatic uptake. Thus, the IPR in human is an important factor for assessing the potential of GLP-1R as an imaging biomarker for pancreatic beta cells.

  • 7.
    Estrada, Sergio
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Preclinical PET-MRI Platform.
    Lubberink, Mark
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Radiology.
    Thibblin, Alf
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Division of Molecular Imaging.
    Sprycha, Margareta
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Division of Molecular Imaging.
    Buchanan, Tim
    UCB Pharma, Brussels, Belgium..
    Mestdagh, Nathalie
    UCB Pharma, Brussels, Belgium..
    Kenda, Benoit
    UCB Pharma, Brussels, Belgium..
    Mercier, Joel
    UCB Pharma, Brussels, Belgium..
    Provins, Laurent
    UCB Pharma, Brussels, Belgium..
    Gillard, Michel
    UCB Pharma, Brussels, Belgium..
    Tytgat, Dominique
    UCB Pharma, Brussels, Belgium.;Sanofi Aventis Deutschland GmbH, Frankfurt, Germany..
    Antoni, Gunnar
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Division of Molecular Imaging.
    [C-11]UCB-A, a novel PET tracer for synaptic vesicle protein 2 A2016In: Nuclear Medicine and Biology, ISSN 0969-8051, E-ISSN 1872-9614, Vol. 43, no 6, p. 325-332Article in journal (Refereed)
    Abstract [en]

    Introduction: Development of a selective and specific high affinity PET tracer, [C-11]UCB-A, for the in vivo study of SV2A expression in humans. Radiochemistry and preclinical studies in rats and pigs including development of a tracer kinetic model to determine V-T. A method for the measurement of percent intact tracer in plasma was developed and the radiation dosimetry was determined in rats. Results: 3-5 GBq of [C-11]UCB-A could be produced with radiochemical purity exceeding 98% with a specific radioactivity of around 65 GBq/mu mol. In vitro binding showed high selective binding towards SV2A. [C-11]UCB-A displayed a dose-dependent and reversible binding to SV2A as measured with PET in rats and pigs and the V-T could be determined by Logan analysis. The dosimetry was favorable and low enough to allow multiple administrations of [C-11]UCB-A to healthy volunteers, and the metabolite analysis showed no sign of labeled metabolites in brain. Conclusions: We have developed the novel PET tracer, [C-11]UCB-A, that can be used to measure SV2A expression in vivo. The dosimetry allows up to 5 administrations of 400 MBq of [C-11]UCB-A in humans. Apart from measuring drug occupancy, as we have shown, the tracer can potentially be used to compare SV2A expression between individuals because of the rather narrow range of baseline V-T values. This will have to be further validated in human studies.

  • 8.
    Fang, Xiaotian T.
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
    Eriksson, Jonas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Preclinical PET-MRI Platform. PET Centre, Uppsala University Hospital, 751 85 Uppsala, Sweden.
    Antoni, Gunnar
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Preclinical PET-MRI Platform. Uppsala University Hospital, 751 85 Uppsala, SwedenUppsala University Hospital, 751 85 Uppsala, Sweden.
    Yngve, Ulrika
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Preclinical PET-MRI Platform. Uppsala University Hospital, 751 85 Uppsala, SwedenUppsala University Hospital, 751 85 Uppsala, Sweden.
    Cato, Linda
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
    Lannfelt, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
    Sehlin, Dag
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
    Syvänen, Stina
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
    Brain mGluR5 in mice with amyloid beta pathology studied with in vivo [(11)C]ABP688 PET imaging and ex vivo immunoblotting2017In: Neuropharmacology, ISSN 0028-3908, E-ISSN 1873-7064, Vol. 113, no Pt A, p. 293-300, article id S0028-3908(16)30459-2Article in journal (Refereed)
    Abstract [en]

    Alzheimer's disease (AD) is characterized by aggregation of amyloid beta (Aβ) into insoluble plaques. Intermediates, Aβ oligomers (Aβo), appear to be the mechanistic cause of disease. The de facto PET AD ligand, [(11)C]PIB, binds and visualizes Aβ plaque load, which does not correlate well with disease severity. Therefore, finding a dynamic target that changes with pathology progression in AD is of great interest. Aβo alter synaptic plasticity, inhibit long-term potentiation, and facilitate long-term depression; key mechanisms involved in memory and learning. In order to convey these neurotoxic effects, Aβo requires interaction with the metabotropic glutamate 5 receptor (mGluR5). The aim was to investigate in vivo mGluR5 changes in an Aβ pathology model using PET. Wild type C57/BL6 (wt) and AβPP transgenic mice (tg-ArcSwe), 4, 8, and 16 months old, were PET scanned with [(11)C]ABP688, which is highly specific to mGluR5, to investigate changes in mGluR5. Mouse brains were extracted postscan and mGluR5 and Aβ protofibril levels were assessed with immunoblotting and ELISA respectively. Receptor-dense brain regions (hippocampus, thalamus, and striatum) displayed higher [(11)C]ABP688 concentrations corresponding to mGluR5 expression pattern. Mice had similar uptake levels of [(11)C]ABP688 regardless of genotype or age. Immunoblotting revealed general decline in mGluR5 expression and elevated levels of mGluR5 in 16 months old tg-ArcSwe compared with wt mice. [(11)C]ABP688 could visualize mGluR5 in the mouse brain. In conclusion, mGluR5 levels were found to decrease with age and tended to be higher in tg-ArcSwe compared with wt mice, however these changes could not be quantified with PET.

