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Gd3+ complexes conjugated to Pittsburgh compound B: potential MRI markers of β-amyloid plaques

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Abstract

In an effort towards the visualization of β-amyloid (Aβ) plaques by T 1-weighted magnetic resonance imaging for detection of Alzheimer’s disease, we report the synthesis and characterization of stable, noncharged Gd3+ complexes of three different 1,4,7,10-tetraazacyclododecane-1,4,7-triacetic acid monoamide derivatives conjugated to Pittsburgh compound B, a well-established marker of Aβ plaques. The ligands L1, L2, and L3 differ in the nature and size of the spacer linking the macrocyclic chelator and the Pittsburgh compound B targeting moiety, which affects their lipophilicity, the octanol–water partition coefficients of the complexes ranging from −0.15 to 0.32. Given their amphiphilic behavior, the complexes form micelles in aqueous solution (critical micellar concentration 1.00–1.49 mM). The parameters determining the relaxivity, including the water exchange rate and the rotational correlation times, were assessed for the monomeric and the micellar form by a combined 17O NMR and 1H nuclear magnetic relaxation dispersion (NMRD) study. They are largely influenced by the aggregation state and the hydrophobic character of the linkers. The analysis of the rotational dynamics for the aggregated state in terms of local and global motions using the Lipari–Szabo approach indicates highly flexible, large aggregates. On binding of the complexes to human serum albumin or to the amyloid peptide Aβ1–40 in solution, they undergo a fourfold and a twofold relaxivity increase, respectively (40 MHz). Proton relaxation enhancement studies confirmed moderate interaction of Gd(L1) and Gd(L3) with human serum albumin, with K A values ranging between 250 and 910 M−1.

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References

  1. Fratiglioni L, Winblad B, von Strauss E (2007) Physiol Behav 92:98–104. doi:10.1016/j.physbeh.2007.05.059

    Article  CAS  PubMed  Google Scholar 

  2. Hardy J, Selkoe DJ (2002) Science 297:353–356. doi:10.1126/science.1072994

    Article  CAS  PubMed  Google Scholar 

  3. Rauk A (2009) Chem Soc Rev 38:2698. doi:10.1039/b807980n

    Article  CAS  PubMed  Google Scholar 

  4. Camus V, Payoux P, Barré L et al (2012) Eur J Nucl Med Mol Imaging 39:621–631. doi:10.1007/s00259-011-2021-8

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  5. Mathis CA, Bacskai BJ, Kajdasz ST, McLellan ME, Frosch MP, Hyman BT, Holt DP, Wang Y, Huang G-F, Debnath ML, Klunk WE (2002) Bioorg Med Chem Lett 12:295–298. doi:10.1016/S0960-894X(01)00734-X

    Article  CAS  PubMed  Google Scholar 

  6. Vandenberghe R, Van Laere K, Ivanoiu A, Salmon E, Bastin C, Triau E, Hasselbalch S, Law I, Andersen A, Korner A, Minthon L, Garraux G, Nelissen N, Bormans G, Buckley C, Owenius R, Thurfjell L, Farrar G, Brooks DJ (2010) Ann Neurol 68:319–329. doi:10.1002/ana.22068

    Article  PubMed  Google Scholar 

  7. Barthel H, Gertz H-J, Dresel S, Peters O, Bartenstein P, Buerger K, Hiemeyer F, Wittemer-Rump SM, Seibyl J, Reininger C, Sabri O (2011) Lancet Neurol 10:424–435. doi:10.1016/S1474-4422(11)70077-1

    Article  CAS  PubMed  Google Scholar 

  8. Verhoeff NPLG, Wilson AA, Takeshita S, Trop L, Hussey D, Singh K, Kung HF, Kung M-P, Houle S (2004) Am J Geriatr Psychiatry 12:584–595. doi:10.1176/appi.ajgp.12.6.584

    PubMed  Google Scholar 

  9. Nordberg A (2004) Lancet Neurol 3:519–527. doi:10.1016/S1474-4422(04)00853-1

    Article  CAS  PubMed  Google Scholar 

  10. Cheng Y, Ono M, Kimura H, Ueda M, Saji H (2012) J Med Chem 55:2279–2286. doi:10.1021/jm201513c

    Article  CAS  PubMed  Google Scholar 

  11. Merbach AE, Helm L, Toth E (2013) The chemistry of contrast agents in medical magnetic resonance imaging, 2nd edn. Wiley, New York

    Book  Google Scholar 

  12. Jack CR Jr, Garwood M, Wengenack TM, Borowski B, Curran GL, Lin J, Adriany G, Gröhn OHJ, Grimm R, Poduslo JF (2004) Magn Reson Med 52:1263–1271. doi:10.1002/mrm.20266

