Synthesis and characterisation of bifunctional MRI contrast agents

O'Connell, Patrick J. (2009). Synthesis and characterisation of bifunctional MRI contrast agents. PhD thesis The Open University.



Macrocyclic ligands based on cyclen form lanthanide complexes with good thermodynamic stability and kinetic inertness due to the large degree of preorganization of the ligand. Conversely, it is these favourable properties which have impeded their development as magnetopharmaceudcals as the functionalization of cyclen remains synthetically challenging. This thesis describes the development of new synthetic routes to substituted cyclen ligands, which after complexation with Gd(III), could have potential as MRI contrast agents.

At present, cyclen is primarily functionalized by alkylation with halide substrates. In an attempt to prepare bifunctional ligands, cyclen was alkylated with derivatised amino acids. Elimination of the halide substrate to give the corresponding alkene was found to be a significant problem using this approach.

As an alternative route to functionalized macrocycles, the Michael addition of cyclen to activated alkenes was investigated. The aza-Michael addition of cyclen to acrylamide was found to be regioselective with the tri-amide substituted cyclen (D03PAM) being the major product. Hydrolysis of D03PAM with 12M HCl gave the corresponding tri-acid substituted cyclen (D03P) in a yield of 90 %. D03P is an analogue of the important cyclen ligand, D03A, which has three acetate substituents. Trifluoromethanesulfonic acid was found to catalyse the conjugate addition of mono-N-Z-cyclen to methyl-2-acetamidoacrylate under mild conditions. This methodology of mono-Z-protecrion followed by acid-catalysed addition and deprotection offers a new and versatile route to tri-N-substituted cyclen derivatives. The addition of cyclen to ethyl-cis-B-cyanoacrylate was regioselective as addition occurred exclusively at the carbon B to the nitrile group.

The ligands D03P and D03PAM were complexed with gadolinium(III) and the T1 spin-lattice relaxation times of the complexes were measured. The corresponding T1-relaxivity values (r1) of Gd(D03P) and Gd(D03PAM) were determined to be 4.0 and 4.6 mM-1s-1 (60 MHz, 25 °C), respectively. These complexes provide significantly better relaxivity values than that of the best-selling MRI contrast agent, Magnevist (Gd-DPTA), which has an value of 2.8mM-1s-1 (60 MHz, 25 °C).

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