Characterization of Diagnostic Tools and Potential Treatments for Alzheimer's Disease Fredrik ...

83 Pages·2016·1.65 MB·English

Characterization of Diagnostic Tools and Potential
Treatments for Alzheimer’s Disease
PET ligands and BACE1 inhibitors

Fredrik Jeppsson
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Characterization of Diagnostic Tools
and Potential Treatments for
Alzheimer’s Disease
PET ligands and BACE1 inhibitors
Fredrik Jeppsson
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Cover picture: “Coronal Brain Slice” Painted by Julian Jeppsson 3 years, 2016.
Articles and figures reprinted with permission
©Fredrik Jeppsson, Stockholm University 2016
ISBN 978-91-7649-531-5

Printed in Sweden by Holmbergs, Malmö 2016
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Till Julian, Nils, Ivar och
Johanna
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List of Publications
I. Johnson AE, Jeppsson F, Sandell J, Wensbo D, Neelissen JA,
Juréus A, Ström P, Norman H, Farde L, Svensson SP.
AZD2184: a radioligand for sensitive detection of β-amyloid
deposits.
J Neurochem. 2009 Mar;108(5):1177-86.

II. Juréus A, Swahn BM, Sandell J, Jeppsson F, Johnson AE,
Johnström P, Neelissen JA, Sunnemark D, Farde L, Svensson SP.
Characterization of AZD4694, a novel fluorinated Aβ plaque
neuroimaging PET radioligand.
J Neurochem. 2010 Aug;114(3):784-94.

III. Mattsson A*, Jeppsson F*, Lundkvist J, Svensson A, Nilsson M,
Sunnemark D, Nilsson KP, Hammarström P, Holtzman DM, Ferm
M, Svensson SP, Juréus A.
Altered amyloid PET ligand binding to ApoE-containing plaques in
Alzheimer´s disease brain in vitro.
Manuscript. (2016)

IV. Jeppsson F, Eketjäll S, Janson J, Karlström S, Gustavsson S, Olsson
LL, Radesäter AC, Ploeger B, Cebers G, Kolmodin K, Swahn BM,
von Berg S, Bueters T, Fälting J.
Discovery of AZD3839, a Potent and Selective BACE1 Inhibitor
Clinical Candidate for the Treatment of Alzheimer Disease.
J Biol Chem. 2012 Nov 30;287(49):41245-57.

V. Eketjäll S, Janson J, Jeppsson F, Svanhagen A, Kolmodin K,
Gustavsson S, Radesäter AC, Eliason K, Briem S, Appelkvist P,
Niva C, Berg AL, Karlström S, Swahn BM, Fälting J.
AZ-4217: A High Potency BACE Inhibitor Displaying Acute
Central Efficacy in Different In vivo Models and Reduced
Amyloid Deposition in Tg2576 Mice.
J Neurosci. 2013 Jun 12;33(24):10075-84.

*Contributed equally
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VI. Eketjäll S, Janson J, Kaspersson K, Bogstedt A, Jeppsson F, Fälting
J, Haeberlein SB, Kugler AR, Alexander RC, Cebers G.
AZD3293: A Novel, Orally Active BACE1 Inhibitor with High
Potency and Permeability and Markedly Slow Off-Rate Kinetics.
J Alzheimers Dis. 2016;50(4):1109-23.

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Additional publications
• Llona-Minguez S, Höglund A, Jacques SA, Johansson L, Calderón-
Montaño JM, Claesson M, Loseva O, Valerie NC, Lundbäck T,
Piedrafita J, Maga G, Crespan E, Meijer L, Burgos Morón E,
Baranczewski P, Hagbjörk AL, Svensson R, Wiita E, Almlöf I, Visnes T,
Jeppsson F, Sigmundsson K, Jensen AJ, Artursson P, Jemth AS,
Stenmark P, Warpman Berglund U, Scobie M, Helleday T.
Discovery of the First Potent and Selective Inhibitors of Human dCTP
Pyrophosphatase 1.
J Med Chem. 2016 Feb 11;59(3):1140-8.

