Gadolinium MRI Contrast Agents Based on Triazine Dendrimers: Relaxivity and In Vivo Pharmacokinetics

Abstract

Four gadolinium (Gd)-based macromolecular contrast agents, <b>G3-(Gd-DOTA)</b>_<b>24</b>, <b>G5-(Gd-DOTA)</b>_<b>96</b>, <b>G3-(Gd-DTPA)</b>_<b>24</b>, and <b>G5-(Gd-DTPA)</b>_<b>96</b>, were prepared that varied in the size of dendrimer (generation three and five), the type of chelate group (DTPA or DOTA), and the theoretical number of metalated chelates (24 and 96). Synthesis relied on a dichlorotriazine derivatized with a DOTA or DTPA ligand that was incorporated into the dendrimer and ultimately metalated with Gd ions. Paramagnetic characteristics and in vivo pharmacokinetics of all four contrast agents were investigated. The DOTA-containing agents, <b>G3-(Gd-DOTA)</b>_<b>24</b> and <b>G5-(Gd-DOTA)</b>_<b>96</b>, demonstrated exceptionally high <i>r</i>1 relaxivity values at off-peak magnetic fields. Additionally, <b>G5-(Gd-DOTA)</b>_<b>96</b> showed increased <i>r</i>1 relaxivity in serum compared to that in PBS, which was consistent with in vivo images. While <b>G3-(Gd-DOTA)</b>_<b>24</b> and <b>G3-(Gd-DTPA)</b>_<b>24</b> were rapidly excreted into the urine, <b>G5-(Gd-DOTA)</b>_<b>96</b> and <b>G5-(Gd-DTPA)</b>_<b>96</b> did not clear as quickly through the kidneys. Molecular simulation of the DOTA-containing dendrimers suggests that a majority of the metalated ligands are accessible to water. These triazine dendrimer-based MRI contrast agents exhibit several promising features such as high in vivo <i>r</i>1 relaxivity, desirable pharmacokinetics, and well-defined structure