34 results on '"Britt-Marie Swahn"'
Search Results
2. Creation of Novel Cores for β-Secretase (BACE-1) Inhibitors: A Multiparameter Lead Generation Strategy
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Britt-Marie Swahn, Ylva Gravenfors, Gunnar Nordvall, Jenny Viklund, Fredrik Rahm, Karin Kolmodin, and Mats Svensson
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biology ,Chemistry ,In silico ,Organic Chemistry ,hERG ,Computational biology ,computer.software_genre ,Scaffold hopping ,Biochemistry ,Prediction methods ,Drug Discovery ,β secretase ,biology.protein ,Data mining ,computer - Abstract
In order to find optimal core structures as starting points for lead optimization, a multiparameter lead generation workflow was designed with the goal of finding BACE-1 inhibitors as a treatment for Alzheimer's disease. De novo design of core fragments was connected with three predictive in silico models addressing target affinity, permeability, and hERG activity, in order to guide synthesis. Taking advantage of an additive SAR, the prioritized cores were decorated with a few, well-characterized substituents from known BACE-1 inhibitors in order to allow for core-to-core comparisons. Prediction methods and analyses of how physicochemical properties of the core structures correlate to in vitro data are described. The syntheses and in vitro data of the test compounds are reported in a separate paper by Ginman et al. [J. Med. Chem. 2013, 56, 4181-4205]. The affinity predictions are described in detail by Roos et al. [J. Chem. Inf. 2014, DOI: 10.1021/ci400374z].
- Published
- 2014
3. Discovery of AZD3839, a Potent and Selective BACE1 Inhibitor Clinical Candidate for the Treatment of Alzheimer Disease
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Karin Kolmodin, Juliette Janson, Britt-Marie Swahn, Stefan von Berg, Tjerk Bueters, Gvido Cebers, Ann-Cathrine Radesäter, Johanna Fälting, Fredrik Jeppsson, Susanne Gustavsson, Bart Ploeger, Sofia Karlström, Susanna Eketjäll, and Lise-Lotte Olsson
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Male ,Indoles ,Amyloid ,Guinea Pigs ,Drug Evaluation, Preclinical ,Cathepsin D ,Biology ,Pharmacology ,Biochemistry ,Cell Line ,Guinea pig ,Mice ,Neurobiology ,Alzheimer Disease ,In vivo ,mental disorders ,Fluorescence Resonance Energy Transfer ,Amyloid precursor protein ,medicine ,Animals ,Aspartic Acid Endopeptidases ,Humans ,Molecular Biology ,Amyloid beta-Peptides ,Dose-Response Relationship, Drug ,Drug discovery ,P3 peptide ,Brain ,Cell Biology ,medicine.disease ,Mice, Inbred C57BL ,Pyrimidines ,Treatment Outcome ,Drug Design ,Disease Progression ,biology.protein ,Female ,Amyloid Precursor Protein Secretases ,Alzheimer's disease ,Biomarkers - Abstract
β-Site amyloid precursor protein cleaving enzyme1 (BACE1) is one of the key enzymes involved in the processing of the amyloid precursor protein (APP) and formation of amyloid β peptide (Aβ) species. Because cerebral deposition of Aβ species might be critical for the pathogenesis of Alzheimer disease, BACE1 has emerged as a key target for the treatment of this disease. Here, we report the discovery and comprehensive preclinical characterization of AZD3839, a potent and selective inhibitor of human BACE1. AZD3839 was identified using fragment-based screening and structure-based design. In a concentration-dependent manner, AZD3839 inhibited BACE1 activity in a biochemical fluorescence resonance energy transfer (FRET) assay, Aβ and sAPPβ release from modified and wild-type human SH-SY5Y cells and mouse N2A cells as well as from mouse and guinea pig primary cortical neurons. Selectivity against BACE2 and cathepsin D was 14 and >1000-fold, respectively. AZD3839 exhibited dose- and time-dependent lowering of plasma, brain, and cerebrospinal fluid Aβ levels in mouse, guinea pig, and non-human primate. Pharmacokinetic/pharmacodynamic analyses of mouse and guinea pig data showed a good correlation between the potency of AZD3839 in primary cortical neurons and in vivo brain effects. These results suggest that AZD3839 effectively reduces the levels of Aβ in brain, CSF, and plasma in several preclinical species. It might, therefore, have disease-modifying potential in the treatment of Alzheimer disease and related dementias. Based on the overall pharmacological profile and its drug like properties, AZD3839 has been progressed into Phase 1 clinical trials in man.
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- 2012
4. Synthesis and evaluation of pyridylbenzofuran, pyridylbenzothiazole and pyridylbenzoxazole derivatives as 18F-PET imaging agents for β-amyloid plaques
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Peter Johnström, Britt-Marie Swahn, David Pyring, Magnus Schou, Margareta Bergh, Jan A.M. Neelissen, Anders Juréus, Samuel P.S. Svensson, Johan Sandell, and Fredrik Jeppsson
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medicine.diagnostic_test ,Chemistry ,Organic Chemistry ,Clinical Biochemistry ,Pharmaceutical Science ,Human brain ,medicine.disease ,Biochemistry ,In vitro ,medicine.anatomical_structure ,Pharmacokinetics ,In vivo ,Positron emission tomography ,Drug Discovery ,Radioligand ,medicine ,Molecular Medicine ,Structure–activity relationship ,Alzheimer's disease ,Molecular Biology - Abstract
The synthesis and SAR of new β-amyloid binding agents are reported. Evaluation of important properties for achieving good signal-to-background ratio is described. Compounds 27, 33, and 36 displayed desirable lipophilic and pharmacokinetic properties. Compound 27 was further evaluated with autoradiographic studies in vitro on human brain tissue and in vivo in Tg2576 mice. Compound 27 showed an increased signal-to-background ratio compared to flutemetamol 4, indicating its suitability as PET ligand for β-amyloid deposits in AD patients. The preparation of the corresponding (18)F-labeled PET radioligand of compound 27 is presented.
