High-Frequency EPR and ENDOR Characterization of MRI Contrast Agents

  • Arnold M. Raitsimring
  • Andrei V. Astashkin
  • Peter Caravan
Part of the Biological Magnetic Resonance book series (BIMR, volume 28)

High-frequency EPR and ENDOR techniques have proved useful in characterizing gadolinium-based MRI contrast agents. The result of these studies is a better understanding of the mechanism of action of these contrast agents, and this in turn has aided the design of more potent nuclear relaxation agents. This chapter first takes a broad overview of MRI contrast agents and the need for EPR studies. High-frequency EPR studies of gadolinium contrast agents have focused on four areas: the field-dependent electronic relaxation behavior of Gd(III) complexes in aqueous solution; an understanding of the parameters that define the crystal field interactions (cfi) among different contrast agents; the hydration number, i.e., the water coordination number in aqueous and biological matrices; the gadolinium–water proton distance. This chapter reviews each of these subject areas in detail, taking a critical approach and pointing out shortcomings of previous work where applicable. This chapter is aimed at scientists interested in the design of new MRI contrast agents, in EPR of high-spin ions, and/or in the coordination chemistry of lanthanide ions in aqueous media.


Magnetic Resonance Imaging Contrast Agent ENDOR Spectrum Electron Spin Echo Pulse ENDOR Nuclear Magnetic Relaxation Dispersion 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. 1.
    Edelman RR, Hesselink JR, Zlatkin MB, Crues JV. 2005. Clinical magnetic resonance imaging, 3rd ed. Philadelphia: Saunders.Google Scholar
  2. 2.
    Caravan P, Ellison JJ, McMurry TJ, Lauffer RB. 1999. Gadolinium(III) chelates as MRI contrast agents: structure, dynamics, and applications. Chem Rev 99:2293–2352.PubMedCrossRefGoogle Scholar
  3. 3.
    Caravan P, Lauffer RB. 2005. Contrast agents: basic principles. In Clinical magnetic resonance imaging, 3rd ed., pp. 357–75. Ed RR Edelman, JR Hesselink, MB Zlatkin, JV Crues. Philadelphia: Saunders.Google Scholar
  4. 4.
    Caravan P. 2006. Strategies for increasing the sensitivity of gadolinium based MRI contrast agents. Chem Soc Rev 35:512–523.PubMedCrossRefGoogle Scholar
  5. 5.
    Lauffer RB. 1991. Targeted relaxation enhancement agents for MRI. Magn Reson Med 22:339.PubMedCrossRefGoogle Scholar
  6. 6.
    Lauffer RB, Parmelee DJ, Dunham SU, Ouellet HS, Dolan RP, Witte S, McMurry TJ, Walovitch RC. 1998. MS-325: Albumin-targeted contrast agent for MR angiography. Radiology 207:529–538.PubMedGoogle Scholar
  7. 7.
    Caravan P, Cloutier NJ, Greenfield MT, McDermid SA, Dunham SU, Bulte JWM, Amedio Jr JC, Looby RJ, Supkowski RM, Horrocks Jr WD, McMurry TJ, Lauffer RB. 2002. The interaction of MS-325 with human serum albumin and its effect on proton relaxation rates. J Am Chem Soc 124:3152–3162.PubMedCrossRefGoogle Scholar
  8. 8.
    Kotek J, Lebduskova P, Hermann P, Vander Elst L, Muller RN, Geraldes CF, Maschmeyer T, Lukes I, Peters JA. 2003. Lanthanide(III) complexes of novel mixed carboxylic-phosphorus acid derivatives of diethylenetriamine: a step towards more efficient MRI contrast agents. Chem Eur J 9:5899–5915.CrossRefGoogle Scholar
  9. 9.
