Solution Structure and Relaxivity of Ln‐DOTXAZA Derivatives

Abstract

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 wellapproved 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 Gdcomplexes revealed pronounced differences in relaxivities from r 1 = 3.9-7.9 mm À 1 s À 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.

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

“…The tetraazido derivative DOTAZA (Scheme 1) has been used previously for the synthesis of various sidechain substituted DOTA derivatives [6a,12b, 31] . It allows the introduction of N ‐oxide groups by two different routes which include either the conjugation of a preformed N ‐oxide derivative via Cu‐catalyzed azide alkyne cycloaddition (CuAAC) or the conjugation of a tertiary amine and the subsequent oxidation to N ‐oxides.…”

“…It is influenced by the order of outer sphere water molecules which can be altered by substituents attached to the DOTA core structure. Charged residues and particularly zwitterionic groups have been found to have the largest impact on the relaxivity of Gd‐DOTA complexes of low molecular weight [6a,13] . Figure 1 highlights the influence of zwitterionic decoration and the hydration number of Gd‐complexes on T 1 relaxivity.…”

“…It is therefore not easy to separate their contribution. The increased molecular mass of Gd‐DOTA‐SB, for example, has been demonstrated to have only a minor impact on the relaxivity of this compound [6a] …”

Medicinal Chemistry of Drugs with N-Oxide Functionalities

“…The good complexation properties of N -oxides have also been used by other researchers to assemble new Gd-based contrast agents for MRI. , In addition, N -oxides are strongly hydrated in an aqueous solution. Like other zwitterions, they can thus be used for conjugation to drugs to improve their solubility, increase their Stokes radius, and reduce unwanted tissue or protein binding. , Along these lines, the decoration of gadoteric acid (Dotarem) with four N -oxide functionalities (not involved in metal binding) led to the development of Gd-DOTA-NOx with almost three times higher relaxivity …”

“…Like other zwitterions, they can thus be used for conjugation to drugs to improve their solubility, increase their Stokes radius, and reduce unwanted tissue or protein binding. 155 , 156 Along these lines, the decoration of gadoteric acid (Dotarem) with four N -oxide functionalities (not involved in metal binding) led to the development of Gd-DOTA-NOx with almost three times higher relaxivity. 157 …”