Design and synthesis of chiral DOTA-based MRI contrast agents with remarkable relaxivities

Abstract

Due to the adverse effects of de-metallation in past concerning FDA-approved gadolinium-based contrast agents (GBCAs), researchers have been focusing on developing safer and more efficient alternatives that could avoid toxicity caused by free gadolinium ions. Herein, two chiral GBCAs, Gd-LS with sulfonate groups and Gd-T with hydroxyl groups, are reported as potential candidates for magnetic reasonance imaging (MRI). The r₁ relaxivities of TSAP, SAP isomers of Gd-LS and SAP isomer of Gd-T at 1.4 T, 37 °C in water are 7.4 mM^-1s^-1, 14.5 mM^-1s^-1 and 5.2 mM^-1s^-1, respectively. Results show that the hydrophilic functional groups introduced to the chiral macrocyclic scaffold of Gd-T and Gd-LS both give constructive influences on the second-sphere relaxivity and enhance the overall r₁ value. Both cases indicate that the design of GBCAs should also focus on the optimal window in Solomon-Bloembergen-Morgan (SBM) theory and the effects caused by the second-sphere and outer-sphere relaxivity.

Fig. 1. The chemical structures of [Ln-T]^- and [Gd-LS]^- studied in this work.

Ln represents Eu(III) and Gd(III), counter-ions, NH₄⁺ or H⁺ are neglected for clarity.

Fig. 2. Synthesis of Ln-LS.

Ln represents Eu(III) and Gd(III); counter ions are not shown for clarity.

Fig. 3. Synthesis of Ln-T.

Ln represents Eu(III), Yb(III) and Gd(III); counter ions are not shown for clarity.

Fig. 4. HPLC traces of Gd-LS (left) and ¹H NMR spectrum of Eu-LS in D₂O(right).

Mixture before isolation (top); 1st peak after isolation (middle); 2nd peak after isolation (bottom).

Fig. 5. ¹H NMR spectra of Eu-T in D₂O, 298 K.

SAP isomer of Eu-T (top); TSAP isomer of Eu-T (bottom).

Fig. 6. Crystal structures of Eu-T.

SAP/corner isomer, from the top view, bottom view and side view (top row, from left to right); TSAP/side isomer, from the top view, bottom view and side view (bottom row, from left to right). Eu (green), N (yellow), O (blue), C (gray) and H (omitted).

Fig. 7. Assessment of kinetic inertness of Gd-LS showing different HPLC traces in 1 N HCl condition.

A merged graph of (TSAP)Gd-LS at RT over 158 h, zoom-in graph showing the peak heights inserted (top, left); (TSAP)Gd-LS, freshly prepared solution (middle, left); (TSAP)Gd-LS, stayed at RT for 158 h (bottom, left); (SAP)Gd-LS, freshly prepared solution (top, right); (SAP)Gd-LS, stayed at RT for 158 h (middle, right); A merged graph of Gd-LS (mixture) at RT over 158 h, zoom-in graph showing the peak heights inserted (bottom, right).

Fig. 8. Biodistribution results of Gd-DOTA (left), Gd-LS (middle) and Gd-T (right) in mice.

The error bars represent the standard deviation.

Fig. 9. MRI phantom images of Gd complexes.

Captured image with increasing concentrations from left to right (0.1–1.3 mM, in 1X Gibco^TM PBS buffer, pH 7.4). Dotarem®, Eovist®, (SAP)Gd-L, (SAP)Gd-LS, (TSAP)Gd-LS, (SAP)Gd-LS, (SAP)Gd-T, (TSAP)Gd-T and PBS buffer were placed from top to bottom accordingly.

Fig. 10. Signal intensity of MRI phantom images of various Gd complexes with different concentrations.

Concentrations were obtained from ICP-MS studies, error bars represent the SD.