Abstract
We have conjugated the tetraazacyclododecane-tetraacetate (DOTA) chelator to Pittsburgh compound B (PiB) forming negatively charged lanthanide complexes, Ln(L4), with targeting capabilities towards aggregated amyloid peptides. The amphiphilic Gd(L4) chelate undergoes micellar aggregation in aqueous solution, with a critical micellar concentration of 0.68 mM, lower than those for the neutral complexes of similar structure. A variable temperature 17O NMR and NMRD study allowed the assessment of the water exchange rate, k 298ex = 9.7 × 106 s−1, about the double of GdDOTA, and for the description of the rotational dynamics for both the monomeric and the micellar forms of Gd(L4). With respect to the analogous neutral complexes, the negative charge induces a significant rigidity of the micelles formed, which is reflected by slower and more restricted local motion of the Gd3+ centers as evidenced by higher relaxivities at 20–60 MHz. Surface Plasmon Resonance results indicate that the charge does not affect significantly the binding strength to Aβ1–40 [K d = 194 ± 11 μM for La(L4)], but it does enhance the affinity constant to human serum albumin [K a = 6530 ± 68 M−1 for Gd(L4)], as compared to neutral counterparts. Protein-based NMR points to interaction of Gd(L4) with Aβ1–40 in the monomer state as well, in contrast to neutral complexes interacting only with the aggregated form. Circular dichroism spectroscopy monitored time- and temperature-dependent changes of the Aβ1–40 secondary structure, indicating that Gd(L4) stabilizes the random coil relative to the α-helix and β-sheet. TEM images confirm that the Gd(L4) complex reduces the formation of aggregated fibrils.
Graphical Abstract
Similar content being viewed by others
References
Fratiglioni L, Winblad B, von Strauss E (2007) Physiol Behav 92:98–104. doi:10.1016/j.physbeh.2007.05.059
Brookmeyer R, Johnson E, Ziegler-Graham K, Arrighi HM (2007) Alzheimers Dement 3:186–191. doi:10.1016/j.jalz.2007.04.381
Holtzman DM, Morris JC, Goate AM (2011) Sci Transl Med 3:77. doi:10.1126/scitranslmed.3002369
McKhann G, Drachman D, Folstein M, Katzman R, Price D, Stadlan EM (1984) Neurology 34:939–944
Dubois B, Feldman HH, Jacova C, Dekosky ST, Barberger-Gateau P, Cummings J, Delacourte A, Galasko D, Gauthier S, Jicha G, Meguro K, O’Brien J, Pasquier F, Robert P, Rossor M, Salloway S, Stern Y, Visser PJ, Scheltens P (2007) Lancet Neurol 6:734–746
Hardy J, Selkoe DJ (2002) Science 297:353–356. doi:10.1126/science.1072994
Rauk A (2009) Chem Soc Rev 38:2698. doi:10.1039/b807980n
Hardy JA, Higgins GA (1992) Science 256:184–185. doi:10.1126/science.1566067
Nordberg A, Rinne JO, Kadir A, Långström B (2010) Nat Rev Neurol 6:78–87. doi:10.1038/nrneurol.2009.217
Doody RS, Thomas RG, Farlow M et al (2014) N Engl J Med 370:311–321. doi:10.1056/NEJMoa1312889
Salloway S et al (2014) N Engl J Med 370:322–333. doi:10.1056/NEJMoa1304839
Karran E, Hardy JA (2014) Ann Neurol 76:185–205. doi:10.1002/ana.24188
Jaunmuktane Z et al (2015) Nature 525:247–250. doi:10.1038/nature15369
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