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- 2012
5. Strategies to improve in vivo toxicology outcomes for basic candidate drug molecules
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Mark C. Wenlock, Lilian Alcaraz, Dearg S. Brown, Niklas Blomberg, Simon Guile, Paul D. Leeson, Thomas Elebring, Michael J. Waring, Britt-Marie Swahn, Kamaldeep K. Chohan, Steve Swallow, Stephen A. St-Gallay, Tim Luker, Andrew Griffin, and Roger John Butlin
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Drug ,Models, Statistical ,Drug Industry ,Molecular Structure ,Chemistry ,media_common.quotation_subject ,Organic Chemistry ,Clinical Biochemistry ,Drug Evaluation, Preclinical ,Discriminant Analysis ,Pharmaceutical Science ,Biochemistry ,Toxicology ,Pharmaceutical Preparations ,In vivo ,Drug Design ,Toxicity Tests ,Drug Discovery ,Animals ,Humans ,Molecular Medicine ,Molecular Biology ,Drug industry ,media_common - Abstract
A valid PLS-DA model to predict attrition in pre-clinical toxicology for basic oral candidate drugs was built. A combination of aromatic/aliphatic balance, flatness, charge distribution and size descriptors helped predict the successful progression of compounds through a wide range of toxicity testing. Eighty percent of an independent test set of marketed post-2000 basic drugs could be successfully classified using the model, indicating useful forward predictivity. The themes within this work provide additional guidance for medicinal design chemists and complement other literature property guidelines.
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- 2011
6. Characterization of AZD4694, a novel fluorinated Aβ plaque neuroimaging PET radioligand
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Peter Johnström, Fredrik Jeppsson, Dan Sunnemark, Johan Sandell, Jan A.M. Neelissen, Allan E. Johnson, Anders Juréus, Lars Farde, Britt-Marie Swahn, and Samuel P.S. Svensson
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Pathology ,medicine.medical_specialty ,Amyloid ,medicine.diagnostic_test ,business.industry ,medicine.disease ,Biochemistry ,Cellular and Molecular Neuroscience ,Positron ,Neuroimaging ,Positron emission tomography ,medicine ,Radioligand ,Alzheimer's disease ,business - Abstract
Positron emission tomography (PET) radioligands that bind selectively to β-amyloid plaques (Aβ) are promising imaging tools aimed at supporting the diagnosis of Alzheimer’s disease and the evaluati ...
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- 2010
7. Liver X receptor agonists with selectivity for LXRβ; N-aryl-3,3,3-trifluoro-2-hydroxy-2-methylpropionamides
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Johanna Lindquist, Britt-Marie Swahn, Jenny Viklund, Jan A.M. Neelissen, Liselotte Öhberg, Istvan Macsari, and Johanna Sjödin
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Agonist ,Stereochemistry ,medicine.drug_class ,Clinical Biochemistry ,Receptors, Cytoplasmic and Nuclear ,Pharmaceutical Science ,Biochemistry ,Chemical synthesis ,Cell Line ,Mice ,Structure-Activity Relationship ,chemistry.chemical_compound ,Genes, Reporter ,In vivo ,Drug Discovery ,medicine ,Animals ,Humans ,Computer Simulation ,Liver X receptor ,Molecular Biology ,Liver X Receptors ,Sulfonamides ,Chemistry ,Aryl ,Organic Chemistry ,Brain ,Biological activity ,Orphan Nuclear Receptors ,Amides ,Up-Regulation ,DNA-Binding Proteins ,Nuclear receptor ,Lactates ,Molecular Medicine ,ATP-Binding Cassette Transporters ,lipids (amino acids, peptides, and proteins) ,Selectivity ,ATP Binding Cassette Transporter 1 - Abstract
The synthesis and SAR of a new series of LXR agonist is reported. The N-Aryl-3,3,3-trifluoro-2-hydroxy-2-methyl-propionamide hits were found in a limited screen of the AstraZeneca compound collection. The effort to optimize these hits into LXRbeta selectivity is described. Compound 20 displayed desirable pharmacokinetic profile and up regulation of ABCA1 and ABCG1 mRNA in the brain were achieved when evaluated in vivo in mice.
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- 2009
8. Open Access to the KCNQ Channel: Retigabine and Second Generation M-current Openers
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Martin Main, Britt-Marie Swahn, Johannes J. Krupp, and Anthony M. Rush
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Adult patients ,business.industry ,medicine.medical_treatment ,Retigabine ,Pharmacology ,Potassium channel ,chemistry.chemical_compound ,Anticonvulsant ,Kcnq channels ,chemistry ,M current ,Adjunctive treatment ,medicine ,business - Abstract
In 2011, Retigabine (Ezogabine; Valeant Pharmaceuticals/GlaxoSmithKline), an opener of KCNQ (Kv7) potassium channels, was approved for the adjunctive treatment of partial-onset seizures in adult patients. In this chapter, we review the story of retigabine, from identification as a novel anticonvulsant through to clinical testing, and detail the ongoing work to identify a second generation of KCNQ channel openers.
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- 2014
9. Two non-racemic preparations of a piperidine-based NMDA antagonist with analgesic activity
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Ulf Larsson, Elisabet Kallin, Håkan Molin, Karin M. Edvinsson, Odd-Geir Berge, Benjamin Pelcman, Alf Claesson, and Britt-Marie Swahn
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N-Methylaspartate ,Ketone ,Stereochemistry ,Clinical Biochemistry ,Analgesic ,Organophosphonates ,Pharmaceutical Science ,Stereoisomerism ,Pharmacology ,Binding, Competitive ,Receptors, N-Methyl-D-Aspartate ,Biochemistry ,Mice ,chemistry.chemical_compound ,Drug Discovery ,Animals ,Receptor ,Molecular Biology ,ED50 ,Pain Measurement ,chemistry.chemical_classification ,Analgesics ,Binding Sites ,Organic Chemistry ,Rats ,Kinetics ,chemistry ,Pipecolic Acids ,Excitatory Amino Acid Antagonists ,Molecular Medicine ,NMDA receptor ,Piperidine - Abstract
(2R,3S,1'R)-3-(1-Hydroxy-2-phosphonoethyl)-2-piperidinecarboxyl ic acid 1 has been synthesized by two different methods. The NMDA receptor binding affinities (Ki values) are 74 nM for compound 1, and 64 nM for the corresponding ketone 2. The analgesic effects were evaluated using the mouse hot-plate test and the mouse formalin model. The ED50 values for the racemates of compounds 1 and 2, using the mouse hotplate and intrathecal injection, were 0.53 and 0.51 nmol, respectively.