    Powell DH, Ni Dhubhghaill OM, Pubanz D, Helm L, Lebedev YS, Schlaepfer W, Merbach AE. 1996. High-pressure NMR kinetics, Part 74: structural and dynamic parameters obtained from 17O NMR, EPR, and NMRD studies of monomeric and dimeric Gd3+ complexes of interest in magnetic resonance imaging: an integrated and theoretically self-consistent approach. J Am Chem Soc 118:9333–9346.CrossRefGoogle Scholar
  10. 10.
    Chen JW, Auteri FP, Budil DE, Belford RL, Clarkson RB. 1994. Use of EPR to investigate rotational dynamics of paramagnetic contrast agents. J Phys Chem 98:13452–13459.CrossRefGoogle Scholar
  11. 11.
    Chen JW, Belford RL, Clarkson RB. 1998. Second-sphere and outer-sphere proton relaxation of paramagnetic complexes: from EPR to NMRD. J Phys Chem A 102:2117–2130.CrossRefGoogle Scholar
  12. 12.
    Wiener EC, Auteri FP, Chen JW, Brechbiel MW, Gansow OA, Schneider DS, Belford RL, Clarkson RB, Lauterbur PC. 1996. Molecular dynamics of ion–chelate complexes attached to starburst dendrimers. J Am Chem Soc 118:7774–7782.CrossRefGoogle Scholar
  13. 13.
    Clarkson RB, Smirnov AI, Smirnova TI, Kang H, Belford RL, Earle K, Freed JH. 1998. Multi-frequency EPR determination of zero field splitting of high spin species in liquids: Gd(III) chelates in water. Mol Phys 95:1325–1332.CrossRefGoogle Scholar
  14. 14.
    Smirnova TI, Smirnov AI, Belford RL, Clarkson RB. 1997. Interaction of MRI gadolinium contrast agents with phospholipid bilayers as studied by 95 GHz EPR. Acta Chem Scand 51:562–566.PubMedCrossRefGoogle Scholar
  15. 15.
    Smirnova TI, Smirnov AI, Belford RL, Clarkson RB. 1998. Lipid magnetic resonance imaging contrast agent interactions: a spin-labeling and a multifrequency EPR study. J Am Chem Soc 120:5060–5072.CrossRefGoogle Scholar
  16. 16.
    Smirnova TI, Smirnov AI, Belford RL, Clarkson RB. 1999. Interaction of Gd(III) MRI contrast agents with membranes: a review of recent EPR studies. MAGMA 8:214–229.PubMedCrossRefGoogle Scholar
  17. 17.
    Borel A, Helm L, Merbach AE. 2004. Molecular dynamics of Gd(III) complexes in aqueous solution by HF EPR. In Biological magnetic resonance: very high frequency (VHF) ESR/EPR, pp. 207–247. Ed O Grinberg, LJ Berliner. New York: Kluwer.Google Scholar
  18. 18.
    Atsarkin VA, Demidov VV, Vasneva GA, Odintsov BM, Belford RL, Raduechel B, Clarkson RB. 2001. Direct measurement of fast electron spin-lattice relaxation: method and application to nitroxide radical solutions and Gd3+ contrast agents. J Phys Chem A 105:9323–9327.CrossRefGoogle Scholar
  19. 19.
    Borel A, Helm L, Merbach AE, Atsarkin VA, Demidov VV, Odintsov BM, Belford RL, Clarkson RB. 2002. T1e in four Gd3+ chelates: LODEPR measurements and models for electron spin relaxation. J Phys Chem A 106:6229–6231.CrossRefGoogle Scholar
  20. 20.
    Hudson A, Lewis JWE. 1970. Electron spin relaxation of 8S ions in solution. Trans Faraday Soc 66:1297–1301.CrossRefGoogle Scholar
  21. 21.
    Slichter CP. 1980. Principles of magnetic resonance. New York: Springer.Google Scholar
  22. 22.
    Poupko R, Baram A, Luz Z. 1974. Dynamic frequency shift in the ESR spectra of transition metal ions. Mol Phys 27:1345–1357.CrossRefGoogle Scholar
  23. 23.
