Rose bengal conjugated gadolinium complex as a new multimodal imaging agent targeting presynaptic vesicular glutamate transporters

Soyeon Kim; Hee-Kyung Kim; Ah Rum Baek; Bokyung Sung; Byeong Woo Yang; Yeoun-Hee Kim; Jung-jin Lee; Ji-ung Yang; Chang-Hoon Shin; Hoesu Jung; Minsup Kim; Art E. Cho; Taekwan Lee; Yongmin Chang

Journal of Industrial and Engineering Chemistry, Vol.95, 83-91, March, 2021

DOI10.1016/j.jiec.2020.12.007 Export Citation

Rose bengal conjugated gadolinium complex as a new multimodal imaging agent targeting presynaptic vesicular glutamate transporters

Soyeon Kim¹, Hee-Kyung Kim², Ah Rum Baek¹, Bokyung Sung¹, Byeong Woo Yang¹, Yeoun-Hee Kim³, Jung-jin Lee³, Ji-ung Yang¹, Chang-Hoon Shin², Hoesu Jung², Minsup Kim⁴, Art E. Cho⁴, Taekwan Lee^{2, †}, and Yongmin Chang^{1, 5, †}

¹Department of Medical & Biological Engineering, Kyungpook National University, 80 Daehak-ro, Buk-gu, Daegu 41566, Republic of Korea
²the Daegu-Gyeongbuk Medical Innovation Foundation, Laboratory Animal Center, 88 Dongnae-ro, Dong-gu, Daegu 41061, Republic of Korea
³R&D Center, Mirae BioPharm. Co., 124, Sagimakgol-ro, Jungwon-gu, Gyeonggi-do, 13207, Republic of Korea
⁴Department of Bioinformatics, Korea University Sejong Campus, 2511 Sejong-ro, Sejong City 30019, Republic of Korea
⁵Department of Molecular Medicine, School of Medicine, Kyungpook National University, 680 Gukchaebosang-ro, Jung-gu, Daegu 41944, Republic of Korea

E-mail:,

Glutamate is an important excitatory neurotransmitter, and vesicular glutamate transporters (VGLUTs) are critical in regulating the extent of glutamate release. Because initial increase and late stage decrease in VGLUT expression were implicated in progressive Alzheimer’s disease (AD), VGLUTs can be a new imaging target for diagnosing AD. In this study, we have designed and synthesized a new multimodal gadolinium contrast agent conjugated with rose bengal to target VGLUTs (Gd-DO3A-RB). In addition to high kinetic and pH stability, magnetic resonance and fluorescence imaging using Gd-DO3A-RB showed high affinity to VGLUT1. Using the AD animal model (5XFAD), in vivo MRI with a Gd-DO3A-RB showed less MR signal enhancement in 5XFAD mouse brain than that of age-matched normal C57BL/6 mouse, suggesting a late stage decrease in VGLUT expression in AD animal model. Therefore, this new VGLUT targeting gadolinium contrast agent demonstrated a strong potential as a new diagnostic tool for AD with multimodal imaging capability.

Keywords:Vesicular glutamate transporter;Rose Bengal;Gadolinium;Magnetic resonance imaging;Alzheimer’s disease

[References]