  • 9.
    Fang, Xiaotian T.
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
    Hultqvist, Greta
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Meier, Silvio R.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
    Antoni, Gunnar
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Preclinical PET-MRI Platform.
    Sehlin, Dag
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
    Syvänen, Stina
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
    High detection sensitivity with antibody-based PET radioligand for amyloid beta in brain2019In: NeuroImage, ISSN 1053-8119, E-ISSN 1095-9572, Vol. 184, p. 881-888Article in journal (Refereed)
    Abstract [en]

    PET imaging of amyloid-beta (A beta) deposits in brain has become an important aid in Alzheimer's disease diagnosis, and an inclusion criterion for patient enrolment into clinical trials of new anti-A beta treatments. Available PET radioligands visualizing A beta bind to insoluble fibrils, i.e. A beta plaques. Levels of prefibrillar A beta forms, e.g. soluble oligomers and protofibrils, correlate better than plaques with disease severity and these soluble species are the neurotoxic form of A beta leading to neurodegeneration. The goal was to create an antibody-based radioligand, recognizing not only fibrillary A beta , but also smaller and still soluble aggregates. We designed and expressed a small recombinant bispecific antibody construct, di-scFv 3D6-8D3, targeting the A beta N-terminus and the transferrin receptor (TfR). Natively expressed at the blood-brain barrier (BBB), TfR could thus be used as a brain-blood shuttle. Di-scFv 3D6-8D3 bound to A beta 1-40 with high affinity and to TfR with moderate affinity. Di-scFv [I-124] 3D6-8D3 was injected in two transgenic mouse models overexpressing human A beta and wild-type control mice and PET scanned at 14, 24 or 72 h after injection. Di-scFv [I-124] 3D6-8D3 was retained in brain of transgenic animals while it was cleared from wild-type lacking A beta . This difference was observed from 24 h onwards, and at 72 h, 18 months old transgenic animals, with high load of A beta pathology, displayed SUVR of 2.2-3.5 in brain while wildtype showed ratios close to unity. A subset of the mice were also scanned with [C-11] PIB. Again wt mice displayed ratios of unity while transgenes showed slightly, non-significantly, elevated SUVR of 1.2, indicating improved sensitivity with novel di-scFv [I-124] 3D6-8D3 compared with [C-11] PIB. Brain concentrations of di-scFv [I-124] 3D6-8D3 correlated with soluble A beta (p < 0.0001) but not with total A beta, i.e. plaque load (p = 0.34). We have successfully created a small bispecific antibody-based radioligand capable of crossing the BBB, subsequently binding to and visualizing intrabrain A beta in vivo. The radioligand displayed better sensitivity compared with [C-11] PIB, and brain concentrations correlated with soluble neurotoxic A beta aggregates.

  • 10. Heurling, Kerstin
    et al.
    Ashton, Nicholas J
    Leuzy, Antoine
    Zimmer, Eduardo R
    Blennow, Kaj
    Zetterberg, Henrik
    Eriksson, Jonas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Preclinical PET-MRI Platform. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Preparative Medicinal Chemistry.
    Lubberink, Mark
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Radiology.
    Schöll, Michael
    Synaptic vesicle protein 2A as a potential biomarker in synaptopathies2019In: Molecular and Cellular Probes, ISSN 1044-7431, E-ISSN 1095-9327, Vol. 97, p. 34-42Article in journal (Refereed)
    Abstract [en]

    Measuring synaptic density in vivo using positron emission tomography (PET) imaging-based biomarkers targeting the synaptic vesicle protein 2A (SV2A) has received much attention recently due to its potential research and clinical applications in synaptopathies, including neurodegenerative and psychiatric diseases. Fluid-based biomarkers in proteinopathies have previously been suggested to provide information on pathology and disease status that is complementary to PET-based measures, and the same can be hypothesized with respect to SV2A. This review provides an overview of the current state of SV2A PET imaging as a biomarker of synaptic density, the potential role of fluid-based biomarkers for SV2A, and related future perspectives.