    Borel A, Toth E, Helm L, Janossy A, Merbach AE. 2000. EPR on aqueous Gd3+ complexes and a new analysis method considering both line widths and shifts. Phys Chem Chem Phys 2:1311–1317.CrossRefGoogle Scholar
  24. 24.
    Bloembergen N, Morgan LO. 1961. Proton relaxation times in paramagnetic solutions: effects of electron spin relaxation. J Chem Phys 34:842–850.CrossRefGoogle Scholar
  25. 25.
    Rast S, Borel A, Helm L, Belorizky E, Fries PH, Merbach AE. 2001. EPR spectroscopy of MRI-related Gd(III) complexes: simultaneous analysis of multiple frequency and temperature spectra, including static and transient crystal field effects. J Am Chem Soc 123:2637–2644.PubMedCrossRefGoogle Scholar
  26. 26.
    Rast S, Fries PH, Belorizky E. 1999. Theoretical study of electronic relaxation processes in hydrated Gd3+ complexes in solutions. J Chim Phys Phys-Chim Biol 96:1543–1550.CrossRefGoogle Scholar
  27. 27.
    Rast S, Fries PH, Belorizky E. 2000. Static zero field splitting effects on the electronic relaxation of paramagnetic metal ion complexes in solution. J Chem Phys 113:8724–8735.CrossRefGoogle Scholar
  28. 28.
    Rast S, Fries PH, Belorizky E, Borel A, Helm L, Merbach AE. 2001. A general approach to the electronic spin relaxation of Gd(III) complexes in solutions: Monte Carlo simulations beyond the Redfield limit. J Chem Phys 115:7554–7563.CrossRefGoogle Scholar
  29. 29.
    Fries PH, Belorizky E. 2005. Electronic relaxation of paramagnetic metal ions and NMR relaxivity in solution: critical analysis of various approaches and application to a Gd(III)-based contrast agent. J Chem Phys 123:124510.PubMedCrossRefGoogle Scholar
  30. 30.
    Belorizky E, Fries PH. 2004. Simple analytical approximation of the longitudinal electronic relaxation rate of Gd(III) complexes in solutions. Phys Chem Chem Phys 6:2341–2351.CrossRefGoogle Scholar
  31. 31.
    Zhou X, Caravan P, Clarkson RB, Westlund PO. 2004. On the philosophy of optimizing contrast agents: an analysis of 1H NMRD profiles and ESR lineshapes of the Gd(III)complex MS-325+HSA. J Magn Reson 167:147–160.PubMedCrossRefGoogle Scholar
  32. 32.
    Brodbeck CM, Iton LE. 1985. The EPR spectra of Gd3+ and Eu3+ in glassy systems. J Chem Phys 83:4285–4299.CrossRefGoogle Scholar
  33. 33.
    Fields RA, Hutchison Jr CA. 1985. The determination of hydrogen coordinates in lanthanum nicotinate dihydrate crystals by gadolinium(III)-proton double resonance. J Chem Phys 82:1711–1722.CrossRefGoogle Scholar
  34. 34.
    Raitsimring AM, Astashkin AV, Poluektov OG, Caravan P. 2005. High-field pulsed EPR and ENDOR of Gd+3 complexes in glassy solutions. Appl Magn Reson 28:281–295.CrossRefGoogle Scholar
  35. 35.
    Benmelouka M. 2006. Multifrequency EPR studies of zero field splitting of Gd(III) based MRI contrast agents in solids and liquids. PhD thesis, École Polytechnique Fédérale de Lausanne.Google Scholar
  36. 36.
    Abragam A, Bleaney B. 1970. Electron paramagnetic resonance of transition metalions. Oxford: Clarendon Press.Google Scholar
  37. 37.
    Bleaney B, Rubins RS. 1961. Explanation of some “forbidden” transitions in paramagnetic resonance. Proc Phys Soc 77:103–112.CrossRefGoogle Scholar
  38. 38.
    Newman DJ, Urban W. 1975. Interpretation of S-state ion EPR spectra. Adv Phys 24:793–844.CrossRefGoogle Scholar
  39. 39.