Lewerenz J, Maher P, Front. Neurosci., 9, 1 (2015)
Wilson NR, Kang J, Hueske EV, Leung T, Varoqui H, Murnick JG, Erickson JD, Liu G, J. Neurosci., 25, 6221 (2005)
Daniels RW, Miller BR, DiAntonio A, Neurobiol. Dis., 41, 415 (2011)
Williams C, Shai RM, Wu Y, Hsu YH, Sitzer T, Spann B, McCleary C, Mo Y, Miller CA, PLoS One, 4, 1 (2009)
Bell KF, Cuello AC, Eur. J. Pharmacol., 545, 11 (2006)
Bell KF, Bennett DA, Cuello AC, J. Neurosci., 27, 10810 (2007)
Daniels RW, Collins CA, Gelfand MV, Dant J, Brooks ES, Krantz DE, DiAntonio A, J. Neurosci., 24, 10466 (2004)
Favre-Besse FC, Poirel O, Bersot T, Kim-Grellier E, Daumas S, Mestikawy SE, Acher FC, Pietrancosta N, Eur. J. Med. Chem., 78, 236 (2014)
Shigeri Y, Seal RP, Shimamoto K, Brain Res. Rev., 45, 250 (2004)
Carrigan CN, Bartlett RD, Esslinger CS, Cybulski KA, Tongcharoensirikul P, Bridges RJ, Thompson CM, J. Med. Chem., 45, 2260 (2002)
Kehrl J, Althaus JC, Showalter HD, Rudzinski DM, Sutton MA, Ueda T, Neurochem. Res., 42, 1823 (2017)
Pietrancosta N, Kessler A, Favre-Besse FC, Triballeau N, Quentin T, Giros B, Mestikawy SE, Acher FC, Bioorg. Med. Chem., 18, 6922 (2010)
Strelow J, et al., Eli Lilly & Company and the National Center for Advancing Translational Sciences, Indianapolis, 2012.
Martineau M, Guzman RE, Fahlke C, Klingauf J, Nat. Commun., 8, 2279 (2017)
Ogita K, Hirata K, Bole DG, Yoshida S, Tamura Y, Leckenby AM, Ueda T, J. Neurochem., 77, 34 (2001)
Bole DG, Ueda T, Neurochem. Res., 30, 363 (2005)
Sun W, Luo L, Feng Y, Qiu Y, Shi C, Meng S, Chen X, Chen H, Adv. Mater., 32, 200037 (2020)
Kumar S, Meena VK, Hazari PP, Sharma SK, Sharma RK, Eur. J. Pharm. Sci., 117, 362 (2018)
Louie A, Chem. Rev., 110(5), 3146 (2010)
Josephson L, Kircher MF, Mahmood U, Tang Y, Weissleder R, Bioconjugate Chem., 13, 554 (2002)
Ren WT, Linag LB, Qi F, Sun ZB, Yang ZY, Huang XQ, Wu QZ, Zhu HY, Yu XF, Quan H, Gong QY, J. Nanomater., 2011, 1 (2011)
Chow EKH, Ho D, Sci. Transl. Med., 5, 216rv4 (2013)
Wu Q, Cheng Q, Yuan S, Qian J, Zhong K, Qian Y, Liu Y, Chem. Sci., 6, 6607 (2015)
Choi G, Kim HK, Baek AR, Kim S, Kim MJ, Kim M, Cho AE, Lee GH, Jung H, Yang J, Lee T, Chang Y, J. Ind. Eng. Chem., 83, 2014 (2020)
Sugita N, Kawabata KI, Sasaki K, Sakata I, Umemura SI, Bioconjugate Chem., 18, 866 (2007)
Andre JP, Geraldes CF, Martins JA, Merbach AE, Prata MI, Santos AC, de Lima JJ, Toth E, Chem. Eur. J., 10, 5804 (2004)
MacRenaris KW, Ma Z, Krueger RL, Carney CE, Meade TJ, Bioconjugate Chem., 27, 465 (2016)
Islam MK, Kim S, Kim HK, Kim YH, Lee YM, Choi G, Baek AR, et al., Bioconjugate Chem., 29, 3614 (2018)