  • 11.
    Hulsart Billström, Gry
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Orthopaedics.
    Selvaraju, Ramkumar
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Preclinical PET-MRI Platform.
    Estrada, Sergio
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Preclinical PET-MRI Platform.
    Lubberink, Mark
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Radiology.
    Asplund, Veronika
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry.
    Bergman, Kristoffer
    TERMIRA, Stockholm, Sweden.
    Marsell, Richard
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Orthopaedics.
    Larsson, Sune
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Orthopaedics.
    Antoni, Gunnar
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Preparative Medicinal Chemistry.
    Non-invasive tri-modal visualisation via PET/SPECT/μCT of recombinant human bone morphogenetic protein-2 retention and associated bone regeneration: A proof of concept2018In: Journal of Controlled Release, ISSN 0168-3659, E-ISSN 1873-4995, Vol. 285, p. 178-186Article in journal (Refereed)
    Abstract [en]

    Bone morphogenetic proteins (BMP's) are vital for bone and cartilage formation, where bone morphogenetic protein-2 (BMP-2) is acknowledged as a growth factor in osteoblast differentiation. However, uncontrolled delivery may result in adverse clinical effects. In this study we investigated the possibility for longitudinal and non-invasive monitoring of implanted [125I]BMP-2 retention and its relation to ossification at the site of implantation. A unilateral critically sized femoral defect was produced in the left limb of rats while the right femur was retained intact as a paired reference control. The defect was filled with a hyaluronan hydrogel with 25% hydroxyapatite alone (carrier control; n = 2) or combined with a mixture of [125I]BMP-2 (150 μg/ml; n = 4). Bone formation was monitored using micro computed tomography (μCT) scans at 1, 3, 5, 7, 9 and 12 weeks. The retention of [125I]BMP-2 was assessed with single photon emission computed tomography (SPECT), and the bone healing process was followed with sodium fluoride (Na18F) using positron emission tomography (PET) at day 3 and at week 2, 4, and 6. A rapid burst release of [125I]BMP-2 was detected via SPECT. This was followed by a progressive increase in uptake levels of [18F]fluoride depicted by PET imaging that was confirmed as bone formation via μCT. We propose that this functional, non-invasive imaging method allows tri-modal visualisation of the release of BMP-2 and the following in vivo response. We suggest that the potential of this novel technique could be considered for preclinical evaluation of novel smart materials on bone regeneration.

  • 12. Jahan, Mahabuba
    et al.
    Johnström, Peter
    Selvaraju, Ramkumar
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Preclinical PET-MRI Platform. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Svedberg, Marie
    Winzell, Maria Sörhede
    Bernström, Jenny
    Kingston, Lee
    Schou, Magnus
    Jia, Zhisheng
    Skrtic, Stanko
    Johansson, Lars
    Korsgren, Olle
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Farde, Lars
    Halldin, Christer
    Eriksson, Olof
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Theranostics.
    The development of a GPR44 targeting radioligand [11C]AZ12204657 for in vivo assessment of beta cell mass.2018In: EJNMMI Research, ISSN 2191-219X, E-ISSN 2191-219X, Vol. 8, article id 113Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: The G-protein-coupled receptor 44 (GPR44) is a beta cell-restricted target that may serve as a marker for beta cell mass (BCM) given the development of a suitable PET ligand.

    METHODS: The binding characteristics of the selected candidate, AZ12204657, at human GPR44 were determined using in vitro ligand binding assays. AZ12204657 was radiolabeled using 11C- or 3H-labeled methyl iodide ([11C/3H]CH3I) in one step, and the conversion of [11C/3H]CH3I to the radiolabeled product [11C/3H]AZ12204657 was quantitative. The specificity of radioligand binding to GPR44 and the selectivity for beta cells were evaluated by in vitro binding studies on pancreatic sections from human and non-human primates as well as on homogenates from endocrine and exocrine pancreatic compartments.

    RESULTS: The radiochemical purity of the resulting radioligand [11C]AZ12204657 was > 98%, with high molar activity (MA), 1351 ± 575 GBq/μmol (n = 18). The radiochemical purity of [3H]AZ12204657 was > 99% with MA of 2 GBq/μmol. Pancreatic binding of [11C/3H]AZ12204657 was co-localized with insulin-positive islets of Langerhans in non-diabetic individuals and individuals with type 2 diabetes (T2D). The binding of [11C]AZ12204657 to GPR44 was > 10 times higher in islet homogenates compared to exocrine homogenates. In human islets of Langerhans GPR44 was co-expressed with insulin, but not glucagon as assessed by co-staining and confocal microscopy.

    CONCLUSION: We radiolabeled [11C]AZ12204657, a potential PET radioligand for the beta cell-restricted protein GPR44. In vitro evaluation demonstrated that [3H]AZ12204657 and [11C]AZ12204657 selectively target pancreatic beta cells. [11C]AZ12204657 has promising properties as a marker for human BCM.

  • 13.
    Jonasson, My
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Radiology.
    Wall, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Radiology.
    Chiotis, Konstantinos
    Division of Clinical Geriatrics, Center for Alzheimer Research, Department of Neurobiology, Care Sciences and Society, Karolinska Institutet, Huddinge, Sweden.
    Leuzy, Antoine
    Division of Clinical Geriatrics, Center for Alzheimer Research, Department of Neurobiology, Care Sciences and Society, Karolinska Institutet, Huddinge, Sweden.
    Eriksson, Jonas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Preclinical PET-MRI Platform.
    Antoni, Gunnar
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Preclinical PET-MRI Platform.
    Nordberg, Agneta
    Division of Clinical Geriatrics, Center for Alzheimer Research, Department of Neurobiology, Care Sciences and Society, Karolinska Institutet, Huddinge, Sweden;Theme Aging, Karolinska University Hospital, Huddinge, Sweden.
    Lubberink, Mark
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Radiology.
    Optimal timing of tau pathology imaging and automatic extraction of a reference region using dynamic [18F]THK5317 PET.2019In: NeuroImage: Clinical, ISSN 0353-8842, E-ISSN 2213-1582, Vol. 22, article id 101681Article in journal (Refereed)
    Abstract [en]