    Astashkin AV, Raitsimring AM, Caravan P. 2004. Pulsed ENDOR study of water coordination to Gd3+ complexes in orientationally disordered systems. J Phys Chem A 108:1990–2001.CrossRefGoogle Scholar
  40. 40.
    Raitsimring AM, Astashkin AV, Baute D, Goldfarb D, Caravan P. 2004. W-Band 17O pulsed electron nuclear double resonance study of gadolinium complexes with water. J Phys Chem A 108:7318–7323.CrossRefGoogle Scholar
  41. 41.
    Edmonds DT and Zussman A. 1972. Pure quadrupole resonance of O-17 in ice. Phys Lett 41A:167–169.Google Scholar
  42. 42.
    Davies ER. 1974. A new pulse ENDOR technique. Phys Lett 47A:1–2.Google Scholar
  43. 43.
    Mims WB. 1965. Pulsed ENDOR. Proc R Soc 283A:452.Google Scholar
  44. 44.
    Caravan P, Astashkin AV, Raitsimring AM. 2003. The Gadolinium(III)–water hydrogen distance in MRI contrast agents. Inorg Chem 42:3972–3974.PubMedCrossRefGoogle Scholar
  45. 45.
    Koenig SH, Brown III RD. 1990. Field-cycling relaxometry of protein solutions and tissue: implications for MRI. Prog Nucl Magn Reson Spectrosc 22:487–567.CrossRefGoogle Scholar
  46. 46.
    Yim MB, Makinen MW. 1986. ENDOR study of Gd3+ complexes in frozen solutions. J Magn Reson 70:89–105.Google Scholar
  47. 47.
    Muller RN, Radüchel B, Laurent S, Platzek J, Piérart C, Mareski P, Vander Elst L.1999. Physicochemical characterization of MS-325, a new gadolinium complex, by multinuclear relaxometry. Eur J Inorg Chem 11:1949–1955.CrossRefGoogle Scholar
  48. 48.
    Vander Elst L, Maton F, laurent S, Seghi F, Chapelle F, Muller RN. 1997. A multinuclear MR study of Gd-EOB-DTPA: comprehensive preclinical characterization of an organ specific MRI contrast agent. Magn Reson Med 38:604–614.PubMedCrossRefGoogle Scholar
  49. 49.
    Getz D, Silver BL. 1974. ESR of Cu2+(H2O)6, I: the oxygen-17 superhyperfine tensors in 63Cu2+ doped zinc Tutton's salt at 20 K. J Chem Phys 61:630–637.CrossRefGoogle Scholar
  50. 50.
    Ranon U, Hyde J. 1966. Electron-nuclear-double-resonance and electron-paramagneticresonance analysis of the ytterbium–fluorine superhyperfine interaction in CaF2:Yb3+. Phys Rev 141:259–274.CrossRefGoogle Scholar
  51. 51.
    Reuben J, Fiat D. 1969. Nuclear magnetic resonance studies of solutions of the rareearthions and their complexes, III: oxygen-17 and proton shifts in aqueous solutions and the nature of aquo and mixed complexes. J Chem Phys 51:4909–4917.CrossRefGoogle Scholar
  52. 52.
    Morton JR, Preston KF. 1978. Atomic parameters for paramagnetic resonance data. J Magn Reson 30:577–582.Google Scholar
  53. 53.
    Zhidomirov GM, Schastnev PV, Chuvylkin ND. 1978. Quantum chemical calculations of magnetic resonance parameters. Moscow: Nauka.Google Scholar
  54. 54.
    Chidambaram R, Sequeira A, Sikka SK. 1964. Neutron-diffraction study of the structure of potassium oxalate monohydrate: lone-pair coordination of the hydrogen-bonded water molecule in crystals. J Chem Phys 41:3616–3622.CrossRefGoogle Scholar
  55. 55.