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
Camus V, Payoux P, Barré L, Desgranges B, Voisin T, Tauber C, La Joie L, Tafani M, Hommet C, Chételat G, Mondon K, de La Sayette V, Cottier JP, Beaufils E, Ribeiro MJ, Gissot V, Vierron E, Vercouillie J, Vellas B, Eustache F, Guilloteau (2012) Eur J Nucl Med Mol Imaging 39:621–631. doi:10.1007/s00259-011-2021-8
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
Cai L, Innis RB, Pike VW (2007) Curr Med Chem 14:19–52. doi:10.2174/092986707779313471
Furumoto S, Okamura N, Iwata R, Yanai K, Arai H, Kudo Y (2007) Curr Top Med Chem 7:1773–1789
Xiong K-L, Yang Q-W, Gong S-G, Zhang W-G (2010) Nucl Med Commun 31:4–11. doi:10.1097/MNM.0b013e32833019f3
Clark CM, Schneider JA, Bedell BJ, Beach TG, Bilker WB, Mintun MA, Pontecorvo MJ, Hefti F, Carpenter AP, Flitter ML, Krautkramer MJ, Kung HF, Coleman RE, Doraiswamy PM, Fleisher AS, Sabbagh MN, Sadowsky CH, Reiman EM, Zehntner SP, Skovronsky DM (2011) J Am Med Assoc 305:275–283. doi:10.1001/jama.2010.2008
Mathis CA, Wang Y, Holt DP, Huang GF, Debnath ML, Klunk WE (2003) J Med Chem 46:2740–2754. doi:10.1021/jm030026b
Klunk WE, Engler H, Nordberg A, Wang Y, Blomqvist G, Holt DP, Bergström M, Savitcheva I, Huang GF, Estrada S, Ausen B, Debnath ML, Barletta J, Price JC, Sandell J, Lopresti BJ, Wall A, Koivisto P, Antoni G, Mathis CA, Långström B (2004) Ann Neurol 55:306–319. doi:10.1002/ana.20009
Landau SM, Breault C, Joshi AD, Pontecorvo M, Mathis CA, Jagust WJ, Mintun MA (2013) J Nucl Med 54:70–77. doi:10.2967/jnumed.112.109009
Klunk WE, Mathis CA (2008) Curr Opin Neurol 21:683–687. doi:10.1097/WCO.0b013e3283168e1a
Zhuang Z-P, Kung M-P, Hou C, Ploessl K, Kung HF (2005) Nucl Med Biol 32:171–184
Serdons K, Verduyckt T, Cleynhens J, Terwinghe C, Mortelmans L, Bormans G, Verbruggen A (2007) Bioorg Med Chem Lett 17:6086–6090. doi:10.1016/j.bmcl.2007.09.055
Cui M-C, Li Z-J, Tang R-K, Liu R-K (2010) Bioorg Med Chem 18:2777–2784. doi:10.1016/j.bmc.2010.02.002
Ono M, Ikeoka R, Watanabe RH, Kimura H, Fuchigami T, Haratake M, Saji H, Nakayama M (2010) ACS Chem Neurosci 1:598–607. doi:10.1021/cn100042d
Ono M, Ikeoka R, Watanabe RH, Kimura H, Fuchigami T, Haratake M, Saji H, Nakayama M (2010) Bioorg Med Chem Lett 20:5743–5748. doi:10.1016/j.bmcl.2010.08.004
Cheng Y, Ono M, Kimura H, Ueda M, Saji H (2012) J Med Chem 55:2279–2286. doi:10.1021/jm201513c
Hickey JL, Donnelly PS (2012) Coord Chem Rev 256:2367–2380. doi:10.1016/j.ccr.2012.03.035
Hayne DJ, Lim S, Donnelly PS (2014) Chem Soc Rev 43:6701–6715. doi:10.1039/c4cs00026a
Merbach AE, Helm L, Toth E (2013) The chemistry of contrast agents in medical magnetic resonance imaging, 2nd edn. Wiley
Caravan P, Ellison JJ, McMurry TJ, Lauffer RB (1999) Chem Rev 99:2293–2352. doi:10.1021/cr980440x
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
Higuchi M, Iwata N, Matsuba Y, Sato K, Sasamoto K, Saido TC (2005) Nat Neurosci 8:527–533. doi:10.1038/nn1422
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
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
