High-performance hepatobiliary dysprosium contrast agent for ultra-high-field magnetic resonance imaging

Ahrum Baek; Hee-kyung Kim; Ji-ung Yang; Garam Choi; Minsup Kim; Art E. Cho; Yeoun-hee Kim; Soyeon Kim; Bokyung Sung; Byeong Woo Yang; Heejin Seo; Gang-Ho Lee; Hun-Kyu Ryeom; Hoesu Jung; Taekwan Lee; Yongmin Chang

Journal of Industrial and Engineering Chemistry, Vol.85, 297-307, May, 2020

DOI10.1016/j.jiec.2020.02.015 Export Citation

High-performance hepatobiliary dysprosium contrast agent for ultra-high-field magnetic resonance imaging

Ahrum Baek¹, Hee-kyung Kim², Ji-ung Yang^{1, 3}, Garam Choi^{1, 4}, Minsup Kim⁵, Art E. Cho⁵, Yeoun-hee Kim⁴, Soyeon Kim¹, Bokyung Sung¹, Byeong Woo Yang¹, Heejin Seo¹, Gang-Ho Lee⁶, Hun-Kyu Ryeom⁷, Hoesu Jung³, Taekwan Lee^{3, †}, and Yongmin Chang^{1, 8, †}

¹Department of Medical & Biological Engineering, Kyungpook National University, Daegu 41944, Republic of Korea
²Institute of Biomedical Engineering Research, Kyungpook National University, Daegu 41944, Republic of Korea
³Laboratory Animal Center, Daegu-Gyeongbuk Medical Innovation Foundation, Daegu 41061, Republic of Korea
⁴Department of R&D center, Myungmoon Bio Co., Hwaseong, Gyeonggi-do 18622, Republic of Korea
⁵Institute of New Drug Research, Korea University Sejong Campus, 2511, Sejong-ro, Sejong City 30019, Republic of Korea
⁶Department of Chemistry, College of Natural Science, Kyungpook National University, Daegu 41944, Republic of Korea
⁷Department of Radiology, School of Medicine, Kyungpook National University, Daegu 41944, Republic of Korea
⁸Department of Molecular Medicine, School of Medicine, Kyungpook National University, Daegu 41944, Republic of Korea

E-mail:,

Ultra-high-field (UHF) magnetic resonance imaging (MRI) can open up new avenues in clinical diagnostic imaging. Its sensitivity can be further improved using contrast agents (CAs). Therefore, developing low-molecular-weight MR CAs that are efficient under UHF is crucial to ensure taking full advantage of MR imaging at UHF. Moreover, designing highly stable UHF liver-specific CA has been challenging. Here, using dysprosium (Dy3+), which relaxes water protons via a Curie relaxation that increases T2 relaxation substantially with the magnetic field strength, we report a new macrocyclic liver specific Dy3+ complex (Dy[DO3A-EOB]). We observed a 7.06 times higher r2/r1 ratio of Dy[DO3A-EOB] at 9.4 T than that of 1.5 T, which suggests a superior negative-enhancing MR CA at UHF. In vivo MR imaging results further demonstrated that Dy[DO3A-EOB] showed a much strong negative enhancement at UHF (9.4 T) than under a low field (1.5 T). It was also found that, in addition to the ligand structure, the metal itself plays an important role in determining the liver uptake pattern of the CA. Therefore, we successfully demonstrated the first example of a small-molecular-weight liver-specific Dy3+ complex acting as a T2 CA with high sensitivity at UHF for diagnosis of liver diseases.

Keywords:Dysprosium;T2 contrast agent;Ultra-high field MRI;Liver

[References]

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[Referenced By]

[1] Fuchs VR, Sox HC, Health Aff., 20, 30 (2001)

[2] Hoult DI, Richards R, J. Magn, Reson., 24, 71 (1976)

[3] Edelstein W, Glover G, Hardy C, Redington R, Magn. Reson. Med., 3, 604 (1986)

[4] Norris DG, Magn J, Reson. Imaging, 18, 519 (2003)

[5] Robitaille PML, Abduljalil AM, Kangarlu A, J. Comput. Assist. Tomo., 24, 2 (2000)

[6] Gareis D, Neuberger T, Behr VC, Jakob PM, Faber C, Griswold MA, Magn. Reson. Eng., 29, 20 (2006)

[7] Sharma R, Nanotech. Res. J., 2, 33 (2009)

[8] Fu R, Brey W, Shetty K, Gor’kov P, Saha S, Long J, Grant S, Chekmenev E, Hu J, Gan Z, J. Magn. Reson., 177, 1 (2005)

