Decoration of 1,4,7,10‐tetraazacyclododecane‐1,4,7,10‐tetraacetic acid (DOTA) with N‐oxides increases the T1 relaxivity of Gd‐complexes

• Published in: ChemistryOpen (Weinheim) 2024-07, Vol.13 (7), p.e202300298-n/a
• Main Authors: Kerpa, Svenja, Schulze, Verena R., Holzapfel, Malte, Cvancar, Lina, Fischer, Markus, Maison, Wolfgang
• Format: Article
• Language: English
• Subjects: Aqueous solutions; Contrast agents; Cu-catalyzed azide alkyne cycloaddition (CuAAC); Ethylenediaminetetraacetic acids; Gadolinium; Gadolinium based contrast agents; Geometry; Hydration; Magnetic resonance imaging; magnetic resonance imaging (MRI); Molecular weight; N-oxides; Nitrogen oxides; NMR; Nuclear magnetic resonance; Oxidation; T1 relaxivity; Tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA); Toxicity; Water
• ISSN: 2191-1363; 2191-1363
• DOI: 10.1002/open.202300298

High 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. Decoration with N‐oxide groups is a valuable method to increase the T1‐relaxivity of the well‐known cyclic Gd‐chelator DOTA. The synthesis of Gd‐DOTA‐NOx has been achieved via copper catalyzed alkyne azide cycloaddition. The complex is water soluble, stable against transchelation, has a twisted square antiprismatic (TSAP) complex geometry and a high T1‐relaxivity of 7.7 mm−1 s−1 (1.41 T, 37 °C).