Poduslo JF, Curran GL, Peterson JA, McCormick DJ, Fauq AH, Khan MA, Wengenack TM (2004) Biochemistry 43:6064–6075. doi:10.1021/bi0359574
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
Sigurdsson EM, Wadghiri YZ, Mosconi L, Blind JA, Knudsen E, Asuni A, Scholtzova H, Tsui WH, Li Y, Sadowski M, Turnbull DH, de Leon MJ, Wisniewski T (2008) Neurobiol Aging 29:836–847. doi:10.1016/j.neurobiolaging.2006.12.018
Wadghiri YZ, Li J, Wang J, Hoang DM, Sun Y, Xu H, Tsui W, Li Y, Boutajangout A, Wang A, de Leon MJ, Wisniewski T (2013) PLoS One 8:e57097. doi:10.1371/journal.pone.0057097
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.200809.021
Petiet A, Satin M, Bertrand A, Wiggins CW, Petit F, Houitte D, Hantraye P, Benavides J, Debeir T, Rooney T, Dhenain M (2011) Neurobiol Aging 33:1533–1544. doi:10.1016/j.neurobiolaging.2011.03.009
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
Martins AF, Morfin J-F, Geraldes CFGC, Tóth É (2014) J Biol Inorg Chem 19:281–295. doi:10.1007/s00775-013-1055-8
Martins AF, Dias DM, Morfin J-F, Lacerda S, Laurents DV, Tóth É, Geraldes CFGC (2015) Chem Eur J 21:5413–5422. doi:10.1002/chem.201406152
Vithanarachchi SM, Allen MJ (2013) Chem Commun 49:4148–4150. doi:10.1039/C2CC36583A
Bort G, Catoen S, Borderies H, Kebsi A, Ballet S, Louin G, Port M, Ferroud C (2014) Eur J Med Chem 87:843–861. doi:10.1016/j.ejmech.2014.10.016
Petiet A, Dhenain M (2011) Curr Med Imaging Rev 7:1–8
Barge A, Cravotto G, Gianolio E, Fedeli F (2006) Contrast Media Mol Imaging 1:184–188. doi:10.1002/cmmi.110
Raiford DS, Fisk CL, Becker ED (1979) Anal Chem 51:2050–2051
Burton DR, Forsen S, Karlstrom G, Dwek R (1979) Progr Nucl Magn Reson Spectrosc 13:1–45. doi:10.1016/0079-6565(79)80012-6
Aime S, Fasano M, Terreno E, Botta M (2001) Protein-bound metal chelates in “The chemistry of contrast agents in medical magnetic resonance imaging”. Toth E, Merbach AE eds. Wiley & Sons
Shuvaev VV, Siest G (1996) FEBS Lett 383:9–12
Myszka DG, Wood SJ, Biere AL (1999) Methods Enzymol 309:386–402
Schleucher J, Schwendinger M, Sattler M, Schmidt P, Schedletzky O, Glaser SJ, Sorensen OW, Griesinger C (1994) J Biomol NMR 4:301–306
Liu M, Mao X, Ye C, Huang H, Nicholson JK, Lindon JC (1998) J Magn Reson 132:125–129
Laurents DV, Gorman PM, Guo M, Rico M, Chakrabartty A, Bruix M (2005) J Biol Chem 280:3675–3685. doi:10.1074/jbc.M409507200
Markley JL, Bax A, Arata Y, Hilbers CW, Kaptein R, Sykes BD, Wright PE, Wüthrich K (1998) Eur J Biochem 256:1–15. doi:10.1046/j.1432-1327.1998.2560001.x
Bernhard C, Moreau M, Lhenry D, Goze C, Boschetti F, Rousselin Y, Brunotte F, Denat F (2012) Chem Eur J 18:7834–7841. doi:10.1002/chem.201200132
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
Tóth É, Helm L, Kellar K, Merbach AE (1999) Chem Eur J 5:1202–1211. doi:10.1002/(SICI)1521-3765
Woods M, Aime S, Botta M, Howard JAK, Moloney JM, Navet M, Parker D, Port M, Rousseaux O (2000) J Am Chem Soc 122:9781–9792. doi:10.1021/ja994492v
Aime S, Barge A, Bruce JI, Botta M, Howard JAK, Moloney JM, Parker D, de Sousa AS, Woods M (1999) J Am Chem Soc 121:5762–5771. doi:10.1021/ja990225d
Dunand FA, Aime S, Merbach AE (2000) J Am Chem Soc 122:1506–1512. doi:10.1021/ja993204s
