Affiliation:
1. Department of Chemistry Institute of Pharmacy Universität Hamburg Bundesstrasse 45 20146 Hamburg Germany
2. Fraunhofer Institute for Applied Polymer Research IAP Center for Applied Nanotechnology CAN Universität Hamburg Bundesstrasse 45 20146 Hamburg Germany
3. Hamburg School of Food Science Institute of Food Chemistry University of Hamburg Grindelallee 117 20146 Hamburg Germany
Abstract
AbstractHigh complex stability and longitudinal relaxivity of Gd‐based contrast agents are important requirements for magnetic resonance imaging (MRI) because they ensure patient safety and contribute to measurement sensitivity. Charged and zwitterionic Gd3+‐complexes of the well‐known chelator 1,4,7,10‐tetraazacyclododecane‐1,4,7,10‐tetraacetic acid (DOTA) provide an excellent basis for the development of safe and sensitive contrast agents. In this report, we describe the synthesis of DOTA‐NOx, a DOTA derivative with four N‐oxide functionalities via “click” functionalization of the tetraazide DOTAZA. The resulting complexes Gd‐DOTA‐NOx and Eu‐DOTA‐NOx are stable compounds in aqueous solution. NMR‐spectroscopic characterization revealed a high excess of the twisted square antiprismatic (TSAP) coordination geometry over square antiprismatic (SAP). The longitudinal relaxivity of Gd‐DOTA‐NOx was found to be r1=7.7 mm−1 s−1 (1.41 T, 37 °C), an unusually high value for DOTA complexes of comparable weight. We attribute this high relaxivity to the steric influence and an ordering effect on outer sphere water molecules surrounding the complex generated by the strongly hydrated N‐oxide groups. Moreover, Gd‐DOTA‐NOx was found to be stable against transchelation with high excess of EDTA (200 eq) over a period of 36 h, and it has a similar in vitro cell toxicity as clinically used DOTA‐based GBCAs.