    [18F]THK5317 is a PET tracer for in-vivo imaging of tau associated with Alzheimer's disease (AD). This work aimed to evaluate optimal timing for standardized uptake value ratio (SUVR) measures with [18F]THK5317 and automated generation of SUVR-1 and relative cerebral blood flow (R1) parametric images. Nine AD patients and nine controls underwent 90 min [18F]THK5317 scans. SUVR-1 was calculated at transient equilibrium (TE) and for seven different 20 min intervals and compared with distribution volume ratio (DVR; reference Logan). Cerebellar grey matter (MRI) was used as reference region. A supervised cluster analysis (SVCA) method was implemented to automatically generate a reference region, directly from the dynamic PET volume without the need of a structural MRI scan, for computation of SUVR-1 and R1 images for a scan duration matching the optimal timing. TE was reached first in putamen, frontal- and parietal cortex at 22 ± 4 min for AD patients and in putamen at 20 ± 0 min in controls. Over all regions and subjects, SUVR20-40-1 correlated best with DVR-1, R2 = 0.97. High correlation was found between values generated using MRI- and SVCA-based reference (R2 = 0.93 for SUVR20-40-1; R2 = 0.94 for R1). SUVR20-40 allows for accurate semi-quantitative assessment of tau pathology and SVCA may be used to obtain a reference region for calculation of both SUVR-1 and R1 with 40 min scan duration.

  • 14.
    Jonasson, My
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Radiology. Univ Uppsala Hosp, Med Phys, Uppsala, Sweden.
    Wall, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Radiology. Univ Uppsala Hosp, PET Ctr, Uppsala, Sweden.
    Chiotis, Konstantinos
    Karolinska Inst, Dept Neurobiol Care Sci & Soc, Ctr Alzheimer Res, Translat Alzheimer Neurobiol, S-14157 Huddinge, Sweden.
    Saint-Aubert, Laure
    Karolinska Inst, Dept Neurobiol Care Sci & Soc, Ctr Alzheimer Res, Translat Alzheimer Neurobiol, S-14157 Huddinge, Sweden.
    Wilking, Helena
    Univ Uppsala Hosp, PET Ctr, Uppsala, Sweden.
    Sprycha, Margareta
    Univ Uppsala Hosp, PET Ctr, Uppsala, Sweden.
    Borg, Beatrice
    Univ Uppsala Hosp, PET Ctr, Uppsala, Sweden.
    Thibblin, Alf
    Univ Uppsala Hosp, PET Ctr, Uppsala, Sweden.
    Eriksson, Jonas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Division of Molecular Imaging. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Preclinical PET-MRI Platform. Univ Uppsala Hosp, PET Ctr, Uppsala, Sweden.
    Sörensen, Jens
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Radiology. Univ Uppsala Hosp, PET Ctr, Uppsala, Sweden.
    Antoni, Gunnar
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Preclinical PET-MRI Platform. Univ Uppsala Hosp, PET Ctr, Uppsala, Sweden.
    Nordberg, Agneta
    Karolinska Inst, Dept Neurobiol Care Sci & Soc, Ctr Alzheimer Res, Translat Alzheimer Neurobiol, S-14157 Huddinge, Sweden.; Karolinska Univ, Huddinge Hosp, Dept Geriatr Med, Stockholm, Sweden.
    Lubberink, Mark
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Radiology. Univ Uppsala Hosp, Med Phys, Uppsala, Sweden.
    Tracer kinetic analysis of (S)-18F-THK5117 as a PET tracer for assessing tau pathology.2016In: Journal of Nuclear Medicine, ISSN 0161-5505, E-ISSN 1535-5667, Vol. 57, no 4, p. 574-581Article in journal (Refereed)
    Abstract [en]

    Because a correlation between tau pathology and the clinical symptoms of Alzheimer's disease (AD) has been hypothesized, there is increasing interest in developing PET tracers that bind specifically to tau protein. The aim of this study was to evaluate tracer kinetic models for quantitative analysis and generation of parametric images for the novel tau ligand (S)-(18)F-THK5117.

    METHODS: 9 subjects (5 with AD, 4 with mild cognitive impairment) received a 90 min dynamic (S)-(18)F-THK5117 PET scan. Arterial blood was sampled for measurement of blood radioactivity and metabolite analysis. VOI-based analysis was performed using plasma-input models; single-tissue and two-tissue (2TCM) compartment models and plasma-input Logan, and reference tissue models; simplified reference tissue model (SRTM), reference Logan and standardised uptake value ratio (SUVr). Cerebellum grey matter was used as reference region. Voxel-level analysis was performed using basis function implementations of SRTM, reference Logan and SUVr. Regionally averaged voxel values were compared to VOI-based values from the optimal reference tissue model and simulations were made to assess accuracy and precision. In addition to 90 min, initial 40 and 60 min data were analysed.