    Article  PubMed Central  PubMed  Google Scholar 

  13. Higuchi M, Iwata N, Matsuba Y, Sato K, Sasamoto K, Saido TC (2005) Nat Neurosci 8:527–533. doi:10.1038/nn1422

    Article  CAS  PubMed  Google Scholar 

  14. Poduslo JF, Wengenack TM, Curran GL, Wisniewski T, Sigurdsson EM, Macura SI, Borowski BJ, Jack CR (2002) Neurobiol Dis 11:315–329. doi:10.1006/nbdi 2002.0550

    Article  CAS  PubMed  Google Scholar 

  15. Wadghiri YZ, Sigurdsson EM, Sadowski M, Elliott JI, Li Y, Scholtzova H, Tang CY, Aguinaldo G, Pappolla M, Duff K, Wisniewski T, Turnbull DH (2003) Magn Reson Med 50:293–302. doi:10.1002/mrm.10529

    Article  CAS  PubMed  Google Scholar 

  16. Poduslo JF, Curran GL, Peterson JA, McCormick DJ, Fauq AH, Khan MA, Wengenack TM (2004) Biochemistry (Mosc) 43:6064–6075. doi:10.1021/bi0359574

    Article  CAS  Google Scholar 

  17. Yang J, Wadghiri YZ, Hoang DM, Tsui W, Sun Y, Chung E, Li Y, Wang A, de Leon M, Wisniewski T (2011) Neuroimage 55:1600–1609. doi:10.1016/j.neuroimage.2011.01.023

    Article  PubMed Central  PubMed  Google Scholar 

  18. Larbanoix L, Burtea C, Laurent S, Van Leuven F, Toubeau G, Elst LV, Muller RN (2010) Neurobiol Aging 31:1679–1689. doi:10.1016/j.neurobiolaging.2008.09.021

    Article  CAS  PubMed  Google Scholar 

  19. Solomon I (1955) Phys Rev 99:559. doi:10.1103/PhysRev.99.559

    Article  CAS  Google Scholar 

  20. Martins AF, Morfin J-F, Kubíčková A, Kubíček V, Buron F, Suzenet F, Salerno M, Lazar AN, Duyckaerts C, Arlicot N, Guilloteau D, Geraldes CFGC, Tóth É (2013) ACS Med Chem Lett 5:436–440. doi:10.1021/ml400042w

    Article  Google Scholar 

  21. Vithanarachchi SM, Allen MJ (2013) Chem Commun 49:4148–4150. doi:10.1039/C2CC36583A

    Article  CAS  Google Scholar 

  22. Barge A, Cravotto G, Gianolio E, Fedeli F (2006) Contrast Media Mol Imaging 1:184–188. doi:10.1002/cmmi.110

    Article  PubMed  Google Scholar 

  23. Leo A, Hansch C, Elkins D (1971) Chem Rev 71:525–616. doi:10.1021/cr60274a001

    Article  CAS  Google Scholar 

  24. Anthony JL, Maginn EJ, Brennecke JF (2001) J Phys Chem B 105:10942–10949. doi:10.1021/jp0112368

    Article  CAS  Google Scholar 

  25. Raiford DS, Fisk CL, Becker ED (1979) Anal Chem 51:2050–2051. doi:10.1021/ac50048a040

    Article  CAS  Google Scholar 

  26. Hugi AD, Helm L, Merbach AE (1985) Helv Chim Acta 68:508–521. doi:10.1002/hlca.19850680224

    Article  CAS  Google Scholar 

  27. Mathis CA, Wang Y, Holt DP, Huang G-F, Debnath ML, Klunk WE (2003) J Med Chem 46:2740–2754. doi:10.1021/jm030026b

    Article  CAS  PubMed  Google Scholar 

  28. Wang Y, Klunk WE, Huang G-F, Debnath ML, Holt DP, Mathis CA (2002) J Mol Neurosci 19:11–16. doi:10.1007/s12031-002-0004-8

    Article  PubMed  Google Scholar 

  29. Thyagarajan BS (1958) Chem Rev 58:439–460. doi:10.1021/cr50021a001

    Article  CAS  Google Scholar 

  30. Schotten C (1884) Ber Dtsch Chem Ges 17:2544–2547. doi:10.1002/cber.188401702178

    Article  Google Scholar 

  31. Baumann E (1886) Ber Dtsch Chem Ges 19:3218–3222. doi:10.1002/cber.188601902348

    Article  Google Scholar 

  32. Mensch J, Oyarzabal J, Mackie C, Augustijns P (2009) J Pharm Sci 98:4429–4468. doi:10.1002/jps.21745

    Article  CAS  PubMed  Google Scholar 

  33. Lin K-S, Debnath ML, Mathis CA, Klunk WE (2009) Bioorg Med Chem Lett 19:2258–2262. doi:10.1016/j.bmcl.2009.02.096

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  34. Earnshaw A, Greenwood N (1997) Chemistry of the elements. Elsevier, Amsterdam