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- 1997
10. Synthesis of 14C-labelled (R)-α-amino-6,7-dimethyl-3-(phosphonomethyl)-2-quinolinepropanoic acid
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Britt-Marie Swahn, Johan Söderberg, Benjamin Pelcman, Alf Claesson, and Fredrik Andersson
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chemistry.chemical_classification ,Bicyclic molecule ,Stereochemistry ,Organic Chemistry ,Quinoline ,Iodide ,chemistry.chemical_element ,Zinc ,Biochemistry ,Chemical synthesis ,Analytical Chemistry ,chemistry.chemical_compound ,chemistry ,Reagent ,Drug Discovery ,Radiology, Nuclear Medicine and imaging ,Carbon-14 ,Spectroscopy ,Derivative (chemistry) - Abstract
The NMDA antagonist (R)-α-amino-6,7-dimethyl-3-(phosphonomethyl)-quinolinepropanoic acid 1 was [ 14 C]-labelled at the 6-methyl group. The quinoline synthesis started from 4-bromo3-methylaniline and the radiolabel was introduced late in the synthetic scheme. The synthesis was accomplished by a NiCl2(dppp)2-catalyzed coupling of the 6-bromoquinoline derivative 6 with a zinc reagent made from [ 14 C]-methyl iodide.
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- 1997
11. AZ-4217: a high potency BACE inhibitor displaying acute central efficacy in different in vivo models and reduced amyloid deposition in Tg2576 mice
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Britt-Marie Swahn, Sveinn Briem, Susanna Eketjäll, Fredrik Jeppsson, Kristina Eliason, Juliette Janson, Alexander Svanhagen, Camilla Niva, Anna-Lena Berg, Sofia Karlström, Karin Kolmodin, Susanne Gustavsson, Johanna Fälting, Ann-Cathrin Radesäter, and Paulina Appelkvist
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Genetically modified mouse ,Male ,Amyloid ,Time Factors ,Pyridones ,Transgene ,Guinea Pigs ,Mice, Transgenic ,Pharmacology ,Isoindoles ,Amyloid beta-Protein Precursor ,Mice ,In vivo ,Alzheimer Disease ,mental disorders ,Amyloid precursor protein ,medicine ,Potency ,Animals ,Aspartic Acid Endopeptidases ,Humans ,Enzyme Inhibitors ,IC50 ,Cells, Cultured ,Cerebral Cortex ,Neurons ,Amyloid beta-Peptides ,biology ,Dose-Response Relationship, Drug ,Chemistry ,General Neuroscience ,Amyloidosis ,P3 peptide ,Articles ,medicine.disease ,Embryo, Mammalian ,Peptide Fragments ,Mice, Inbred C57BL ,Disease Models, Animal ,Mutation ,biology.protein ,Female ,Amyloid Precursor Protein Secretases - Abstract
Aβ, the product of APP (amyloid precursor protein), has been implicated in the pathophysiology of Alzheimer's disease (AD). β-Site APP cleaving enzyme1 (BACE1) is the enzyme initiating the processing of the APP to Aβ peptides. Small molecule BACE1 inhibitors are expected to decrease Aβ-peptide generation and thereby reduce amyloid plaque formation in the brain, a neuropathological hallmark of AD. BACE1 inhibition thus addresses a key mechanism in AD and its potential as a therapeutic target is currently being addressed in clinical studies. Here, we report the discovery and the pharmacokinetic and pharmacodynamic properties of BACE1 inhibitor AZ-4217, a high potency compound (IC(50) 160 pm in human SH-SY5Y cells) with an excellent in vivo efficacy. Central efficacy of BACE1 inhibition was observed after a single dose in C57BL/6 mice, guinea pigs, and in an APP transgenic mouse model of cerebral amyloidosis (Tg2576). Furthermore, we demonstrate that in a 1 month treatment paradigm BACE1 inhibition of Aβ production does lower amyloid deposition in 12-month-old Tg2576 mice. These results strongly support BACE1 inhibition as concretely impacting amyloid deposition and therefore potentially an important approach for therapeutic intervention in AD.
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- 2013
12. Biotransformation of two β-secretase inhibitors including ring opening and contraction of a pyrimidine ring
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Britt-Marie Swahn, Sofia Karlström, Jörg Holenz, Tjerk Bueters, Jonas Malmquist, Dominika Turek, Stefan von Berg, Göran Eklund, and Anders Lindgren
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Male ,Indoles ,Pyrimidine ,Stereochemistry ,Pharmaceutical Science ,Mass Spectrometry ,Rats, Sprague-Dawley ,chemistry.chemical_compound ,Biotransformation ,In vivo ,Pyridine ,Imidazole ,Animals ,Humans ,Enzyme Inhibitors ,Pharmacology ,chemistry.chemical_classification ,Chemistry ,In vitro ,Rats ,Metabolic pathway ,Enzyme ,Pyrimidines ,Cyclization ,Rabbits ,Amyloid Precursor Protein Secretases ,Chromatography, Liquid - Abstract
Recently, the discovery of the aminoisoindoles as potent and selective inhibitors of β-secretase was reported, including the close structural analogs compound (S)-1-pyridin-4-yl-4-fluoro-1-(3-(pyrimidin-5-yl)phenyl)-1H-isoindol-3-amine [(S)-25] and (S)-1-(2-(difluoromethyl)pyridin-4-yl)-4-fluoro-1-(3-(pyrimidin-5-yl)phenyl)-1H-isoindol-3-amine hemifumarate (AZD3839), the latter being recently progressed to the clinic. The biotransformation of (S)-25 was investigated in vitro and in vivo in rat, rabbit, and human and compared with AZD3839 to further understand the metabolic fate of these compounds. In vitro, CYP3A4 was the major responsible enzyme and metabolized both compounds to a large extent in the commonly shared pyridine and pyrimidine rings. The main proposed metabolic pathways in various in vitro systems were N-oxidation of the pyridine and/or pyrimidine ring and conversion to 4-pyrimidone and pyrimidine-2,4-dione. Both compounds were extensively metabolized, and more than 90% was excreted in feces after intravenous administration of radiolabeled compound to the rat. Here, the main pathways were N-oxidation of the pyridine and/or pyrimidine ring and a ring contraction of the pyrimidine ring into an imidazole ring. Ring-contracted metabolites accounted for 25% of the total metabolism in the rat for (S)-25, whereas the contribution was much smaller for AZD3839. This metabolic pathway was not foreseen on the basis of the obtained in vitro data. In conclusion, we discovered an unusual metabolic pathway of aryl-pyrimidine–containing compounds by a ring-opening reaction followed by elimination of a carbon atom and a ring closure to form an imidazole ring.