    RESULTS: Plasma-input Logan distribution volume ratio (DVR)-1 values agreed well with 2TCM DVR-1 values (R2=0.99, slope=0.96). SRTM binding potential (BPND) and reference Logan DVR-1 values were highly correlated with plasma-input Logan DVR-1 (R2=1.00, slope≈1.00) while SUVr70-90-1 values correlated less well and overestimated binding. Agreement between parametric methods and SRTM was best for reference Logan (R2=0.99, slope=1.03). SUVr70-90-1 values were almost 3 times higher than BPND values in white matter and 1.5 times higher in grey matter. Simulations showed poorer accuracy and precision for SUVr70-90-1 values than for the other reference methods. SRTM BPND and reference Logan DVR-1 values were not affected by a shorter scan duration of 60 min.

    CONCLUSION: SRTM BPND and reference Logan DVR-1 values were highly correlated with plasma-input Logan DVR-1 values. VOI-based data analyses indicated robust results for scan durations of 60 min. Reference Logan generated quantitative (S)-(18)F-THK5117 DVR-1 parametric images with the greatest accuracy and precision, and with a much lower white matter signal than seen with SUVr-1 images.

  • 15.
    Mitran, Bogdan
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Theranostics.
    Guler, R.
    KTH Royal Inst Technol, Stockholm, Sweden.
    Roche, Francis P.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Vascular Biology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Lindström, Elin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Radiology.
    Selvaraju, Ramkumar
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Preclinical PET-MRI Platform.
    Heetwood, F.
    KTH Royal Inst Technol, Stockholm, Sweden.
    Rinne, Sara S.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Theranostics.
    Claesson-Welsh, Lena
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Vascular Biology.
    Tolmachev, Vladimir
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medical Radiation Science.
    Ståhl, S.
    KTH Royal Inst Technol, Stockholm, Sweden.
    Orlova, Anna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medical Radiation Science. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Theranostics.
    Löfblom, J.
    KTH Royal Inst Technol, Stockholm, Sweden.
    Novel high affinity affibody for radionuclide imaging of VEGFR2 in glioma vasculature: proof-of-principle in murine model2017In: European Journal of Nuclear Medicine and Molecular Imaging, ISSN 1619-7070, E-ISSN 1619-7089, Vol. 44, p. S239-S239Article in journal (Other academic)
  • 16.
    Mitran, Bogdan
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Theranostics.
    Güler, Rezan
    KTH Royal Inst Technol, Dept Prot Sci, Sch Engn Sci Chem Biotechnol & Hlth, Stockholm, Sweden.
    Roche, Francis P.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Vascular Biology.
    Lindström, Elin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Theranostics.
    Selvaraju, Ramkumar
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Preclinical PET-MRI Platform. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Theranostics.
    Fleetwood, Filippa
    KTH Royal Inst Technol, Dept Prot Sci, Sch Engn Sci Chem Biotechnol & Hlth, Stockholm, Sweden.
    Rinne, Sara S.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Theranostics.
    Claesson-Welsh, Lena
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Vascular Biology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Tolmachev, Vladimir
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Vascular Biology.
    Ståhl, Stefan
    KTH Royal Inst Technol, Dept Prot Sci, Sch Engn Sci Chem Biotechnol & Hlth, Stockholm, Sweden.
    Orlova, Anna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Theranostics. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Löfblom, John
    KTH Royal Inst Technol, Dept Prot Sci, Sch Engn Sci Chem Biotechnol & Hlth, Stockholm, Sweden.
    Radionuclide imaging of VEGFR2 in glioma vasculature using biparatopic affibody conjugate: proof-of-principle in a murine model2018In: Theranostics, ISSN 1838-7640, E-ISSN 1838-7640, Vol. 8, no 16, p. 4462-4476Article in journal (Refereed)
    Abstract [en]

    Vascular endothelial growth factor receptor-2 (VEGFR2) is a key mediator of angiogenesis and therefore a promising therapeutic target in malignancies including glioblastoma multiforme (GBM). Molecular imaging of VEGFR2 expression may enable patient stratification for antiangiogenic therapy. The goal of the current study was to evaluate the capacity of the novel anti-VEGFR2 biparatopic affibody conjugate (Z(VEGFR2)-Bp(2)) for in vivo visualization of VEGFR2 expression in GBM.

    Methods: Z(VEGFR2)-Bp(2) coupled to a NODAGA chelator was generated and radiolabeled with indium-111. The VEGFR2-expressing murine endothelial cell line MS1 was used to evaluate in vitro binding specificity and affinity, cellular processing and targeting specificity in mice. Further tumor targeting was studied in vivo in GL261 glioblastoma orthotopic tumors. Experimental imaging was performed.