[9] Caravan P, Ellison JJ, McMurry TJ, Lauffer RB, Chem. Rev., 99(9), 2293 (1999)

[10] Geraldes CF, Laurent S, Contrast Media. Mol. Imaging, 4, 1 (2009)

[11] Aime S, Crich SG, Gianolio E, Giovenzana G, Tei L, Terreno E, Coord. Chem. Rev., 250, 1562 (2006)

[12] Caravan P, Farrar CT, Frullano L, Uppal R, Contrast Media. Mol. Imaging, 4, 89 (2009)

[13] Berry I, Chambon C, Gigaud M, Derache V, Manelfe C, Eur. Radiol., 4, 445 (1994)

[14] Ericsson A, Bach-Gansmo T, Niklasson F, Hemmingsson A, Acta Radiol., 36, 41 (1995)

[15] Lewis MM, Milne M, Bartha R, Hudson RH, Can. J. Chem., 93, 244 (2014)

[16] Woods M, Woessner DE, Sherry AD, Chem. Soc. Rev., 35, 500 (2006)

[17] Kellar KE, Fossheim SL, Koenig SH, Investig. Radiol., 33, 835 (1998)

[18] Bertini I, Capozzi F, Luchinat C, Nicastro G, Xia Z, J. Phys. Chem., 97, 6351 (1993)

[19] Vega AJ, Fiat D, Mol. Phys., 31, 347 (1976)

[20] Norek M, Peters JA, Prog. Nucl. Magn. Reson. Spectrosc., 59, 64 (2011)

[21] Caravan P, Greenfield M, J. Bulte, Magn. Reson. Med., 46, 917 (2001)

[22] Vander Elst L, Roch A, Gillis P, Laurent S, Botteman F, Bulte JW, Muller RN, Magn. Reson. Med., 47, 1121 (2002)

[23] Soesbe TC, Ratnakar SJ, Milne M, Zhang S, Do QN, Kovacs Z, Sherry AD, Magn. Reson. Med., 71, 1179 (2014)

[24] Soesbe TC, Merritt ME, Green KN, Rojas-Quijano FA, Sherry AD, Magn. Reson. Med., 66, 1697 (2011)

[25] Park JC, Park JK, Lee GT, Kim DH, Cha HS, Park TY, Kim MJ, Chang YM, Cha HJ, Seo JH, J. Ind. Eng. Chem., 77, 408 (2019)

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

[27] 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)

[28] Tag CG, Sauer-Lehnen S, Weiskirchen S, Borkham-Kamphorst E, Tolba RH, Tacke F, Weiskirchen R, J. Vis. Exp., e52438 (2015).

[29] Sherry AD, Caravan P, Lenkinski RE, J. Magn. Reson. Imaging, 30, 1240 (2009)

[30] Kim R, Eur. J. Clin. Invest, 33, 1 (2003)

[31] Buxhofer-Ausch V, Secky L, Wlcek K, Svoboda M, Kounnis V, Briasoulis E, Tzakos AG, Jaeger W, Thalhammer T, J. Drug Deliv., 863539, 1 (2013)

[32] Svoboda M, Riha J, Wlcek K, Jaeger W, Thalhammer T, Curr. Drug Metab., 12, 139 (2011)

[33] Glaeser H, Mandery K, Sticht H, Fromm M, Konig J, Br. J. Pharmacol., 159, 698 (2010)

[34] Weaver YM, Hagenbuch B, J. Membr. Biol., 236, 279 (2010)

[35] Schlessinger A, Khuri N, Giacomini KM, Sali A, Curr. Top. Med. Chem., 13, 843 (2013)

[36] Tweedle MF, J. Alloy. Compd., 180, 317 (1992)

[37] Liu Y, Meyer C, Xu C, Weng H, Hellerbrand C, ten Dijke P, Dooley S, Am. J. Physiol. Gastrointest. Liver Physiol., 304, G449 (2012)

[38] Planchamp C, Montet X, Frossard JL, Quadri R, Stieger B, Meier PJ, Ivancevic KM, Vallee JP, Terrier F, Pastor CM, Investig. Radiol., 40, 187 (2005)

[39] Pastor CM, Mullhaupt B, Stieger B, Drug Metab. Dispos., 42, 675 (2014)

[40] Slitt AL, Allen K, Morrone J, Aleksunes LM, Chen C, Maher JM, Manautou JE, Cherrington NJ, Klaassen CD, Biochim. Biophys. Acta, 1768, 637 (2007)

[41] Libra A, Fernetti C, Lorusso V, Visigalli M, Anelli PL, Staud F, Tiribelli C, Pascolo L, J. Pharmacol. Exp. Ther., 319, 809 (2006)