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- 2013
13. New heteroaryl-spaced phosphono α-amino acids are competitive NMDA antagonists with analgesic activity
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Benjamin Pelcman, Odd-Geir Berge, Mats P. Sandberg, Yevgeni Besidski, Britt-Marie Swahn, Håkan Molin, and Alf Claesson
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chemistry.chemical_classification ,Stereochemistry ,Organic Chemistry ,Clinical Biochemistry ,Analgesic ,Pharmaceutical Science ,Biochemistry ,Amino acid ,chemistry ,Drug Discovery ,Molecular Medicine ,NMDA receptor ,Molecular Biology ,Binding affinities - Abstract
The synthesis and the NMDA receptor binding affinities of α-amino-3-(phosphonomethyl)-2-naphthalene-propanoic acid, α-amino-3-(phosphonomethyl)-2-benzofuranpropanoic acid, a series of substituted (R)-α-amino-3-(phosphonomethyl)-2-quinolinepropanoic acids, (R)-α-amino-3-(phosphonomethyl)-1,8-naphthyridine-2-propanoic acid and (R)-α-amino-3-(phosphonomethyl)-1,6-naphthyridine-2-propanoic acid are reported.
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- 1996
14. ChemInform Abstract: Synthesis and Evaluation of Pyridylbenzofuran, Pyridylbenzothiazole and Pyridylbenzoxazole Derivatives as18F-PET Imaging Agents for β-Amyloid Plaques
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Britt-Marie Swahn and et al. et al.
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Biochemistry ,Chemistry ,β amyloid ,General Medicine ,Pet imaging - Published
- 2012
15. New aminoimidazoles as β-secretase (BACE-1) inhibitors showing amyloid-β (Aβ) lowering in brain
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Ylva, Gravenfors, Jenny, Viklund, Jan, Blid, Tobias, Ginman, Sofia, Karlström, Jacob, Kihlström, Karin, Kolmodin, Johan, Lindström, Stefan, von Berg, Fredrik, von Kieseritzky, Krisztian, Bogar, Can, Slivo, Britt-Marie, Swahn, Lise-Lotte, Olsson, Patrik, Johansson, Susanna, Eketjäll, Johanna, Fälting, Fredrik, Jeppsson, Kia, Strömberg, Juliette, Janson, and Fredrik, Rahm
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Male ,Models, Molecular ,Amyloid β ,hERG ,Guinea Pigs ,Pharmacology ,Crystallography, X-Ray ,Permeability ,Cell Line ,Mice ,Structure-Activity Relationship ,Dogs ,In vivo ,Drug Discovery ,Potency ,Animals ,Aspartic Acid Endopeptidases ,Humans ,Tissue Distribution ,Amyloid beta-Peptides ,biology ,Molecular Structure ,Chemistry ,Cellular Assay ,Imidazoles ,Brain ,Stereoisomerism ,Peptide Fragments ,Mice, Inbred C57BL ,β secretase ,biology.protein ,Molecular Medicine ,Female ,Amyloid Precursor Protein Secretases - Abstract
Amino-2H-imidazoles are described as a new class of BACE-1 inhibitors for the treatment of Alzheimer’s disease. Synthetic methods, crystal structures, and structure–activity relationships for target activity, permeability, and hERG activity are reported and discussed. Compound (S)-1m was one of the most promising compounds in this report, with high potency in the cellular assay and a good overall profile. When guinea pigs were treated with compound (S)-1m, a concentration and time dependent decrease in Aβ40 and Aβ42 levels in plasma, brain, and CSF was observed. The maximum reduction of brain Aβ was 40–50%, 1.5 h after oral dosing (100 μmol/kg). The results presented highlight the potential of this new class of BACE-1 inhibitors with good target potency and with low effect on hERG, in combination with a fair CNS exposure in vivo.
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- 2012
16. IC‐P‐045: Comparison of beta‐amyloid imaging using congo red and thioflavin T derivatives
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Johan Sandell, Fredrik Jeppsson, Lars Farde, Britt-Marie Swahn, Peter Johnström, Frederick Cope, Anders Juréus, Anna Mattsson, Zsolts Cselényi, and Samuel P.S. Svensson
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Amyloid ,Epidemiology ,Health Policy ,Molecular biology ,Congo red ,Psychiatry and Mental health ,Cellular and Molecular Neuroscience ,chemistry.chemical_compound ,Developmental Neuroscience ,chemistry ,Thioflavin ,Neurology (clinical) ,Geriatrics and Gerontology ,Beta (finance) - Published
- 2012
17. Synthesis and evaluation of pyridylbenzofuran, pyridylbenzothiazole and pyridylbenzoxazole derivatives as ¹⁸F-PET imaging agents for β-amyloid plaques
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Britt-Marie, Swahn, Johan, Sandell, David, Pyring, Margareta, Bergh, Fredrik, Jeppsson, Anders, Juréus, Jan, Neelissen, Peter, Johnström, Magnus, Schou, and Samuel, Svensson
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Benzoxazoles ,Fluorine Radioisotopes ,Amyloid beta-Peptides ,Aminopyridines ,Brain ,Contrast Media ,Mice, Transgenic ,Mice ,Structure-Activity Relationship ,Alzheimer Disease ,Positron-Emission Tomography ,Animals ,Humans ,Benzothiazoles ,Radiopharmaceuticals ,Benzofurans - Abstract
The synthesis and SAR of new β-amyloid binding agents are reported. Evaluation of important properties for achieving good signal-to-background ratio is described. Compounds 27, 33, and 36 displayed desirable lipophilic and pharmacokinetic properties. Compound 27 was further evaluated with autoradiographic studies in vitro on human brain tissue and in vivo in Tg2576 mice. Compound 27 showed an increased signal-to-background ratio compared to flutemetamol 4, indicating its suitability as PET ligand for β-amyloid deposits in AD patients. The preparation of the corresponding (18)F-labeled PET radioligand of compound 27 is presented.