Kim HK, Park JA, Kim KM, Nasiruzzaman SM, Kang DS, Lee J, Chang Y, Kim TJ, Chem. Commun., 46, 8442 (2010)
Baek A, Kim HK, Yang JU, Choi GR, Kim MS, Cho AE, Kim YH, Kim SY, Sung SK, Yang BW, Seo HJ, Lee GH, Ryeom HK, Jung HS, Lee TW, Chang YM, J. Ind. Eng. Chem., 85, 297 (2020)
Jung KH, Kim HK, Park JA, Nam KS, Lee GH, Chang Y, Kim TJ, ACS Med. Chem. Lett., 3, 1003 (2012)
Almqvist J, Huang Y, Laaksonen A, Wang DN, Hovmoller S, Protein Sci., 16, 1819 (2007)
Schrodinger Release 2019-2: Prime, Schrodinger, LLC, New York, NY, 2019.
Schrodinger Release 2019-2: SiteMap, Schrodinger, LLC, New York, NY, 2019.
Schrodinger Release 2019-2: Glide, Schrodinger, LLC, New York, NY, 2019.
Schrodinger Release 2019-2: LigPrep, Schrodinger, LLC, New York, NY, 2019.
Lesuisse C, Qiu D, Bose CM, Nakaso K, Rupp F, Mol. Brain Res., 81, 92 (2000)
Hogendoorn C, Roszczenko-Jasinska P, Martinez-Gomez NC, de Graaff J, Grassl P, Pol A, den Camp HJO, Daumann LJ, Appl. Environ. Microbiol., 84, e02887 (2018)
Polasek M, Caravan P, Inorg. Chem., 52(7), 4084 (2013)
Prasanna SW, Poorani G, Kumar MS, Aruna P, Ganesan S, Mater. Express, 4, 359 (2014)
Khoza P, Antunes E, Chen JY, Nyokong T, J. Lumines., 134, 784 (2013)
Wahsner J, Gale EM, Rodriguez-Rodriguez A, Caravan P, Chem. Rev., 119(2), 957 (2019)
Idee JM, Port M, Robic C, Medina C, Sabatou M, Corot C, J. Magn. Reson. Imaging, 30, 1249 (2009)
Marckmann P, Skov L, Rossen K, Dupont A, Damholt MB, Heaf JG, Thomsen HS, J. Am. Soc. Nephrol., 17, 2359 (2006)
Ersoy H, Rybicki FJ, Magn J, Reson. Imaging, 26, 1190 (2007)
Park JH, Gurunathan S, Choi YJ, Han W, Song H, Kim JH, J. Ind. Eng. Chem., 47, 62 (2017)
Herzog E, Takamori S, Jahn R, Brose N, Wojcik SM, J. Neurochem., 99, 1011 (2006)
Fremeau RT, Troyer MD, Pahner I, Nygaard GO, Tran CH, Reimer RJ, Bellocchio EE, Fortin D, Storm-Mathisen J, Edwards RH, Neuron, 31, 247 (2001)
Eimer WA, Vassar R, Mol. Neurodegener., 8, 1 (2013)
Kashani A, Lepicard E, Poirel O, Videau C, David JP, Fallet-Bianco C, Simon A, Delacourte A, Giros B, Epelbaum J, Betancur C, Mestikawy SE, Neurobiol. Aging, 29, 1619 (2008)
Menard C, Quirion R, Vigneault E, Bouchard S, Ferland G, Mestikawy SE, Gaudreau P, Neurobiol. Aging, 36, 1471 (2015)
Timmer NM, Metaxas A, van der Stelt I, Kluijtmans LA, van Berckel BN, Verbeek MM, J. Alzheimers Dis, 39, 89 (2014)
Bell KF, Ducatenzeiler A, Ribeiro-da-Silva A, Duff K, Bennett DA, Cuello AC, Neurobiol. Aging, 27, 1644 (2006)
Rodriguez-Perdigon M, Tordera RM, Gil-Bea FJ, Gerenu G, Ramirez MJ, Solas M, Hippocampus, 26, 1303 (2016)

