Solution Structure and Relaxivity of Ln‐DOTXAZA Derivatives

• Published in: European journal of inorganic chemistry 2022-11, Vol.2022 (32), p.n/a
• Main Authors: Holzapfel, Malte, Baldau, Torben, Kerpa, Svenja, Guadalupi, Gianmarco, Qi, Bing, Liu, Yang, Parak, Wolfgang J., Maison, Wolfgang
• Format: Article
• Language: English
• Subjects: Alkynes; Chains; Click chemistry; Contrast agents; Cycloaddition; DOTA; Gadolinium; Imaging agents; Inorganic chemistry; Lanthanides; NMR; Nuclear magnetic resonance; Relaxivity; Structural analysis
• ISSN: 1434-1948; 1099-0682
• DOI: 10.1002/ejic.202200432

Herein we report the synthesis and structural analysis of tunable 1,4,7,10‐tetraazacyclododecane‐1,4,7,10‐tetraacetic acid (DOTA)‐derivatives bearing azidoethyl side chains. According to the number of azidoethyl side chains, the compounds are termed DOTXAZA (with X=1–4). All derivatives retain the well‐approved DOTA scaffold for metal complexation with 8 coordinating functionalities and are applicable to Cu‐catalyzed alkyne‐azide cycloaddition (CuAAC). They may thus be used to assemble new Gd‐based contrast agents (GBCAs) with tailored pharmacokinetic or MRI properties retaining the high stability of clinically used DOTA‐derived GBCAs. The complex geometry of all DOTXAZA derivatives was investigated in solution with NMR‐spectroscopy of the corresponding Eu‐complexes. A correlation of complex geometry with the longitudinal relaxivity of corresponding Gd‐complexes revealed an increase in relaxivity with increasing substitution number in the DOTXAZA series. Moreover, CuAAC‐modified DOTAZA‐derivatives with neutral, charged, and zwitterionic groups were prepared. Although of similar molecular mass, the corresponding Gd‐complexes revealed pronounced differences in relaxivities from r1=3.9–7.9 mm−1 s−1 in water at 1.5 T and 37 °C. Relaxivities of these complexes were found to be strongly dependent on side chain charge and are most likely determined by second‐sphere water effects. Gd‐Based contrast agents (GBCAs) are essential reagents in clinical diagnosis via MRI. We report four members of the DOTXAZA series, which are valuable scaffolds for the assembly of new GBCAs with improved relaxivity and tailored pharmacokinetic or targeting properties by Cu‐catalyzed alkyne‐azide cycloaddition (CuAAC).