PEGylated DOTA‐AHA‐Based GdIII Chelates: A Relaxometric Study

Abstract

AbstractThree PEGylated derivatives of 6‐amino‐2‐[4,7,10‐tris(carboxymethyl)‐1,4,7,10‐tetrazacyclododec‐1‐yl]hexanoic acid (DOTA‐AHA) with different molecular weights were prepared and characterized. Their GdIII chelates were studied in aqueous solution through variable‐temperature 1H nuclear magnetic relaxation dispersion (NMRD) and 17O NMR spectroscopy to determine their relaxivities and the parameters that govern them. The relaxivity varied from 5.1 to 6.5 mM–1 s–1 (37 °C and 60 MHz) as the molecular weight of the polyethylene glycol (PEG) chain increased and was slightly higher than that of the parent chelate Gd(DOTA‐AHA), owing to a small contribution of a slow global rotation of the complexes. A variable‐temperature 1H NMR spectroscopy study of several LnIII chelates of DOTA‐A(PEG750)HA allowed the determination of the isomeric M/m ratio (M = square‐antiprismatic isomer and m = twisted square‐antiprismatic isomer; the latter presents a much faster water exchange), which was estimated to be ca. 1:0.2 for the GdIII chelate, very close to that of [Gd(DOTA)]–. This explains why the PEGylated GdIII chelate has a water rate exchange similar to that of [Gd(DOTA)]–. The predominance of the M isomer is a consequence of the bulky PEG moiety, which does not favor the stabilization of the m isomer in sterically crowded systems at the substituent site, in contrast to what happens with less packed asymmetrical DOTA‐type chelates with substitution at one of the four acetate C(α) atoms.