Aime S, Barge A, Botta M, De Sousa AS, Parker D (1998) Angew Chem Int Ed 37:2673–2675. doi:10.1002/(SICI)1521-3773(19981016)37:19<2673:AID-ANIE2673>3.0.CO;2-#
Aime S, Botta M, Garda Z, Kucera BE, Tircso G, Young VG, Woods M (2011) Inorg Chem 50:7955–7965 and references therein. doi:10.1021/ic2012827
Ruloff R, Tóth É, Scopelliti R, Tripier R, Handle H, Merbach AE (2002) Chem Commun 22:2630–2631. doi:10.1039/B207713B
Jászberényi Z, Moriggi L, Schmidt P, Weidensteiner C, Kneuer R, Merbach AE, Helm L, Tóth É (2007) J Biol Inorg Chem 12:406–420. doi:10.1007/s00775-006-0197-3
Mensch J, Oyarzabal J, Mackie C, Augustijns P (2009) J Pharm Sci 98:4429–4468. doi:10.1002/jps.21745
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. doi:10.1021/ja017168k
Moriggi L, Yaseen MA, Helm L, Caravan P (2012) Chem Weinh Bergstr Ger 18:3675–3686. doi:10.1002/chem.201103344
Giardiello M, Botta M, Lowe MP (2011) J Incl Phenom Macrocycl Chem 71:435–444. doi:10.1007/s10847-011-0009-4
Ramakrishnan M, Kandimalla KK, Wengenack TM, Howell KG, Poduslo JF (2009) Biochemistry 48:10405–10415. doi:10.1021/bi900523q
LeVine H (1993) Protein Sci 2:404–410. doi:10.1002/pro.5560020312
Lendel C, Bolognesi B, Wahlström A, Dobson CM, Gräslund A (2010) Biochemistry 49:1358–1360. doi:10.1021/bi902005t
Abelein A, Bolognesi B, Dobson CM, Gräslund A, Lendel C (2012) Biochemistry 51:126–137. doi:10.1021/bi201745g
Hoyer W, Grönwall C, Jonsson A, Ståhl S, Härd T (2008) Proc Natl Acad Sci 105:5099–5104. doi:10.1073/pnas.0711731105
Wahlström A, Hugonin L, Perálvarez-Marín A, Jarvet J, Gräslund A (2008) FEBS J 275:5117–5128. doi:10.1111/j.1742-4658.2008.06643.x
Bai Y, Milne JS, Mayne L, Englander SW (1993) Proteins 17:75–86
Hou L, Shao H, Zhang Y, Li H, Menon NK, Neuhaus EB, Brewer JM, Byeon I-JL, Ray DG, Vitek MP, Iwashita T, Makula RA, Przybyla AB, Zagorski MG (2004) J Am Chem Soc 126:1992–2005. doi:10.1021/ja036813f
Danielsson J, Andersson A, Jarvet J, Gräslund A (2006) Magn Reson Chem 44:S114–S121. doi:10.1002/mrc.1814
Chang ES-H, Liao T-Y, Lim T-S, Fann W, Chen RP-Y (2009) J Mol Biol 385:1257–1265. doi:10.1016/j.jmb.2008.11.009
Jarvet J, Damberg P, Danielsson J, Johansson I, Eriksson LEG, Gräslund A (2003) FEBS Lett 555:371–374. doi:10.1016/S0014-5793(03)01293-6
Greenfield NJ (1996) Anal Biochem 235:1–10
Greenfield NJ (2007) Nat Protoc 1:2876–2890. doi:10.1038/nprot.2006.202
Kelly MA, Chellgren BW, Rucker AL, Troutman JM, Fried MG, Miller A-F, Creamer TP (2001) Biochemistry 40:14376–14383. doi:10.1021/bi011043a
Danielsson J, Jarvet J, Damberg P, Gräslund A (2005) FEBS J 272:3938–3949. doi:10.1111/j.1742-4658.2005.04812.x
Kochi A, Lee HJ, Vithanarachchi SM, Padmini V, Allen MJ, Lim MH (2015) Curr Alzheimer Res 12:415–423
Grüning CSR, Klinker S, Wolff M, Schneider M, Toksök K, Klein AN, Nagel-Steger L, Willbold D, Hoyer W (2013) J Biol Chem 288:37104-3711. doi:10.1074/jbc.M113.513432
Narayan P, Orte A, Clarke RW, Bolognesi B, Hook S, Ganzinger KA, Meehan S, Wilson MR, Dobson CM, Klenerman D (2012) Nature Struct Mol Biol 19:79–83. doi:10.1038/nsmb.2191
