Multifunctional imaging of amyloid-beta peptides with a new gadolinium-based contrast agent in Alzheimer’s disease

Garam Choi; Hee-Kyung Kim; Ah Rum Baek; Soyeon Kim; Min Jung Kim; Minsup Kim; Art E. Cho; Gang-Ho Lee; Hoesu Jung; Ji-ung Yang; Taekwan Lee; Yongmin Chang

Journal of Industrial and Engineering Chemistry, Vol.83, 214-223, March, 2020

DOI10.1016/j.jiec.2019.11.031 Export Citation

Multifunctional imaging of amyloid-beta peptides with a new gadolinium-based contrast agent in Alzheimer’s disease

Garam Choi^{1, 2}, Hee-Kyung Kim³, Ah Rum Baek¹, Soyeon Kim¹, Min Jung Kim¹, Minsup Kim⁴, Art E. Cho⁴, Gang-Ho Lee⁵, Hoesu Jung⁶, Ji-ung Yang^{1, 6}, Taekwan Lee^{6, †}, and Yongmin Chang^{1, 7, †}

¹Department of Medical & Biological Engineering, Kyungpook National University, Daegu 41944, Republic of Korea
²Department of R&D Center, Myungmoon Bio Co., Hwaseong, Gyeonggi-do 18622, Republic of Korea
³Institute of Biomedical Engineering Research, Kyungpook National University, Daegu 41944, Republic of Korea
⁴Department of Bioinformatics, Korea University Sejong Campus, Sejong 30019, Republic of Korea
⁵Department of Chemistry, College of Natural Science, Kyungpook National University, Daegu 41944, Republic of Korea
⁶Laboratory Animal Center, Daegu-Gyeongbuk Medical Innovation Foundation, Daegu 41061, Republic of Korea
⁷Department of Molecular Medicine, School of Medicine, Kyungpook National University, Daegu 41944, Republic of Korea

E-mail:,

Multifunctional imaging of the deposition of amyloid-beta (Aβ) aggregates in the brain is of great importance in diagnosing Alzheimer’s disease. Herein, we report a multifunctional Aβ-targeting smallmolecular- weight gadolinium (Gd)-based contrast agent (CA), Gd-DO3A-Chal (a new Gd-chelate conjugated with chalcone), that showed 8 times higher binding affinity to Aβ aggregates than a previously reported Gd-chelate conjugated with Pittsburgh compound B. Gd-DO3A-Chal showed multimodal imaging capability. As a new fluorescence imaging probe, Gd-DO3A-Chal showed a good match with immunostained images using 6E10 monoclonal antibodies for the detection of Aβ aggregates in 5XFAD transgenic mouse brain sections. For in vivo magnetic resonance (MR) imaging without bloodbrain barrier disruption, longitudinal relaxation time (T1)-weighted MR images after intravenous administration of Gd-DO3A-Chal showed signal enhancement of the Aβ distribution in living 5XFAD transgenic mouse brain. Therefore, in vivo MR images for Aβ detection in addition to fluorescent optical images of Aβ aggregates with high specificity and sensitivity using this new multifunctional Aβ-targeting CA were successfully demonstrated.

Keywords:Gadolinium complex;Magnetic resonance contrast agent;Chalcone;Derivative;Multifunctional imaging;Amyloid imaging

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[1] Roberson ED, Mucke L, Science, 314, 781 (2006)

[2] Fratiglioni L, Winblad B, von Strauss E, Physiol. Behav., 92, 98 (2007)

[3] Adlard PA, Cummings BJ, Neurobiol. Aging, 25, 725 (2004)

[4] Puzzo D, Gulisano W, Arancio O, Palmeri A, Neuroscience, 307, 26 (2015)

[5] Benilova I, Karran E, De Strooper B, Nat. Neurosci., 15, 349 (2012)

[6] Hardy JA, Higgins GA, Science, 256, 184 (1992)

[7] Hardy J, Selkoe DJ, Science, 297, 353 (2002)

[8] Reinhard C, Hebert SS, De Strooper B, Embo J., 24, 3996 (2005)

[9] Braak H, Braak E, Acta Neuropathol., 82, 239 (1991)

[10] Arriagada PV, Growdon JH, Hedley-Whyte ET, Hyman BT, Neurology, 42, 631 (1992)

[11] Lee SY, Jeon SI, Jung S, Chung IJ, Ahn CH, Adv. Drug Deliv. Rev., 76, 60 (2014)

[12] Kuil J, Velders AH, van Leeuwen FW, Bioconjugate Chem., 21, 1709 (2010)

[13] Ghosh SC, Ghosh P, Wilganowski N, Robinson H, Hall MA, Dickinson G, Pinkston KL, Harvey BR, Sevick-Muraca EM, Azhdarinia A, J. Med. Chem., 56, 406 (2013)

[14] Kim HK, Jung HY, Park JA, Huh MI, Jung JC, Chang Y, Kim TJ, J. Mater. Chem., 20, 5411 (2010)

[15] Louie A, Chem. Rev., 110(5), 3146 (2010)

[16] Wadghiri YZ, Sigurdsson EM, Sadowski M, Elliott JI, Li Y, Scholtzova H, Tang CY, Aguinaldo G, Pappolla M, Duff K, Magn. Reson. Med., 50, 293 (2003)

[17] Yang J, Wadghiri YZ, Hoang DM, Tsui W, Sun Y, Chung E, Li Y, Wang A, de Leon M, Wisniewski T, Neuroimage, 55, 1600 (2011)