    Sikka SK, Momin SN, Rajagopal H, Chidambaram R. 1968. Neutron-diffraction refinement of the crystal structure of barium chlorate monohydrate Ba(ClO3)2•H2O. J Chem Phys 48:1883–1889.CrossRefGoogle Scholar
  56. 56.
    Cossy C, Helm L, Powell DH, Merbach AE. 1995. A change in coordination number from nine to eight along the lanthanide(III) aqua ion series in solution: a neutron diffraction study. New J Chem 19:27–35.Google Scholar
  57. 57.
    Raitsimring AM, Astashkin AV, Baute D, Goldfarb D, Poluektov OG, Lowe MP, Zech SG, Caravan P. 2006. Determination of the hydration number of gadolinium(III) complexes by high-field pulsed 17O ENDOR spectroscopy. Chem Phys Chem 7:1590–1597.PubMedGoogle Scholar
  58. 58.
    Zech S, Sun W-C, Jacques V, Caravan P, Astashkin AV, Raitsimring AM. 2005. Probing the water coordination of protein-targeted MRI contrast agents by pulsed ENDOR spectroscopy. ChemPhysChem 6:2570–2577.PubMedCrossRefGoogle Scholar
  59. 59.
    Cotton FA, Wilkinson G. 1988. Advanced inorganic chemistry, 5th ed. New York: John Wiley.Google Scholar
  60. 60.
    Ruloff R, Muller RN, Pubanz D, Merbach AE. 1998. A tripod gadolinium(III) poly(amino carboxylate) relevant to magnetic resonance imaging: structural and dynamical 17O NMR and 1H NMRD studies. Inorg Chim Acta 275–276:15–23.CrossRefGoogle Scholar
  61. 61.
    Lowe MP, Parker D, Reany O, Aime S, Botta M, Castellano G, Gianolio E, Pagliarin R. 2001. pH-dependent modulation of relaxivity and luminescence in macrocyclic gadolinium and europium complexes based on reversible intramolecular sulfonamide ligation. J Am Chem Soc 123:7601–7609.PubMedCrossRefGoogle Scholar
  62. 62.
    Bruce JI, Dickins RS, Govenlock LJ, Gunnlaugsson T, Lopinski S, Lowe MP, Parker D,Peacock RD, Perry JJB, Aime S, Botta M. 2000. The selectivity of reversible oxy-anion binding in aqueous solution at a chiral europium and terbium center: signaling of carbonate chelation by changes in the form and circular polarization of luminescence emission. J Am Chem Soc 122:9674–9684.CrossRefGoogle Scholar
  63. 63.
    Supkowski RM, Horrocks Jr WD. 1999. Displacement of inner-sphere water molecules from Eu3+ analogues of Gd3+ MRI contrast agents by carbonate and phosphate anions: dissociation constants from luminescence data in the rapid-exchange limit. Inorg Chem 38:5616–5619.PubMedCrossRefGoogle Scholar
  64. 64.
    Aime S, Gianolio E, Terreno E, Giovenzana GB, Pagliarin R, Sisti M, Palmisano G, Botta M, Lowe MP, Parker D. 2000. Ternary Gd(III)L-HSA adducts: evidence for the replacement of inner-sphere water molecules by coordinating groups of the protein: implications for the design of contrast agents for MRI. J Biol Inorg Chem 5:488–497.PubMedGoogle Scholar
  65. 65.
    Kimura T, Nagaishi R, Kato Y, Yoshida Z. 2001. Luminescence study on preferential solvation of europium(III) in water/non-aqueous solvent mixtures. J Alloys Compd 323–324:164–168.CrossRefGoogle Scholar

Copyright information

© Springer-Verlag New York 2009

Authors and Affiliations

  • Arnold M. Raitsimring
    • 1
  • Andrei V. Astashkin
    • 2
  • Peter Caravan
    • 2
  1. 1.EPIX PharmaceuticalsCambridgeNew England
  2. 2.Department of ChemistryUniversity of ArizonaTucsonUSA

Personalised recommendations