[1] Lewerenz J, Maher P, Front. Neurosci., 9, 1 (2015)

[2] Wilson NR, Kang J, Hueske EV, Leung T, Varoqui H, Murnick JG, Erickson JD, Liu G, J. Neurosci., 25, 6221 (2005)

[3] Daniels RW, Miller BR, DiAntonio A, Neurobiol. Dis., 41, 415 (2011)

[4] Williams C, Shai RM, Wu Y, Hsu YH, Sitzer T, Spann B, McCleary C, Mo Y, Miller CA, PLoS One, 4, 1 (2009)

[5] Bell KF, Cuello AC, Eur. J. Pharmacol., 545, 11 (2006)

[6] Bell KF, Bennett DA, Cuello AC, J. Neurosci., 27, 10810 (2007)

[7] Daniels RW, Collins CA, Gelfand MV, Dant J, Brooks ES, Krantz DE, DiAntonio A, J. Neurosci., 24, 10466 (2004)

[8] Favre-Besse FC, Poirel O, Bersot T, Kim-Grellier E, Daumas S, Mestikawy SE, Acher FC, Pietrancosta N, Eur. J. Med. Chem., 78, 236 (2014)

[9] Shigeri Y, Seal RP, Shimamoto K, Brain Res. Rev., 45, 250 (2004)

[10] Carrigan CN, Bartlett RD, Esslinger CS, Cybulski KA, Tongcharoensirikul P, Bridges RJ, Thompson CM, J. Med. Chem., 45, 2260 (2002)

[11] Kehrl J, Althaus JC, Showalter HD, Rudzinski DM, Sutton MA, Ueda T, Neurochem. Res., 42, 1823 (2017)

[12] Pietrancosta N, Kessler A, Favre-Besse FC, Triballeau N, Quentin T, Giros B, Mestikawy SE, Acher FC, Bioorg. Med. Chem., 18, 6922 (2010)

[13] Strelow J, et al., Eli Lilly & Company and the National Center for Advancing Translational Sciences, Indianapolis, 2012.

[14] Martineau M, Guzman RE, Fahlke C, Klingauf J, Nat. Commun., 8, 2279 (2017)

[15] Ogita K, Hirata K, Bole DG, Yoshida S, Tamura Y, Leckenby AM, Ueda T, J. Neurochem., 77, 34 (2001)

[16] Bole DG, Ueda T, Neurochem. Res., 30, 363 (2005)

[17] Sun W, Luo L, Feng Y, Qiu Y, Shi C, Meng S, Chen X, Chen H, Adv. Mater., 32, 200037 (2020)

[18] Kumar S, Meena VK, Hazari PP, Sharma SK, Sharma RK, Eur. J. Pharm. Sci., 117, 362 (2018)

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

[20] Josephson L, Kircher MF, Mahmood U, Tang Y, Weissleder R, Bioconjugate Chem., 13, 554 (2002)

[21] Ren WT, Linag LB, Qi F, Sun ZB, Yang ZY, Huang XQ, Wu QZ, Zhu HY, Yu XF, Quan H, Gong QY, J. Nanomater., 2011, 1 (2011)

[22] Chow EKH, Ho D, Sci. Transl. Med., 5, 216rv4 (2013)

[23] Wu Q, Cheng Q, Yuan S, Qian J, Zhong K, Qian Y, Liu Y, Chem. Sci., 6, 6607 (2015)

[24] Choi G, Kim HK, Baek AR, Kim S, Kim MJ, Kim M, Cho AE, Lee GH, Jung H, Yang J, Lee T, Chang Y, J. Ind. Eng. Chem., 83, 2014 (2020)

[25] Sugita N, Kawabata KI, Sasaki K, Sakata I, Umemura SI, Bioconjugate Chem., 18, 866 (2007)

[26] Andre JP, Geraldes CF, Martins JA, Merbach AE, Prata MI, Santos AC, de Lima JJ, Toth E, Chem. Eur. J., 10, 5804 (2004)

[27] MacRenaris KW, Ma Z, Krueger RL, Carney CE, Meade TJ, Bioconjugate Chem., 27, 465 (2016)

[28] Islam MK, Kim S, Kim HK, Kim YH, Lee YM, Choi G, Baek AR, et al., Bioconjugate Chem., 29, 3614 (2018)

[29] Kim HK, Park JA, Kim KM, Nasiruzzaman SM, Kang DS, Lee J, Chang Y, Kim TJ, Chem. Commun., 46, 8442 (2010)