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- 2012
18. Aminoimidazoles as BACE-1 inhibitors: the challenge to achieve in vivo brain efficacy
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Britt-Marie Swahn, Niklas Plobeck, Karin Kolmodin, J. Lindstrom, Fernando Sehgelmeble, Didier Rotticci, Stefan von Berg, Biljana Georgievska, Johanna Fälting, Susanne Gustavsson, Stefan Berg, Jan A.M. Neelissen, Jörg Holenz, M. Sundstrom, Lise-Lotte Olsson, Margareta Ek, and Jacob Kihlström
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Models, Molecular ,Clinical Biochemistry ,Pharmaceutical Science ,Pharmacology ,Crystallography, X-Ray ,Biochemistry ,Cell Line ,Mice ,In vivo ,Alzheimer Disease ,Drug Discovery ,Hydrolase ,Animals ,Aspartic Acid Endopeptidases ,Amines ,Molecular Biology ,Amyloid beta-Peptides ,Bicyclic molecule ,Chemistry ,Organic Chemistry ,Imidazoles ,Brain ,Wild type mice ,Peptide Fragments ,Mice, Inbred C57BL ,Cell culture ,β secretase ,Molecular Medicine ,Efflux ,Amyloid Precursor Protein Secretases - Abstract
The evaluation of a series of bicyclic aminoimidazoles as potent BACE-1 inhibitors is described. The crystal structures of compounds 14 and 23 in complex with BACE-1 reveal hydrogen bond interactions with the protein important for achieving potent inhibition. The optimization of permeability and efflux properties of the compounds is discussed as well as the importance of these properties for attaining in vivo brain efficacy. Compound (R)-25 was selected for evaluation in vivo in wild type mice and 1.5h after oral co-administration of 300μmol/kg (R)-25 and efflux inhibitor GF120918 the brain Aβ40 level was reduced by 17% and the plasma Aβ40 level by 76%.
- Published
- 2011
19. IC‐P‐083: Beta‐amyloid binding of [3]AZD4694 and [3H]AV45 in vitro
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Anders Juréus, Samuel P.S. Svensson, Britt-Marie Swahn, Fredrik Jeppsson, Johan Sandell, Zsolts Cselényi, and Lars Farde
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Psychiatry and Mental health ,Cellular and Molecular Neuroscience ,Developmental Neuroscience ,Biochemistry ,Epidemiology ,Chemistry ,Health Policy ,Beta-amyloid binding ,Neurology (clinical) ,Geriatrics and Gerontology ,In vitro - Published
- 2011
20. Recent Progress in the Discovery of Kv7 Modulators
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Ismet Dorange and Britt-Marie Swahn
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Heart disorder ,Epilepsy ,Heartbeat ,Auditory nuclei ,medicine ,Premovement neuronal activity ,SUPERFAMILY ,Pharmacology ,Biology ,medicine.disease ,Familial Epilepsy ,Neuroscience ,Ion channel - Abstract
Publisher Summary This chapter focuses on recent progress in the discovery of Kv7 modulators. The Kv7 ion channels belong to the voltage-gated ion channel superfamily. There are five known members, Kv7.1–Kv7.5. These potassium-selective channel proteins are found in cardiac tissue, the central and peripheral nervous system, and in the inner ear and some auditory nuclei. Kv7 channels can homo- or heteromultimerize to form various tetramers having different pharmacological properties, and can also associate with other auxiliary proteins, further diversifying the biological response. Kv7 channels play a central role in regulating several critical cell functions, such as regulation of the heartbeat or modulation of the neuronal activity. It is thus understandable that as therapeutic targets, this class of ion channels has attracted attention. The identification of Kv7 human mutations that lead to heart disorders (Kv7.1) and to neonatal familial epilepsy (K7.2 and Kv7.3) has raised hope in finding new treatments in cardiology and epilepsy.
