A simple approach to a new T8-POSS based MRI contrast agent†
A fast and simple route was developed to synthesize a new T8-silsesquioxane based contrast agent for potential application in Magnetic Resonance Imaging. For this purpose the novel C2-thiol-functionalized T8-silsesquioxane (3) was constructed as a carrier molecule as well as the DOTA based gadolinium(III) complex (11) equipped with allyl terminated linkers was prepared. The linkage of the complexes to the T8-silsesquioxane was performed via an UV-light catalyzed thiol–ene click reaction within one hour which affords the desired product 13 in a yield of 80%. The successful transformation as well as the intactness of the cube was confirmed by spectroscopic methods and mass spectrometry. This new and simple approach offers a highly effective access to T8-silsesquioxanes functionalized with eight metal complexes. Longitudinal relaxivity measurements of compound 13 (9.5 ± 0.9 mM−1 s−1) at 3 T in HEPES buffered cell culture medium (physiological conditions) show a significant enhancement of r1 per 1 mM gadolinium in comparison to the clinically applied contrast agent Dotarem™ (3.4 mM−1 s−1). In relation to the former reported T8-silsesquioxane based contrast agent Gadoxane G (10.6 mM−1 s−1) a similar relaxivity is found. As the T8-core of polyhedral oligosilsesquioxanes (POSS) based contrast agents undergoes a hydrolysis process depending on the pH, long-term r1 measurements in different solutions (water, cell culture medium and HEPES buffered medium) as well as 1H, 1H/29Si HSQC and PGSE diffusion 1H NMR spectroscopic investigations on aqueous solutions were performed. In solutions featuring an approximately neutral pH (D2O, pD = 7.0; water and HEPES buffered medium, pH = 7.4–7.5) contrast agent 13 (t1/2 = 2.4 d, HEPES/medium) shows a slower decomposition of the T8-cage in comparison to the previously synthesized Gadoxane G (t1/2 = 15 ± 3 h, HEPES/medium). However, under more basic conditions (medium, pH = 8.4–8.5) the decomposition process of 13 is considerably accelerated (t1/2 ∼ 55–60 min), indicating a higher sensitivity of the T8-cage to pH shifts into the basic range similar to Gadoxane G.