PEGylated DOTA‐AHA‐Based Gd III Chelates: A Relaxometric Study

Three 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 Gd III chelates were studied in aqueous solution through variable‐temperature 1 H nuclear magnetic relaxation dispersion (NMRD) and 17 O NMR spectroscopy to determine their relaxivities and the parameters that govern them. The relaxivity varied from 5.1 to 6.5 m M –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 1 H NMR spectroscopy study of several Ln III chelates of DOTA‐A(PEG 750 )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 Gd III chelate, very close to that of [Gd(DOTA)] – . This explains why the PEGylated Gd III 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.