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- 2011
21. Radiosynthesis of the candidate beta-amyloid radioligand [(11)C]AZD2184: Positron emission tomography examination and metabolite analysis in cynomolgus monkeys
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Britt-Marie Swahn, Jan Andersson, Lars Farde, David Wensbo, Sjoerd J. Finnema, Balázs Gulyás, Katarina Varnäs, Christer Halldin, Zsolt Cselényi, Svante Nyberg, and Samuel P.S. Svensson
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Aminopyridines ,Mass Spectrometry ,Cellular and Molecular Neuroscience ,Imaging, Three-Dimensional ,In vivo ,medicine ,Radioligand ,Dosimetry ,Animals ,Whole Body Imaging ,Benzothiazoles ,Carbon Radioisotopes ,Chromatography, High Pressure Liquid ,Radiochemistry ,medicine.diagnostic_test ,Chemistry ,business.industry ,Radiosynthesis ,Brain ,Effective dose (pharmacology) ,In vitro ,Macaca fascicularis ,Positron emission tomography ,Positron-Emission Tomography ,Nuclear medicine ,business ,Ex vivo - Abstract
Beta-amyloid accumulation is associated with the pathogenesis of Alzheimer's disease (AD). AZD2184, a new radioligand for high-contrast positron emission tomography (PET) imaging of Abeta-deposits, has recently been developed and characterized in vitro and in rodents ex vivo. The objective of this study was to label AZD2184 with carbon-11, to perform in vivo characterization of [(11)C]AZD2184 ([(11)C]5) in the cynomolgus monkey brain as well as whole-body dosimetry, and to examine the metabolism of the labeled radioligand. [(11)C]5 was prepared by a two-step radiosynthesis starting with the reaction of 5-(6-(tert-butyldimethylsilyloxy)benzo[d]thiazol-2-yl)pyridin-2-amine with [(11)C]methyl iodide followed by deprotection using water. Four brain PET measurements in two cynomolgus monkeys and one whole-body PET measurement were performed with [(11)C]5. There was a high and rapid brain uptake (2.2-3.4% of injected dose at 2 min). The distribution of brain radioactivity was fairly uniform, with early to late-brain concentration ratios (peak vs. 60 min) higher for [(11)C]5 than ratios previously reported for [(11)C]PIB (8.2 and 4.6, respectively). Based on the whole-body data, it was estimated that an effective dose in an adult male would be 6.2 muSv/MBq and thus would be safe from a radiation point of view for multiple scans within the same year. [(11)C]5 shows binding characteristics, suggesting low levels of white-matter retention, and may thus provide improved contrast when compared with currently used PET radioligands for visualization of Abeta-deposits. On the basis of the labeling chemistry and the results of the biological evaluation, we conclude that [(11)C]5 should be useful for routine clinical studies.
- Published
- 2010
22. ChemInform Abstract: New Heteroaryl-Spaced Phosphono-α-amino Acids are Competitive NMDA Antagonists with Analgesic Activity
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Håkan Molin, Benjamin Pelcman, Alf Claesson, Britt-Marie Swahn, Odd-Geir Berge, Mats P. Sandberg, and Yevgeni Besidski
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chemistry.chemical_classification ,Chemistry ,Stereochemistry ,Analgesic ,NMDA receptor ,General Medicine ,Binding affinities ,Amino acid - Abstract
The synthesis and the NMDA receptor binding affinities of α-amino-3-(phosphonomethyl)-2-naphthalene-propanoic acid, α-amino-3-(phosphonomethyl)-2-benzofuranpropanoic acid, a series of substituted (R)-α-amino-3-(phosphonomethyl)-2-quinolinepropanoic acids, (R)-α-amino-3-(phosphonomethyl)-1,8-naphthyridine-2-propanoic acid and (R)-α-amino-3-(phosphonomethyl)-1,6-naphthyridine-2-propanoic acid are reported.
- Published
- 2010
23. Characterization of AZD4694, a novel fluorinated Abeta plaque neuroimaging PET radioligand
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Anders, Juréus, Britt-Marie, Swahn, Johan, Sandell, Fredrik, Jeppsson, Allan E, Johnson, Peter, Johnström, Jan A M, Neelissen, Dan, Sunnemark, Lars, Farde, and Samuel P S, Svensson
- Subjects
Aged, 80 and over ,Male ,Fluorine Radioisotopes ,Amyloid beta-Peptides ,Hydrocarbons, Fluorinated ,Fluorine Compounds ,Mice, Transgenic ,Plaque, Amyloid ,Binding, Competitive ,Rats ,Rats, Sprague-Dawley ,Mice ,Radioligand Assay ,Alzheimer Disease ,Positron-Emission Tomography ,Animals ,Humans ,Female ,Aged ,Benzofurans ,Injections, Intraventricular - Abstract
Positron emission tomography (PET) radioligands that bind selectively to beta-amyloid plaques (Abeta) are promising imaging tools aimed at supporting the diagnosis of Alzheimer's disease and the evaluation of new drugs aiming to modify amyloid plaque load. For extended clinical use, there is a particular need for PET tracers labeled with fluorine-18, a radionuclide with 110 min half-life allowing for central synthesis followed by wide distribution. The development of fluorinated radioligands is, however, challenging because of the lipophilic nature of aromatic fluorine, rendering fluorinated ligands more prone to have high non-specific white matter binding. We have here developed the new benzofuran-derived radioligand containing fluorine, AZD4694 that shows high affinity for beta-amyloid fibrils in vitro (K(d) = 2.3 +/- 0.3 nM). In cortical sections from human Alzheimer's disease brain [(3)H]AZD4694 selectively labeled beta-amyloid deposits in gray matter, whereas there was a lower level of non-displaceable binding in plaque devoid white matter. Administration of unlabeled AZD4694 to rat showed that it has a pharmacokinetic profile consistent with good PET radioligands, i.e., it quickly entered and rapidly cleared from normal rat brain tissue. Ex vivo binding data in aged Tg2576 mice after intravenous administration of [(3)H]AZD4694 showed selective binding to beta-amyloid deposits in a reversible manner. In Tg2576 mice, plaque bound [(3)H]AZD4694 could still be detected 80 min after i.v. administration. Taken together, the preclinical profile of AZD4694 suggests that fluorine-18 labeled AZD4694 may have potential for PET-visualization of cerebral beta-amyloid deposits in the living human brain.
- Published
- 2010
24. Competitive NMDA antagonist that base their activity on a unique conformational effect
- Author
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Britt-Marie Swahn, H»kan Molin, Mats Sandberg, Alf Claesson, and Karin M. Edvinsson
- Subjects
chemistry.chemical_classification ,Base (chemistry) ,Chemistry ,Hydrogen bond ,Stereochemistry ,Organic Chemistry ,Clinical Biochemistry ,Cyclohexane conformation ,Pharmaceutical Science ,Biochemistry ,Drug Discovery ,Molecular Medicine ,NMDA receptor ,Enantiomer ,Molecular Biology - Abstract
The synthesis of two NMDA antagonist, cis -3-(1-oxi-2-phosphonoethyl)-2-piperidine-carboxylic acid and cis -3-(1-hydroxy-2-phosphonoethyl)-2-piperidinecarboxylic acid ( 1 and 2 ), is reported. The enantiomers of 1 were also prepared. NMR analysis showed that 1 prefers a 3 ax , 2 eq chair conformation due to internal hydrogen bonding.