• Gad H, Koolmeister T, Jemth AS, Eshtad S, Jacques SA, Ström CE,
Svensson LM, Schultz N, Lundbäck T, Einarsdottir BO, Saleh A,
Göktürk C, Baranczewski P, Svensson R, Berntsson RP, Gustafsson R,
Strömberg K, Sanjiv K, Jacques-Cordonnier MC, Desroses M,
Gustavsson AL, Olofsson R, Johansson F, Homan EJ, Loseva O,
Bräutigam L, Johansson L, Höglund A, Hagenkort A, Pham T, Altun M,
Gaugaz FZ, Vikingsson S, Evers B, Henriksson M, Vallin KS, Wallner
OA, Hammarström LG, Wiita E, Almlöf I, Kalderén C,
Axelsson H, Djureinovic T, Puigvert JC, Häggblad M, Jeppsson F,
Martens U, Lundin C, Lundgren B, Granelli I, Jensen AJ, Artursson P,
Nilsson JA, Stenmark P, Scobie M, Berglund UW, Helleday T.
MTH1 inhibition eradicates cancer by preventing sanitation of the dNTP
pool.
Nature. 2014 Apr 10;508(7495):215-21.

• Janson J, Eketjäll S, Tunblad K, Jeppsson F, Von Berg S, Niva C,
Radesäter AC, Fälting J, Visser SA.
Population PKPD modeling of BACE1 inhibitor-induced reduction in Aβ
levels in vivo and correlation to in vitro potency in primary cortical
neurons from mouse and guinea pig.
Pharm Res. 2014 Mar;31(3):670-83.

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• Forsberg A, Juréus A, Cselényi Z, Eriksdotter M, Freund-Levi Y,
Jeppsson F, Swahn BM, Sandell J, Julin P, Schou M, Andersson J,
Johnström P, Varnäs K, Halldin C, Farde L, Svensson S.
Low background and high contrast PET imaging of amyloid-β with
[11C]AZD2995 and [11C]AZD2184 in Alzheimer's disease patients.
Eur J Nucl Med Mol Imaging. 2013 Apr;40(4):580-93.

• Ginman T, Viklund J, Malmström J, Blid J, Emond R, Forsblom R,
Johansson A, Kers A, Lake F, Sehgelmeble F, Sterky KJ, Bergh M,
Lindgren A, Johansson P, Jeppsson F, Fälting J, Gravenfors Y, Rahm F.
Core refinement toward permeable β-secretase (BACE-1) inhibitors with
low hERG activity.
J Med Chem. 2013 Jun 13;56(11):4181-205.

• Gravenfors Y, Viklund J, Blid J, Ginman T, Karlström S, Kihlström J,
Kolmodin K, Lindström J, von Berg S, von Kieseritzky F, Bogar K, Slivo
C, Swahn BM, Olsson LL, Johansson P, Eketjäll S, Fälting J, Jeppsson
F, Strömberg K, Janson J, Rahm F.
New aminoimidazoles as β-secretase (BACE-1) inhibitors showing
amyloid-β (Aβ) lowering in brain.
J Med Chem. 2012 Nov 8;55(21):9297-311.

• Swahn BM, Kolmodin K, Karlström S, von Berg S, Söderman P, Holenz
J, Berg S, Lindström J, Sundström M, Turek D, Kihlström J, Slivo C,
Andersson L, Pyring D, Rotticci D, Ohberg L, Kers A, Bogar K, von
Kieseritzky F, Bergh M, Olsson LL, Janson J, Eketjäll S, Georgievska B,
Jeppsson F, Fälting J.
Design and synthesis of β-site amyloid precursor protein cleaving enzyme
(BACE1) inhibitors with in vivo brain reduction of
β-amyloid peptides.
J Med Chem. 2012 Nov 8;55(21):9346-61.

• Swahn BM, Sandell J, Pyring D, Bergh M, Jeppsson F, Juréus A,
Neelissen J, Johnström P, Schou M, Svensson S.
Synthesis and evaluation of pyridylbenzofuran, pyridylbenzothiazole and
pyridylbenzoxazole derivatives as ¹ F-PET imaging agents for β-amyloid
plaques.
Bioorg Med Chem Lett. 2012 Jul⁸ 1;22(13):4332-7.

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