Scheme 5.1. Ligands coordinating with Mn(II), and have two inner sphere water molecules
5.8 Conclusion
To develop safer MRI probes with enhanced efficacy, ligand H2pmpa and its corresponding bis(aquated) Mn(II) complex, 5B, have been investigated.
DFT‒based structural optimisation of the complex implied its pentagonal bipyramidal geometry having two inner sphere water molecules in the axial positions and the coordinating ligand in the equatorial plane.
The complex showed comparable stability to that of [Mn(EDTA)]2– complex and better stability in comparison to the previously reported bis(aquated) Mn(II) complexes.
The two bound waters afforded high r1 relaxivity value of 5.88 mM–1s–1 at 1.41 T, pH ~ 7.4 and at 25 °C, which was almost constant in the pH range 5‒10.
T1‒weighted phantom MR images of complex 5B under clinical MRI scanner showed good image intensity to use it as MRI CA with a lower dose than the commercially available one.
The complex holds promise regarding the development of highly efficient Mn(II)‒based MR imaging probes as an alternative to Gd(III)‒based CAs.
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The main aim of this work has been the development of new, better and safer MRI contrast agents, compared to the existing contrast agents, that exhibit good water solubility, giving better contrast and reducing acquisition time; for the possible future applications in the field of MRI.
The water soluble, aquated Gd(III) complex of ligand H4peada, 2A showed r1 realxivity value of 6.08 mM–1s–1 at 1.41 T, 25 °C and pH ~ 7.4. While the r1 relaxivity values of the commercially available Gd(III)–based MRI contrast agents are in the range 4.4–5.2 mM–1s–1, with comparable thermodynamic and kinetic stability to that of commercially available [Gd(DTPA)(H2O)]– complex, complex 2A can be thought of as an alternative to the currently used MRI contrast agents with enhanced contrast.
In contrast to the current trend of decreasing the r1 relaxivity values of the commercially available Gd(III)–based MRI contrast agents with increasing field strength, the Gd(III) complex of ligand H4bedik, 3A provided a higher r1 realxivity value of 12.40 mM–1s–1 at 14.1 T, 25 °C and pH ~ 7.4. With better thermodynamic and kinetic stability than that of the commercially available [Gd(DTPA)(H2O)]– complex, complex 3A holds promise regarding the development of MRI imaging probes that can be used at higher magnetic fields.
Looking for a safer MRI contrast agent for patients having severe renal diseases or who underwent liver transplantation, Mn(II) complex of ligand H4bedik, 4A with one inner sphere water molecule provided the r1 realxivity value of 3.11 mM–1s–1 at 1.41 T, 25 °C and pH ~ 7.4.
In addition to this, at 14.1 T, the higher r1 and r2 realxivity values of the complex (r1 = 6.29 mM–
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1s–1 and r2 = 132.77 mM–1s–1 , 25 °C and pH ~ 7.4) reinforce its candidature as a future T1 and T2 dual mode MRI contrast agent at higher magnetic field.
Next step towards safer and powerful imaging involved the synthesis of bis(aquated) Mn(II) complex of ligand H2pmpa, 5B with r1 realxivity value of 5.88 mM–1s–1 at 1.41 T, 25 °C and pH ~ 7.4. The favourable relaxation properties and thermodynamic stability of the complex make it a promising candidate for the development of effective MRI contrast agents for safer and emerging applications in MRI.
The results included in this thesis suggest the possibility of new water soluble and water coordinated Gd(III) and Mn(II)–based candidates for clinically useful MRI contrast agents.
Further study on solution dynamic properties and biocompatibility should be preferred. In addition to the reported complexes, the following organic ligands and their corresponding Gd(III), Mn(II) and Fe(III) complexes could be synthesised and studied as the next generation MRI contrast agents.
Scheme. Proposed ligands for synthesising new MRI contrast agents.
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