- Published
- 1992
25. Synthesis and evaluation of 2-pyridylbenzothiazole, 2-pyridylbenzoxazole and 2-pyridylbenzofuran derivatives as 11C-PET imaging agents for beta-amyloid plaques
- Author
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Britt-Marie Swahn, Michaela Vallin, Margareta Bergh, Fredrik Jeppsson, Johan Sandell, Allan E. Johnson, Daniel Sohn, Jonas Malmström, Samuel P.S. Svensson, David Pyring, Can Slivo, Jan A.M. Neelissen, Erwan Arzel, Anders Juréus, and David Wensbo
- Subjects
Genetically modified mouse ,Transgene ,Clinical Biochemistry ,Pharmaceutical Science ,Mice, Transgenic ,Biochemistry ,Mice ,Radioligand Assay ,Structure-Activity Relationship ,Pharmacokinetics ,In vivo ,Drug Discovery ,Structure–activity relationship ,Animals ,Benzothiazoles ,Carbon Radioisotopes ,Molecular Biology ,Benzofurans ,Benzoxazoles ,Amyloid beta-Peptides ,Chemistry ,Organic Chemistry ,In vitro ,Positron-Emission Tomography ,Lipophilicity ,Molecular Medicine ,Half-Life - Abstract
The syntheses and SAR of new series of beta-amyloid binding agents are reported. The effort to optimize signal-to-background ratios for these ligands are described. Compounds 8, 21 and 30 displayed desirable lipophilicity and pharmacokinetic properties. Compounds 8 and 21 were evaluated with in vitro autoradiographic studies and in vivo in APP/PS1 transgenic mice. It is shown that it was possible to increase the signal-to-background ratios compared to PIB 1, as demonstrated by compounds 8 and 21.
- Published
- 2009
26. P2‐023: AZD4694: Fluorinated Positron Emission Tomography (PET) radioligand for detection of β‐amyloid deposits
- Author
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Britt-Marie Swahn, Lars Farde, Christer Halldin, Magnus Schou, Jan A.M. Neelissen, Allan E. Johnson, Fredrik Jeppsson, Anna K. Sundgren-Andersson, Zsolts Cselényi, Samuel P.S. Svensson, Anders Juréus, Johan Sandell, and Peter Johnström
- Subjects
medicine.diagnostic_test ,Epidemiology ,Chemistry ,Health Policy ,Psychiatry and Mental health ,Cellular and Molecular Neuroscience ,Nuclear magnetic resonance ,Developmental Neuroscience ,β amyloid ,Positron emission tomography ,Radioligand ,Brain positron emission tomography ,medicine ,Neurology (clinical) ,Geriatrics and Gerontology - Published
- 2009
27. S4‐04‐07: Bace Inhibitors for the Treatment of Alzheimer's Disease
- Author
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Peter Söderman, Britt-Marie Swahn, Fredrik Jeppson, Anki Radesäter, Biljana Georgievska, Johanna Fälting, Susanna Eketjäll, and Jan A.M. Neelissen
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Psychiatry and Mental health ,Cellular and Molecular Neuroscience ,Developmental Neuroscience ,Epidemiology ,business.industry ,Health Policy ,Medicine ,Neurology (clinical) ,Disease ,Geriatrics and Gerontology ,Pharmacology ,business - Published
- 2009
28. IC‐P‐141: AZD4694: Fluorinated Positron Emission Tomography (PET) radioligand for detection of β‐amyloid deposits
- Author
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Anna K. Sundgren‐Andersson, Samuel P.S. Svensson, Britt‐Marie Swahn, Anders Juréus, Johan Sandell, Allan E. Johnson, Fredrik Jeppsson, Jan A.M. Neelissen, Christer Halldin, Peter Johnström, Magnus Schou, Zsolts Cselényi, and Lars Farde
- Subjects
Psychiatry and Mental health ,Cellular and Molecular Neuroscience ,Developmental Neuroscience ,Epidemiology ,Health Policy ,Neurology (clinical) ,Geriatrics and Gerontology - Published
- 2009
29. Design and synthesis of 6-anilinoindazoles as selective inhibitors of c-Jun N-terminal kinase-3
- Author
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Tatjana Weigelt, Fernando Huerta, Elisabet Kallin, Britt-Marie Swahn, Yafeng Xue, Liselotte Öhberg, Jenny Viklund, Jonas Malmström, and Patrick Womack
- Subjects
Indazoles ,Molecular model ,Stereochemistry ,High-throughput screening ,Clinical Biochemistry ,Pharmaceutical Science ,Crystallography, X-Ray ,Biochemistry ,Chemical synthesis ,Sensitivity and Specificity ,Substrate Specificity ,Mitogen-Activated Protein Kinase 14 ,Inhibitory Concentration 50 ,Structure-Activity Relationship ,Mitogen-Activated Protein Kinase 10 ,Drug Discovery ,Structure–activity relationship ,Mitogen-Activated Protein Kinase 8 ,Binding site ,Molecular Biology ,Protein Kinase Inhibitors ,chemistry.chemical_classification ,Binding Sites ,biology ,Chemistry ,Kinase ,Organic Chemistry ,c-jun ,Active site ,General Medicine ,Protein Structure, Tertiary ,Enzyme ,Terminal (electronics) ,Enzyme inhibitor ,Drug Design ,biology.protein ,Molecular Medicine - Abstract
The structure-based design and synthesis of a new series of c-Jun N-terminal kinase-3 inhibitors with selectivity against JNK1 and p38alpha is reported. The novel series of substituted 6-anilinoindazoles were designed based on a combination of hits from high throughput screening and X-ray crystal structure information of the compounds crystallized into the JNK3 ATP binding active site.