    Results: [In-111]In-NODAGA-Z(VEGFR2)-Bp(2) bound specifically to VEGFR2 (K-D=33 +/- 18 pM). VEGFR2-mediated accumulation was observed in liver, spleen and lungs. The tumor-to-organ ratios 2 h post injection for mice bearing MS1 tumors were approximately 11 for blood, 15 for muscles and 78 for brain. Intracranial GL261 glioblastoma was visualized using SPECT/CT. The activity uptake in tumors was significantly higher than in normal brain tissue. The tumor-to-cerebellum ratios after injection of 4 mu g [In-111]In-NODAGA-Z(VEGFR2)-Bp(2) were significantly higher than the ratios observed for the 40 mu g injected dose and for the non-VEGFR2 binding size-matched conjugate, demonstrating target specificity. Microautoradiography of cryosectioned CNS tissue was in good agreement with the SPECT/CT images.

    Conclusion: The anti-VEGFR2 affibody conjugate [In-111]In-NODAGA-Z(VEGFR2)-Bp(2) specifically targeted VEGFR2 in vivo and visualized its expression in a murine GBM orthotopic model. Tumor-to-blood ratios for [In-111]In-NODAGA-Z(VEGFR2)-Bp(2) were higher compared to other VEGFR2 imaging probes. [In-111]In-NODAGA-Z(VEGFR2)-Bp(2) appears to be a promising probe for in vivo noninvasive visualization of tumor angiogenesis in glioblastoma.

  • 17.
    Nordeman, Patrik
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Preclinical PET-MRI Platform.
    Chow, Shiao Y.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Organic Pharmaceutical Chemistry.
    Odell, A. F.
    Univ Leeds, St James Univ Hosp, England.
    Antoni, Gunnar
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Preclinical PET-MRI Platform.
    Odell, Luke R.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Organic Pharmaceutical Chemistry.
    Palladium-mediated C-11-carbonylations using aryl halides and cyanamide2017In: Organic and biomolecular chemistry, ISSN 1477-0520, E-ISSN 1477-0539, Vol. 15, no 22, p. 4875-4881Article in journal (Refereed)
    Abstract [en]

    A robust and high-yielding radiochemical synthesis of C-11-N-cyanobenzamides using a palladium-mediated aminocarbonylation with C-11-CO, aryl halides and cyanamide is described. The bidentate ligand 1,1'-bis(diphenylphosphino)ferrocene provided C-11-N-cyanobenzamides from aryl-iodides, bromides, triflates and even chlorides in 28-79% radiochemical yield after semi-preparative HPLC. To further highlight the utility of this method, novel C-11-N-cyanobenzamide analogs of flufenamic acid, meflanamic acid, dazoxiben and tamibarotene were synthesized in 34-71% radiochemical yields.

  • 18.
    Nordeman, Patrik
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Division of Molecular Imaging.
    Johansson, Leif B. G.
    Linkoping Univ, Dept Chem, IFM, S-58183 Linkoping, Sweden..
    Back, Marcus
    Linkoping Univ, Dept Chem, IFM, S-58183 Linkoping, Sweden..
    Estrada, Sergio
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Preclinical PET-MRI Platform.
    Hall, Håkan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Preclinical PET-MRI Platform.
    Sjölander, Daniel
    Linkoping Univ, Dept Chem, IFM, S-58183 Linkoping, Sweden..
    Westermark, Gunilla T.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Westermark, Per
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical and experimental pathology.
    Nilsson, Lars
    Univ Oslo, Dept Pharmacol, N-0316 Oslo, Norway..
    Hammarström, Per
    Linkoping Univ, Dept Chem, IFM, S-58183 Linkoping, Sweden..
    Nilsson, K. Peter R.
    Linkoping Univ, Dept Chem, IFM, S-58183 Linkoping, Sweden..
    Antoni, Gunnar
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Division of Molecular Imaging.
    C-11 and F-18 Radiolabeling of Tetra- and Pentathiophenes as PET-Ligands for Amyloid Protein Aggregates2016In: ACS Medicinal Chemistry Letters, ISSN 1948-5875, E-ISSN 1948-5875, Vol. 7, no 4, p. 368-373Article in journal (Refereed)
    Abstract [en]

    Three oligothiophenes were evaluated as PET ligands for the study of local and systemic amyloidosis ex vivo using tissue from patients with amyloid deposits and in vivo using healthy animals and PET-CT. The ex vivo binding studies revealed that all three labeled compounds bound specifically to human amyloid deposits. Specific binding was found in the heart, kidney, liver, and spleen. To verify the specificity of the oligothiophenes toward amyloid deposits, tissue sections with amyloid pathology were stained using the fluorescence exhibited by the compounds and evaluated with multiphoton microscopy. Furthermore, a in vivo monkey PET-CT study showed very low uptake in the brain, pancreas, and heart of the healthy animal indicating low nonspecific binding to healthy tissue. The biological evaluations indicated that this is a promising group of compounds for the visualization of systemic and localized amyloidosis.