[18] Zhou J, Fa H, Yin W, Zhang J, Hou C, Huo D, Zhang D, Zhang H, Mater. Sci. Eng. C-Biomimetic Supramol. Syst., 37, 348 (2014)

[19] Zhang D, Fa HB, Zhou JT, Li S, Diao XW, Yin W, Clin. Radiol., 70, 74 (2015)

[20] Martins AF, Morfin JF, Kubickova A, Kubicek V, Buron f, Suzenet F, Salerno M, Lazar AN, Duyckaerts C, Arlicot N, ACS Med. Chem. Lett., 4, 436 (2013)

[21] Poduslo JF, Wengenack TM, Curran GL, Wisniewski T, Sigurdsson EM, Macura SI, Borowski BJ, Jack CR, Neurobiol. Dis., 11, 315 (2002)

[22] Poduslo JF, Curran GL, Peterson JA, McCormick DJ, Fauq AH, Khan MA, Wengenack TM, Biochemistry, 43, 6064 (2004)

[23] Wengenack TM, Jack CR, Garwood M, Poduslo JF, Eur. J. Nucl. Med. Mol. Imaging, 35, 82 (2008)

[24] Bae YH, Park K, J. Control. Release, 153, 198 (2011)

[25] Mroczko B, Groblewska M, Litman-Zawadzka A, Kornhuber J, Lewczuk P, J. Neural Transm., 125, 177 (2018)

[26] Pajouhesh H, Lenz GR, NeuroRx, 2, 541 (2005)

[27] Eckroat TJ, Mayhoub AS, Garneau-Tsodikova S, Beilstein J. Org. Chem., 9, 1012 (2013)

[28] Ono M, Haratake M, Mori H, Nakayama M, Bioorg. Med. Chem., 15, 6802 (2007)

[29] Baek AR, Kim HK, Park S, Lee GH, Kang HJ, Jung JC, Park HS, Ryeom HK, Kim TJ, Chang Y, J. Med. Chem., 60, 4861 (2017)

[30] Laurent S, Vander Elst L, Henoumont C, Muller R, Contrast Media Mol. Imaging, 5, 305 (2010)

[31] Morcos S, Eur. J. Radiol., 66, 175 (2008)

[32] Islam MK, Kim S, Kim HK, Kim YH, Lee YM, Choi G, Baek AR, Sung BK, Kim M, Cho AE, Bioconjugate Chem., 29, 3614 (2018)

[33] Schrodinger Release 2019-1: LigPrep, Schrodinger, LLC, New York, NY, 2019.

[34] Schrodinger Release 2019-1: Glide, Schrodinger, LLC, New York, NY, 2019.

[35] Schrodinger Release 2019-1: LigPrep, Schrodinger, LLC, New York, NY, 2019.

[36] Sondag CM, Dhawan G, Combs CK, J. Neuroinflammation, 6, 1 (2009)

[37] Jung SJ, Park SH, Lee EJ, Park JH, Kong YB, Rho JK, Hur MG, Yang SD, Park YD, Arch. Pharm. Res., 38, 1992 (2015)

[38] Sutharsan J, Dakanali M, Capule CC, Haidekker MA, Yang J, Theodorakis EA, ChemMedChem, 5, 56 (2010)

[39] Olsen JS, Brown C, Capule CC, Rubinshtein M, Doran TM, Srivastava RK, Feng C, Nilsson BL, Yang J, Dewhurst S, J. Biol. Chem., 285, 35488 (2010)

[40] Chang WM, Dakanali M, Capule CC, Sigurdson CJ, Yang J, Theodorakis EA, ACS Chem. Neurosci., 2, 249 (2011)

[41] Kouyoumdjian H, Zhu DC, El-Dakdouki MH, Lorenz K, Chen J, Li W, Huang X, ACS Chem. Neurosci., 4, 575 (2013)

[42] Meadowcroft MD, Connor JR, Yang QX, Front. Neurosci., 9, 255 (2015)

[43] Zhuang CL, Zhang W, Sheng CQ, Zhang WN, Xing CG, Miao ZY, Chem. Rev., 117(12), 7762 (2017)

[44] Ramalho J, Semelka R, Ramalho M, Nunes R, AlObaidy M, Castillo M, Am. J. Neuroradiol., 37, 1192 (2016)

[45] Kanda T, Oba H, Toyoda K, Kitajima K, Furui S, Jpn. J. Radiol., 34, 3 (2016)

[46] Singh SK, Gaur R, Kumar A, Fatima R, Mishra L, Srikrishna S, Neurotoxic. Res., 26, 331 (2014)

[47] Brogi S, Butini S, Maramai S, Colombo R, Verga L, Lanni C, De Lorenzi E, Lamponi S, Andreassi M, Bartolini M, CNS Neurosci. Ther., 20, 624 (2014)

[48] Aime S, Cabella C, Colombatto S, Crich SG, Gianolio E, Maggioni F, J. Magn. Reson. Imaging, 16, 394 (2002)

[49] Caravan P, Chem. Soc. Rev., 35, 512 (2006)

[50] Bort G, Catoen S, Borderies H, Kebsi A, Ballet S, Louin G, Port M, Ferroud C, Eur. J. Med. Chem., 87, 843 (2014)

[51] Martins AF, Morfin JF, Geraldes CF, Toth E, JBIC J. Biol. Inorg. Chem., 19, 281 (2014)