α-Aryl substituted GdDOTA derivatives, the perfect contrast agents for MRI?

Enhancing the performance of Gd3+ chelates as relaxation agents for MRI has the potential to lower doses, improving safety and mitigating the environmental impact on our surface waters. More than three decades of research into manipulating the properties of Gd3+ have failed to develop a chelate that simultaneously optimizes all relevant parameters and affords maximal relaxivity. Introducing aryl substituents into the α-position of the pendant arms of a GdDOTA chelate affords chelates that, for the first time, simultaneously optimize all physico-chemical properties. Slowing tumbling by binding to human serum albumin affords a relaxivity of 110 ± 5 mM−1 s−1, close to the maximum possible. As discrete chelates, these α-aryl substituted GdDOTA chelates exhibit relaxivities that are 2–3 times higher than those of currently used agents, even at the higher fields (1.5 & 3.0 T) used in modern clinical MRI.


Figure S1. S3
The temperature dependence of the 17 O NMR reduced transverse relaxation rate constant of solvent water of solutions of GdDOTFA (left) and GdDOTBA (right) at pH 6.6 and 11.7 T.

Figure S2. S3
Left: Relaxometric titration of human serum albumin into a 0.09 mM solution of GdDOTFA at 298 K and 0.47 T (red circles).For comparative purposes the effect on the relaxation rate

Figure S3. S4
The NMRD profile of GdDOTFA in human serum (seronorm) recorded at 310 K and a total [Gd] = 0.5 mM (open red diamonds).The ordinate axis is not expressed in terms of relaxivity, but in terms of the paramagnetic effect on the relaxation rate constant of 1 H 2 O without correction for concentration.For comparative purposes the NMRD profile of GdDOTFA in aqueous solution at 310 K at the same concentration is shown (closed blue diamonds).The concentration of GdDOTFA bound to HSA in serum is estimated to be in the range of 50 M.

Figure S4. S5
The structures of Gd 3+ chelates used as contrast agents that are either in clinical trials or already in clinical use.The relaxivities of these agents are shown in Figures 4 & 5.
Coordinated water molecules are not shown, but these chelates are coordinatively saturated when CN=9, the maximum number of coordinated water molecules can therefore be calculated by subtracting the denticity of the ligand from 9.

Figure S5. S6
The calculated relaxivity, as function of the water exchange lifetime ( M ), of a Gd 3+ chelate with electronic relaxation characteristics comparable to those of GdDOTA ( 2 = 1.6 × 10 -19 s -2 ,  V = 7.7 ps) if the rate of molecular tumbled had been slowed such that  R =100 ns (left) and  R = 2 ns (right) at different magnetic field strengths.When  R is long, the value of  M is shorter at higher magnetic fields.

Figure S6. S6
The calculated relaxivity, as function of the water exchange lifetime ( M ), of a Gd 3+ chelate with electronic relaxation characteristics comparable to those of GdDOTFA ( 2 = 6.8 × 10 -18 s -2 ,  V = 25 ps) if the rate of molecular tumbled had been slowed such that  R =100 ns (left) and  R = S2 2 ns (right) at different magnetic field strengths.The significance of optimizing electronic relaxation is evident when comparing with the relaxivity that achieved in Figure S3.

Figure S7. S7
The water proton relaxation rate constant (R 1 ) measured during incubation of a 0. a Gd 3+ chelate with electronic relaxation characteristics comparable to those of GdDOTA ( 2 = 1.6 × 10 -19 s -2 ,  V = 7.7 ps) if the rate of molecular tumbled had been slowed such that  R =100 ns (left) and  R = 2 ns (right) at different magnetic field strengths.When  R is long, the value of  M is shorter at higher magnetic fields.

Figure S6
. The calculated relaxivity, as function of the water exchange lifetime ( M ), of a Gd 3+ chelate with electronic relaxation characteristics comparable to those of GdDOTFA ( 2 = 6.8 × 10 -18 s -2 ,  V = 25 ps) if the rate of molecular tumbled had been slowed such that  R =100 ns (left) and  R = 2 ns (right) at different magnetic field strengths.The significance of optimizing electronic relaxation is evident when comparing with the relaxivity that achieved in Figure S3.
constant of HSA (black diamonds) and GdDOTFA alone (open diamonds) are shown.Right: Relaxometric titration of human serum albumin into a 0.10 mM solution of GdDOBTA at 298 K and 0.47 T.

Figure S1 .Figure S3 .S5Figure S4 .Figure S5 .
Figure S1.The temperature dependence of the 17 O NMR reduced transverse relaxation rate constant of solvent water of solutions of GdDOTFA (left) and GdDOTBA (right) at pH 6.6 and 11.7 T.

Figure S7 .
Figure S7.The water proton relaxation rate constant (R 1 ) measured during incubation of a 0.42 mM solution of GdDOTFA (blue open circles) and a 0.46 mM solution of GdDOTA (black triangles) in 1M HCl at 298K.Measured at 298K and 32 MHz.