  • 19.
    Olsen, Malin
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
    Aguilar, Ximena
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
    Sehlin, Dag
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
    Fang, Xiaotian T.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
    Antoni, Gunnar
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Preclinical PET-MRI Platform.
    Erlandsson, Anna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
    Syvänen, Stina
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
    Astroglial Responses to Amyloid-Beta Progression in a Mouse Model of Alzheimer's Disease2018In: Molecular Imaging and Biology, ISSN 1536-1632, E-ISSN 1860-2002, Vol. 20, no 4, p. 605-614Article in journal (Refereed)
    Abstract [en]

    Alzheimer's disease (AD) is a neurodegenerative disorder characterized by amyloid-beta (A beta) deposition, hyperphosphorylation of tau, and neuroinflammation. Astrocytes, the most abundant glial cell type in the nervous system, respond to neurodegenerative disorders through astrogliosis, i.e., converting to a reactive inflammatory state. The aim of this study was to investigate how in vivo quantification of astrogliosis using positron emission tomography (PET) radioligand deuterium-l-[C-11]deprenyl ([C-11]DED), binding to enzyme monoamine oxidase-B (MAO-B) which is overexpressed in reactive astrocytes during AD, corresponds to expression of glial fibrillary acidic protein (GFAP) and vimentin, i.e., two well-established markers of astrogliosis, during A beta pathology progression. APP(ArcSwe) mice (n = 37) and wild-type (WT) control mice (n = 23), 2-16-month old, were used to investigate biomarkers of astrogliosis. The radioligand, [C-11]DED, was used as an in vivo marker while GFAP, vimentin, and MAO-B were used to investigate astrogliosis and macrophage-associated lectin (Mac-2) to investigate microglia/macrophage activation by immunohistochemistry of the mouse brain. A beta and GFAP levels were also measured with ELISA in brain homogenates. The intrabrain levels of aggregated A beta and reactive astrocytes were found to be elevated in APP(ArcSwe) compared with WT mice. GFAP and vimentin expression increased with age, i.e., with A beta pathology, in the APP(ArcSwe) mice. This was not the case for in vivo marker [C-11]DED that showed elevated binding of the same magnitude in APP(ArcSwe) mice compared with WT mice at both 8 and 16 months. Further, immunohistochemistry indicated that there was limited co-expression of MAO-B and GFAP. MAO-B levels are increased early in A beta pathology progression, while GFAP and vimentin appear to increase later, most likely as a consequence of abundant A beta plaque formation. Thus, [C-11]DED is a useful PET radioligand for the detection of changes in MAO-B at an early stage of AD progression but does not measure the total extent of astrogliosis at advanced stages of A beta pathology.

  • 20.
    Persson, Jonas
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Ekselius: Psychiatry.
    Szalisznyo, Krisztina
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Ekselius: Psychiatry.
    Antoni, Gunnar
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Preclinical PET-MRI Platform. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Preparative Medicinal Chemistry.
    Wall, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Radiology.
    Fällmar, David
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Radiology.
    Zora, Hatice
    Bodén, Robert
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Ekselius: Psychiatry.
    Phosphodiesterase 10A levels are related to striatal function in schizophrenia: a combined positron emission tomography and functional magnetic resonance imaging study2019In: European Archives of Psychiatry and Clinical Neuroscience, ISSN 0940-1334, E-ISSN 1433-8491Article in journal (Refereed)
    Abstract [en]

    Pharmacological inhibition of phosphodiesterase 10A (PDE10A) is being investigated as a treatment option in schizophrenia. PDE10A acts postsynaptically on striatal dopamine signaling by regulating neuronal excitability through its inhibition of cyclic adenosine monophosphate (cAMP), and we recently found it to be reduced in schizophrenia compared to controls. Here, this finding of reduced PDE10A in schizophrenia was followed up in the same sample to investigate the effect of reduced striatal PDE10A on the neural and behavioral function of striatal and downstream basal ganglia regions. A positron emission tomography (PET) scan with the PDE10A ligand [11C]Lu AE92686 was performed, followed by a 6 min resting-state magnetic resonance imaging (MRI) scan in ten patients with schizophrenia. To assess the relationship between striatal function and neurophysiological and behavioral functioning, salience processing was assessed using a mismatch negativity paradigm, an auditory event-related electroencephalographic measure, episodic memory was assessed using the Rey auditory verbal learning test (RAVLT) and executive functioning using trail-making test B. Reduced striatal PDE10A was associated with increased amplitude of low-frequency fluctuations (ALFF) within the putamen and substantia nigra, respectively. Higher ALFF in the substantia nigra, in turn, was associated with lower episodic memory performance. The findings are in line with a role for PDE10A in striatal functioning, and suggest that reduced striatal PDE10A may contribute to cognitive symptoms in schizophrenia.

  • 21.
    Spiegelberg, Diana
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medical Radiation Science.
    Mortensen, Anja C
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medical Radiation Science.
    Selvaraju, Ram K
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Preclinical PET-MRI Platform.
    Eriksson, Olof
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Division of Molecular Imaging.
    Stenerlöw, Bo
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medical Radiation Science.
    Nestor, Marika
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medical Radiation Science. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Otolaryngology and Head and Neck Surgery.
    Molecular imaging of EGFR and CD44v6 for prediction and response monitoring of HSP90 inhibition in an in vivo squamous cell carcinoma model.2016In: European Journal of Nuclear Medicine and Molecular Imaging, ISSN 1619-7070, E-ISSN 1619-7089, Vol. 43, no 5, p. 974-982Article in journal (Refereed)
    Abstract [en]

    PURPOSE: Heat shock protein 90 (HSP90) is essential for the activation and stabilization of numerous oncogenic client proteins. AT13387 is a novel HSP90 inhibitor promoting degradation of oncogenic proteins upon binding, and may also act as a radiosensitizer. For optimal treatment there is, however, the need for identification of biomarkers for patient stratification and therapeutic response monitoring, and to find suitable targets for combination treatments. The aim of this study was to assess the response of surface antigens commonly expressed in squamous cell carcinoma to AT13387 treatment, and to find suitable biomarkers for molecular imaging and radioimmunotherapy in combination with HSP90 inhibition.