- Published
- 2005
30. Dichloromethane as reactant in synthesis: an expedient transformation of prolinamide to a novel pyrrolo[1,2-c]imidazolone
- Author
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Hans Jurgen Federsel, Lars Lilljequist, Erik Koenberg, and Britt Marie Swahn
- Subjects
Transformation (genetics) ,chemistry.chemical_compound ,Ammonia ,Bicyclic molecule ,Chemistry ,Organic Chemistry ,Lactam ,Organic chemistry ,Nuclear magnetic resonance spectroscopy ,Ethyl ester ,Dichloromethane - Abstract
This investigation has clearly demonstrated that reacting (S)-prolinamide (generated in situ from (S)-proline ethyl ester and ammonia) with dichloromethane affords the novel, chiral pyrroloimidazolone
- Published
- 1990
31. Correction to New Aminoimidazoles as β-Secretase (BACE-1) Inhibitors Showing Amyloid-β (Aβ) Lowering in Brain
- Author
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Jacob Kihlström, Johan Lindström, Fredrik Jeppsson, Johanna Fälting, Can Slivo, Tobias Ginman, Susanna Eketjäll, Jenny Viklund, Fredrik Rahm, Patrik Johansson, Jan Blid, Britt-Marie Swahn, Juliette Janson, Karin Kolmodin, Ylva Gravenfors, Krisztián Bogár, Stefan von Berg, Lise-Lotte Olsson, Kia Strömberg, Fredrik von Kieseritzky, and Sofia Karlström
- Subjects
Amyloid β ,Biochemistry ,Chemistry ,Drug Discovery ,β secretase ,Molecular Medicine - Published
- 2012
32. [18F]AZD4694—A new PET radioligand for sensitive detection of β-amyloid deposits
- Author
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Britt-Marie Swahn, Magnus Schou, Samuel P.S. Svensson, Lars Farde, Peter Johnström, Zsolts Cselényi, Fredrik Jeppsson, Christer Halldin, Jan A.M. Neelissen, Johan Sandell, and Anders Juréus
- Subjects
Neurology ,Biochemistry ,Chemistry ,β amyloid ,Cognitive Neuroscience ,Radioligand - Published
- 2010
33. ChemInform Abstract: Dichloromethane as Reactant in Synthesis: An Expedient Transformation of Prolinamide to a Novel Pyrrolo(1,2-c)imidazolone
- Author
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Erik Koenberg, Hans Jurgen Federsel, Britt Marie Swahn, and Lars Lilljequist
- Subjects
chemistry.chemical_compound ,Ammonia ,Transformation (genetics) ,chemistry ,Organic chemistry ,General Medicine ,Ethyl ester ,Dichloromethane - Abstract
This investigation has clearly demonstrated that reacting (S)-prolinamide (generated in situ from (S)-proline ethyl ester and ammonia) with dichloromethane affords the novel, chiral pyrroloimidazolone
- Published
- 1990
34. Low background and high contrast PET imaging of amyloid-β with [11C]AZD2995 and [11C]AZD2184 in Alzheimer’s disease patients
- Author
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Jan Andersson, Per Julin, Magnus Schou, Zsolt Cselényi, Johan Sandell, Peter Johnström, Yvonne Freund-Levi, Christer Halldin, Britt-Marie Swahn, Anders Juréus, Samuel P.S. Svensson, Fredrik Jeppsson, Anton Forsberg, Katarina Varnäs, Maria Eriksdotter, and Lars Farde
- Subjects
Male ,Pathology ,Amyloid β ,PET imaging ,Aminopyridines ,Disease ,030218 nuclear medicine & medical imaging ,Mice ,Radioligand Assay ,0302 clinical medicine ,Carbon Radioisotopes ,Aged, 80 and over ,[11C]AZD2995 ,Benzoxazoles ,High contrast ,Aniline Compounds ,medicine.diagnostic_test ,Amyloid-β imaging ,Brain ,General Medicine ,Middle Aged ,Magnetic Resonance Imaging ,Positron emission tomography ,Radiology Nuclear Medicine and imaging ,Female ,Original Article ,Alzheimer's disease ,Alzheimer’s disease ,Protein Binding ,medicine.medical_specialty ,Mice, Transgenic ,Sensitivity and Specificity ,03 medical and health sciences ,Alzheimer Disease ,medicine ,Animals ,Humans ,Radiology, Nuclear Medicine and imaging ,Benzothiazoles ,Aged ,Amyloid beta-Peptides ,Binding Sites ,business.industry ,Case-control study ,Magnetic resonance imaging ,Pet imaging ,medicine.disease ,Thiazoles ,Case-Control Studies ,Positron-Emission Tomography ,[11C]AZD2184 ,Radiopharmaceuticals ,business ,030217 neurology & neurosurgery - Abstract
Purpose The aim of this study was to evaluate AZD2995 side by side with AZD2184 as novel PET radioligands for imaging of amyloid-β in Alzheimer’s disease (AD). Methods In vitro binding of tritium-labelled AZD2995 and AZD2184 was studied and compared with that of the established amyloid-β PET radioligand PIB. Subsequently, a first-in-human in vivo PET study was performed using [11C]AZD2995 and [11C]AZD2184 in three healthy control subjects and seven AD patients. Results AZD2995, AZD2184 and PIB were found to share the same binding site to amyloid-β. [3H]AZD2995 had the highest signal-to-background ratio in brain tissue from patients with AD as well as in transgenic mice. However, [11C]AZD2184 had superior imaging properties in PET, as shown by larger effect sizes comparing binding potential values in cortical regions of AD patients and healthy controls. Nevertheless, probably due to a lower amount of nonspecific binding, the group separation of the distribution volume ratio values of [11C]AZD2995 was greater in areas with lower amyloid-β load, e.g. the hippocampus. Conclusion Both AZD2995 and AZD2184 detect amyloid-β with high affinity and specificity and also display a lower degree of nonspecific binding than that reported for PIB. Overall [11C]AZD2184 seems to be an amyloid-β radioligand with higher uptake and better group separation when compared to [11C]AZD2995. However, the very low nonspecific binding of [11C]AZD2995 makes this radioligand potentially interesting as a tool to study minute levels of amyloid-β. This sensitivity may be important in investigating, for example, early prodromal stages of AD or in the longitudinal study of a disease modifying therapy. Electronic supplementary material The online version of this article (doi:10.1007/s00259-012-2322-6) contains supplementary material, which is available to authorized users.
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