    Google Scholar 

  35. Levin VA (1980) J Med Chem 23:682–684

    Article  CAS  PubMed  Google Scholar 

  36. Bornebroek M, Verzijlbergen JF, Haan J, Van Scheyen EJ, Verhoeff NP, Pauwels EK, Roos RA (1996) Nucl Med Commun 17:929–933

    Article  CAS  PubMed  Google Scholar 

  37. Saito Y, Buciak J, Yang J, Pardridge WM (1995) Proc Natl Acad Sci USA 92:10227–10231

    Article  CAS  PubMed  Google Scholar 

  38. Nicolle GM, Toth E, Eisenwiener K-P, Mäcke HR, Merbach AE (2002) J Biol Inorg Chem 7:757–769. doi:10.1007/s00775-002-0353-3

    Article  CAS  PubMed  Google Scholar 

  39. Powell DH, Dhubhghaill OMN, Pubanz D, Helm L, Lebedev YS, Schlaepfer W, Merbach AE (1996) J Am Chem Soc 118:9333–9346. doi:10.1021/ja961743g

    Article  CAS  Google Scholar 

  40. Caravan P, Ellison JJ, McMurry TJ, Lauffer RB (1999) Chem Rev 99:2293–2352. doi:10.1021/cr980440x

    Article  CAS  PubMed  Google Scholar 

  41. Caravan P, Cloutier NJ, Greenfield MT, McDermid SA, Dunham SU, Bulte JWM, Amedio JC Jr, Looby RJ, Supkowski RM, Horrocks WD Jr, McMurry TJ, Lauffer RB (2002) J Am Chem Soc 124:3152–3162

    Article  CAS  PubMed  Google Scholar 

  42. Moriggi L, Yaseen MA, Helm L, Caravan P (2012) Chem Eur J 18:3675–3686. doi:10.1002/chem.201103344

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  43. Giardiello M, Botta M, Lowe MP (2011) J Incl Phenom Macrocycl Chem 71:435–444. doi:10.1007/s10847-011-0009-4

    Article  CAS  Google Scholar 

  44. Henrotte V, Vander Elst L, Laurent S, Muller RN (2007) JBIC J Biol Inorg Chem 12:929–937. doi:10.1007/s00775-007-0247-5

    Google Scholar 

  45. Silverio S, Torres S, Martins AF, Martins JA, Andre JP, Helm L, Prata MIM, Santos AC, Geraldes CFGC (2009) Dalton Trans 4656–4670

Download references

Acknowledgments

This work was financially supported by Fundação para a Ciência e a Tecnologia, Portugal (PhD grant SFRH/BD/46370/2008 to AFM) and Rede Nacional de RMN (project REDE/1517/RMN/2005) for the acquisition of the Varian VNMRS 600 NMR spectrometer in Coimbra and the French-Portuguese PESSOA project. This work was carried out in the frame of the European Actions TD1004 “Theragnostics Imaging and Therapy” and TD1007 “PET-MRI”.

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Authors and Affiliations

  1. Centre de Biophysique Moléculaire, CNRS, Université d’Orléans, Rue Charles Sadron, 45071, Orléans Cedex 2, France

    André F. Martins, Jean-François Morfin & Éva Tóth

  2. Department of Life Sciences, Faculty of Sciences and Technology, University of Coimbra, P.O. Box 3046, 3001-401, Coimbra, Portugal

    André F. Martins & Carlos F. G. C. Geraldes

Authors
  1. André F. Martins
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  2. Jean-François Morfin
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  3. Carlos F. G. C. Geraldes
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  4. Éva Tóth
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Corresponding authors

Correspondence to Carlos F. G. C. Geraldes or Éva Tóth.

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Responsible Editor: Valerie C. Pierre

Electronic supplementary material

Below is the link to the electronic supplementary material. The electronic supplementary material contains: details of the synthesis, NMRD profiles, details of the analysis of the 17O NMR and NMRD data.

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Martins, A.F., Morfin, JF., Geraldes, C.F.G.C. et al. Gd3+ complexes conjugated to Pittsburgh compound B: potential MRI markers of β-amyloid plaques. J Biol Inorg Chem 19, 281–295 (2014). https://doi.org/10.1007/s00775-013-1055-8

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