    METHODS: Cancer cell proliferation and radioimmunoassays were used to evaluate the effect of AT13387 on target antigen expression in vitro. Inhibitor effects were then assessed in vivo in mice-xenografts. Animals were treated with AT13387 (5 × 50 mg/kg), and were imaged with PET using either (18)F-FDG or (124)I-labelled tracers for EGFR and CD44v6, and this was followed by ex-vivo biodistribution analysis and immunohistochemical staining.

    RESULTS: AT13387 exposure resulted in high cytotoxicity and possible radiosensitization with IC50 values below 4 nM. Both in vitro and in vivo AT13387 effectively downregulated HSP90 client proteins. PET imaging with (124)I-cetuximab showed a significant decrease of EGFR in AT13387-treated animals compared with untreated animals. In contrast, the squamous cell carcinoma-associated biomarker CD44v6, visualized with (124)I-AbD19384 as well as (18)F-FDG uptake, were not significantly altered by AT13387 treatment.

    CONCLUSION: We conclude that AT13387 downregulates HSP90 client proteins, and that molecular imaging of these proteins may be a suitable approach for assessing treatment response. Furthermore, radioimmunotherapy targeting CD44v6 in combination with AT13387 may potentiate the radioimmunotherapy outcome due to radiosensitizing effects of the drug, and could potentially lead to a lower dose to normal tissues.

  • 22.
    Tovedal, Thomas
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Anaesthesiology and Intensive Care.
    Lubberink, Mark
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Radiology.
    Morell, Arvid
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Radiology.
    Estrada, Sergio
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Preclinical PET-MRI Platform.
    Golla, Sandeep S V
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Radiology.
    Myrdal, Gunnar
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Thoracic Surgery.
    Lindblom, Rickard P. F.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Thoracic Surgery.
    Thelin, Stefan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Thoracic Surgery.
    Sörensen, Jens
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Radiology.
    Antoni, Gunnar
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Preclinical PET Platform.
    Lennmyr, Fredrik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Anaesthesiology and Intensive Care.
    Blood Flow Quantitation by Positron Emission Tomography During Selective Antegrade Cerebral Perfusion2017In: Annals of Thoracic Surgery, ISSN 0003-4975, E-ISSN 1552-6259, Vol. 103, no 2, p. 610-616Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Perfusion strategies during aortic surgery usually comprise hypothermic circulatory arrest (HCA), often combined with selective antegrade cerebral perfusion (SACP) or retrograde cerebral perfusion. Cerebral blood flow (CBF) is a fundamental parameter for which the optimal level has not been clearly defined. We sought to determine the CBF at a pump flow level of 6 mL/kg/min, previously shown likely to provide adequate SACP at 20°C in pigs.

    METHODS: Repeated positron emission tomography (PET) scans were used to quantify the CBF and glucose metabolism throughout HCA and SACP including cooling and rewarming. Eight pigs on cardiopulmonary bypass were assigned to either HCA alone (n = 4) or HCA+SACP (n = 4). The CBF was measured by repeated [(15)O]water PET scans from baseline to rewarming. The cerebral glucose metabolism was examined by [(18)F]fluorodeoxyglucose PET scans after rewarming to 37°C.

    RESULTS: Cooling to 20°C decreased the cortical CBF from 0.31 ± 0.06 at baseline to 0.10 ± 0.02 mL/cm(3)/min (p = 0.008). The CBF was maintained stable by SACP of 6 mL/kg/min during 45 minutes. After rewarming to 37°C, the mean CBF increased to 0.24 ± 0.07 mL/cm(3)/min, without significant differences between the groups at any time-point exclusive of the HCA period. The net cortical uptake (Ki) of [(18)F]fluorodeoxyglucose after rewarming showed no significant difference between the groups.

    CONCLUSIONS: Cooling autoregulated the CBF to 0.10 mL/cm(3)/min, and 45 minutes of SACP at 6 mL/kg/min maintained the CBF in the present model. Cerebral glucose metabolism after rewarming was similar in the study groups.

1 - 22 of 22
CiteExportLink to result list
Permanent link
Cite
Citation style
  • apa
  • ieee
  • modern-language-association-8th-edition
  • vancouver
  • Other style
More styles
Language
  • de-DE
  • en-GB
  • en-US
  • fi-FI
  • nn-NO
  • nn-NB
  • sv-SE
  • Other locale
More languages
Output format
  • html
  • text
  • asciidoc
  • rtf