Louveau A, Smirnov I, Keyes TJ, Eccles JD, Rouhani SJ, Peske JD, Derecki NC, Castle D, Mandell JW, Lee KS, Harris TH, Kipnis J (2015) Nature 523:337–343. doi:10.1038/nature14432
Erickson MA, Banks WA (2013) J Cereb Blood Flow Metab 33:1500–1513. doi:10.1038/jcbfm.2013.135
Bell RD, Winkler EA, Singh I, Sagare AP, Deane R, Wu Z, Holtzman DM, Betsholtz C, Armulik A, Sallstrom J, Berk BC, Zlokovic BV (2012) Nature 485:512–516. doi:10.1038/nature11087
Montagne A, Barnes SR, Sweeney MD, Halliday MR, Sagare AP, Zhao Z, Toga AW, Jacobs RE, Liu CY, Amezcua L, Harrington MG, Chui HC, Law M, Zlokovic BV (2015) Neuron 85:296–302. doi:10.1016/j.neuron.2014.12.032
Xia W, Yang T, Smith IM, Shen Y, Walsh DM, Selkoe DJ (2009) Arch Neurol 66:190–199. doi:10.1001/archneurol.2008.565
Villemagne VL, Perez VA, Pike KE, Kok WM, Rowe CC, White AR, Bourgeat P, Salvado O, Bedo J, Hutton CA, Faux NJ, Masters CL, Barnham KJ (2010) J Neurosci 30:6315–6322. doi:10.1523/JNEUROSCI.5180-09.2010
Powell DH, Ni Dhubhghaill OM, Pubanz D, Helm L, Lebedev YS, Schlaepfer W, Merbach AE (1996) J Am Chem Soc 118:9333–9346. doi:10.1021/ja961743g
Henrotte V, Vander Elst L, Laurent S, Muller RN (2007) J Biol Inorg Chem 12:929–937. doi:10.1007/s00775-007-0247-5
Silverio S, Torres S, Martins AF, Martins JA, Andre JP, Helm L, Prata MIM, Santos AC, Geraldes CFGC (2009) Dalton Trans 4656–4670. doi:10.1039/B823402G
Acknowledgments
This work was supported by the Portuguese Fundação para a Ciência e Tecnologia (FCT; grants SFRH/BD/46370/2008 to A. F. M., REEQ/481/QUI/2006, RECI/QEQ-QFI/0168/2012 and CENTRO-07-CT62-FEDER-002012), by the Coimbra Chemistry Centre (project PEst-OE/QUI/UI0313/2014), the Rede Nacional de RMN (REDE/1517/RMN/2005), in part by FEDER—European Regional Development Fund through the COMPETE Program (Operational Program for Competitiveness) and by the French-Portuguese PHC PESSOA project. E. T. acknowledges support from La Ligue contre le Cancer and D. V. L. the support of the Spanish Ministry of Science and Innovation grants CTQ 2010-21567-C02-02 and SAF2013-49179-C2-2-R. This work was carried out in the frame of the European COST Actions TD1004 “Theragnostics Imaging and Therapy” and TD1007 “PET-MRI”.
Author information
Authors and Affiliations
Corresponding author
Additional information
Dedicated to the memory of Professor Robert J. P. Williams.
Electronic supplementary material
Below is the link to the electronic supplementary material.
775_2015_1316_MOESM1_ESM.pdf
Supplementary material 1 (PDF 5803 kb) 1H Aβ1-40 line width changes in the presence of Gd(L4) (Figure S1), far-UV CD spectra of 40 μM Aβ1-40 in 10 mM sodium phosphate buffer, pH 7.3 as a function of time (Figure S2), equations for the analysis of 1H NMRD and 17O NMR data
Rights and permissions
About this article
Cite this article
Martins, A.F., Oliveira, A.C., Morfin, JF. et al. Associating a negatively charged GdDOTA-derivative to the Pittsburgh compound B for targeting Aβ amyloid aggregates. J Biol Inorg Chem 21, 83–99 (2016). https://doi.org/10.1007/s00775-015-1316-9
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00775-015-1316-9