Zwitterionic [Gd-(DOTA)] MRI Probes: Influence of Sulfobetaine Linker Length on Relaxivity

Macrocyclic chelators are a development platform for new Gd-(III)-based contrast agents (GBCAs) for magnetic resonance imaging. Zwitterionic modification of these Gd-(III)-complexes has been reported to improve their solubility, relaxivity, and stability, resulting in enhanced imaging performance and safety due to lower doses and reduced in vivo retention. Herein, the synthesis of zwitterionic Gd-(III)-complexes based on 1,4,7,10-tetraazacyclododecane-N,N',N″,N‴-tetraacetic acid (DOTA) bearing sulfobetaine groups is reported. The sulfobetaine carbon spacer length (CSL) was varied, and the relaxivity of the complexes was evaluated at 1.4 and 7 T to assess the influence of charge separation on relaxivity. Measurements were performed in water and saline to probe potential salt effects of the different zwitterions. All GBCAs showed relatively high relaxivities compared to similar nonzwitterionic [Gd-(DOTA)]-derivatives. The highest value in water (r ₁ = 8.33 ± 0.14 mm^-1 s^-1) was observed for 7b (CSL = two methylene groups). The impact of CSL on relaxivity in water was moderate. In saline, relaxivity decreased by 13.5-19.8% for compounds 7a, 7b, and 7d (CSL = 1, 2, and 4 methylene groups). Only derivative 7c (CSL = 3 methylene groups) had a slightly increased relaxivity in saline (+4.2%). These findings indicate that the CSL of sulfobetaine groups has only a minor effect on the relaxivity of Gd-(III) complexes in deionized water. However, it has a significant effect on relaxivity in saline and can thus influence the performance under physiological conditions as evaluated with a first in vivo application in mice. A CSL of three methylene groups is thus optimal for the design of zwitterionic GBCAs.