Abstract
The relaxivity of MRI contrast agents can be increased by increasing the size of the contrast agent and by increasing concentration of the bound gadolinium. Large multi-site ligands able to coordinate several metal centres show increased relaxivity as a result. In this paper, an “aza-type Michael” reaction is used to prepare cyclen derivatives that can be attached to organosilicon frameworks via hydrosilylation reactions. A range of organosilicon frameworks were tested including silsesquioxane cages and dimethylsilylbenzene derivatives. Michael donors with strong electron withdrawing groups could be used to alkylate cyclen on three amine centres in a single step. Hydrosilylation successfully attached these to mono-, di-, and tri-dimethylsilyl-substituted benzene derivatives. The europium and gadolinium complexes were formed and studied using luminescence spectroscopy and relaxometry. This showed the complexes to contain two bound water moles per lanthanide centre and T1 relaxation time measurements demonstrated an increase in relaxivity had been achieved, in particular for the trisubstituted scaffold 1,3,5-tris((pentane-sDO3A)dimethylsilyl)benzene-Gd3. This showed a marked increase in the relaxivity (13.1 r1p/mM−1s−1).
Highlights
The selective substation and functionalization of aza macrocyclic rings has long been a rich area of synthetic endeavour
Derivatization, typically at the nitrogen centres, attaches additional functional groups such as carbonyl, ester, alcohol amine and amide functionalities [12,13,14,15] that increase the number and type of donor atoms available for chelation to the central metal ion. This is important for the lanthanide ions, which have high coordination numbers (9–10) and a preference for hard donor atoms such as nitrogen or oxygen
Alkylation using reactive organohalides has been the method of choice for the derivatisation of cyclen and this method has produced ligands for lanthanides, such as europium and terbium, which have been used as the basis for luminescent probes and sensors [8,16,17,18], and gadolinium that has been employed as contrast agents for MRI [11,19,20]
Summary
The selective substation and functionalization of aza macrocyclic rings has long been a rich area of synthetic endeavour This has been due, in no small part, to the extensive use of the macrocycle cyclen (1,4,7,10-tetraazadodecane) as a scaffold to construct ligands for the coordination and complexation for a diverse array of metals, ranging from transition metals, such as zinc, nickel, rhenium, and technetium [1,2,3,4], to the larger lanthanide ions, such as europium, terbium, and gadolinium [5,6,7].
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