[30] Baek A, Kim HK, Yang JU, Choi GR, Kim MS, Cho AE, Kim YH, Kim SY, Sung SK, Yang BW, Seo HJ, Lee GH, Ryeom HK, Jung HS, Lee TW, Chang YM, J. Ind. Eng. Chem., 85, 297 (2020)

[31] Jung KH, Kim HK, Park JA, Nam KS, Lee GH, Chang Y, Kim TJ, ACS Med. Chem. Lett., 3, 1003 (2012)

[32] Almqvist J, Huang Y, Laaksonen A, Wang DN, Hovmoller S, Protein Sci., 16, 1819 (2007)

[33] Schrodinger Release 2019-2: Prime, Schrodinger, LLC, New York, NY, 2019.

[34] Schrodinger Release 2019-2: SiteMap, Schrodinger, LLC, New York, NY, 2019.

[35] Schrodinger Release 2019-2: Glide, Schrodinger, LLC, New York, NY, 2019.

[36] Schrodinger Release 2019-2: LigPrep, Schrodinger, LLC, New York, NY, 2019.

[37] Lesuisse C, Qiu D, Bose CM, Nakaso K, Rupp F, Mol. Brain Res., 81, 92 (2000)

[38] Hogendoorn C, Roszczenko-Jasinska P, Martinez-Gomez NC, de Graaff J, Grassl P, Pol A, den Camp HJO, Daumann LJ, Appl. Environ. Microbiol., 84, e02887 (2018)

[39] Polasek M, Caravan P, Inorg. Chem., 52(7), 4084 (2013)

[40] Prasanna SW, Poorani G, Kumar MS, Aruna P, Ganesan S, Mater. Express, 4, 359 (2014)

[41] Khoza P, Antunes E, Chen JY, Nyokong T, J. Lumines., 134, 784 (2013)

[42] Wahsner J, Gale EM, Rodriguez-Rodriguez A, Caravan P, Chem. Rev., 119(2), 957 (2019)

[43] Idee JM, Port M, Robic C, Medina C, Sabatou M, Corot C, J. Magn. Reson. Imaging, 30, 1249 (2009)

[44] Marckmann P, Skov L, Rossen K, Dupont A, Damholt MB, Heaf JG, Thomsen HS, J. Am. Soc. Nephrol., 17, 2359 (2006)

[45] Ersoy H, Rybicki FJ, Magn J, Reson. Imaging, 26, 1190 (2007)

[46] Park JH, Gurunathan S, Choi YJ, Han W, Song H, Kim JH, J. Ind. Eng. Chem., 47, 62 (2017)

[47] Herzog E, Takamori S, Jahn R, Brose N, Wojcik SM, J. Neurochem., 99, 1011 (2006)

[48] Fremeau RT, Troyer MD, Pahner I, Nygaard GO, Tran CH, Reimer RJ, Bellocchio EE, Fortin D, Storm-Mathisen J, Edwards RH, Neuron, 31, 247 (2001)

[49] Eimer WA, Vassar R, Mol. Neurodegener., 8, 1 (2013)

[50] Kashani A, Lepicard E, Poirel O, Videau C, David JP, Fallet-Bianco C, Simon A, Delacourte A, Giros B, Epelbaum J, Betancur C, Mestikawy SE, Neurobiol. Aging, 29, 1619 (2008)

[51] Menard C, Quirion R, Vigneault E, Bouchard S, Ferland G, Mestikawy SE, Gaudreau P, Neurobiol. Aging, 36, 1471 (2015)

[52] Timmer NM, Metaxas A, van der Stelt I, Kluijtmans LA, van Berckel BN, Verbeek MM, J. Alzheimers Dis, 39, 89 (2014)

[53] Bell KF, Ducatenzeiler A, Ribeiro-da-Silva A, Duff K, Bennett DA, Cuello AC, Neurobiol. Aging, 27, 1644 (2006)

[54] Rodriguez-Perdigon M, Tordera RM, Gil-Bea FJ, Gerenu G, Ramirez MJ, Solas M, Hippocampus, 26, 1303 (2016)