Skip to main content
Article thumbnail
Location of Repository

High relaxivity contrast agents for magnetic resonance imaging (MRI)

By Marco Giardiello

Abstract

The development of Gd(III)-based contrast agents for MRI applications has intensified in recent years due to the paramagnetic ion’s long electron spin relaxation time and large effective magnetic moment, µeff. Secondly, the exploitation of the long lived luminescent properties of the Ln(III) ions has lead to the development of luminescent lanthanide probes for sensing, time resolved immunoassay and imaging applications. Herein a series of novel Ln-DO3A based complexes are reported. Modulation of relaxivity, r1, (Gd) and emission intensity (Eu, Tb, Sm and Dy) has been achieved in three ways: \ud Firstly, mono- and bis-methyl Ln-dpp-DO3A based complexes have been prepared, where dpp is a pendant diphenylphosphinamide moiety. These show pH responsive relaxivity (Gd) and luminescence (Eu) with calculated pKa values of 8.65 (± 0.09) and 8.59 (± 0.14). Sensitised emission of Eu(III), Tb(III), Dy(III) and Sm(III) has been observed following excitation of the dpp antenna at λex ~ 270 nm. Relaxivities have been measured as r1 = 7.9 mMˉ¹sˉ¹and r1 = 8.2 mMˉ¹sˉ¹ in acidic media, q = 2 and r1 = 5.4 mMˉ¹sˉ¹ and r1 = 4.4 mMˉ¹sˉ¹ in basic media, q = 1 for the mono- and bis-methyl Gd-dpp-DO3A complexes respectively. The pH responsive behaviour has been attributed to the reversible ligation of the dpp moiety. \ud Secondly, non-covalent attachment of the mono- and bis-methyl Gd-dpp-DO3A-based complexes to Human Serum Albumin (HSA) at pH 7.4 resulted in a 64% (r1 = 11.7 mMˉ¹sˉ ¹) and a 146% (r1 = 16.0 mMˉ¹sˉ¹) enhancement in relaxivity, with binding affinities, K, determined from luminescence studies as K = 22,268 ± 12% Mˉ¹and K = 20,059 ± 14% Mˉ¹ for the mono- and bis-methyl dpp Eu-dpp-DO3A complexes respectively. The negatively charged [Gd-dpp-aDO3A]3ˉ complex was developed in order to improve the observed relaxivity of the HSA bound species: r1 = 16.0 mMˉ¹sˉ¹, K = 17,915 (± 14%) Mˉ¹. Competitive binding studies with the fluorescent probes dansylsarcosine and warfarin showed each of the dpp complex analogues to bind preferentially to HSA site II, only the S-enantiomer of the mono-methyl Gd-dpp-DO3A showed an affinity for site I. \ud Finally, an accumulation and activation strategy following enzyme activity has been demonstrated. Neutral q = 2 Gd(III) ethyl and acetoxymethyl ester Ln-DO3MA based complexes have shown decreased relaxivity in the presence of carbonate due to the inner sphere water molecule displacement by bidentate anion binding. The binding is suppressed by the introduction of negative charge to the complex following enzymatic hydrolysis of the ester groups, resulting in ~ 84% relaxivity enhancement (Gd) as well as Eu luminescence quenching. The high observed relaxivity of the ethyl ester model: r1 = 10.2 mMˉ¹sˉ¹ is attributed to the extremely short observed water exchange lifetime, τm = 7.9 ns

Publisher: University of Leicester
Year: 2007
OAI identifier: oai:lra.le.ac.uk:2381/7701

Suggested articles

Citations

  1. (P–O); m/z (HR-ESMS+) [M+H]+ calcd for C29H40N5O7PTb; 760.1913, found;
  2. (1976). Acta Cryst., doi
  3. (1996). All About Albumin: Biochemistry, Genetics and Mediacal Applications', doi
  4. (2006). Bioconjugate Chem., doi
  5. (2001). Chemistry of the F-Block Elements',
  6. (1969). Complexometric Titrations,
  7. (1987). Contrast Agent Basics in Cardiovascular Magnetic Resonance', doi
  8. (2006). Contrast Med. doi
  9. (1974). Critical Stability Constants', doi
  10. (1992). Crown Compounds: Towards Future Applications; Tailoring Macrocycles for Medical Applications', doi
  11. (2005). Drug Deliver. Rev.,
  12. (2005). grade Bioorganic Chemistry, 10 credits, 2.1 grade 7.4.2 Training Courses Departmental Induction,
  13. (1993). Handbook of Photochemistry, Second Edition',
  14. (1994). Inorganic Chemistry, Second Edition', doi
  15. (2003). Ions Biol. Syst.,
  16. (1967). Lanthanide Actinide Chemistry; Donor Properties of Pyrophosphate Derivitives', doi
  17. (1989). Lanthanide Probes in Life, Chemical and Earth Sciences, Theory and Practice; Luminescent Probes', doi
  18. (2002). Magnetic Resonance Angiography, Second Edition',
  19. (1998). Physical Chemistry, 6 th Edition',
  20. (1999). Principles of Fluoresence Spectroscopy, 2 nd Edition',
  21. (1998). Soc.; Perkin Trans. doi
  22. (2004). The Cell; A Molecular Approach 4 th Edition',
  23. (2001). The Chemistry of Contrast Agents doi
  24. (2001). The Chemistry of Contrast Agents in Magnetic Resonance Imaging; Physical Principles of Medicinal Imaging by Nuclear Magnetic Resonance', doi
  25. (2001). The Chemistry of Contrast Agents in Magnetic Resonance Imaging; Protein Bound Metal Chelates', doi
  26. (1999). The f Elements',
  27. (2002). Topics in Current Chemistry Vol 221; Blood Pool MRI Contrast Agents: Properties and Characterisation', doi
  28. (2002). Topics in Current Chemistry; New Classes of MRI Contrast Agents', doi
  29. (2001). Unpublished results,

To submit an update or takedown request for this paper, please submit an Update/Correction/Removal Request.