Gadolinium complexes of bifunctional Diethylenetriaminepentaacetic Acid (DTPA)-bis(amides) as Copper responsive smart Magnetic Resonance Imaging Contrast Agents (MRI CAs)

We present the synthesis and characterization of DTPA-bis(histidylamide) (1a), DTPA-bis(aspartamide) (1b), and their gadolinium complexes of the type [Gd(L)(H₂O)] (2a: L = 1a; 2b: L = 1b). Thermodynamic stabilities and R₁ relaxivities of 2a-b compare well with Omniscan®, a well-known commercial, extracellular (ECF) MRI CA which adopts the DTPA-bis(amide) framework for the chelate: R₁ = 5.5 and 5.1 mM^-1 for 2a and 2b, respectively. Addition of the Cu(II) ion to a solution containing 2b triggers relaxivity enhancement to raise R₁ as high as 15.3 mM ^-1, which corresponds to a 300% enhancement. Such an increase levels off at the concentration beyond two equiv. of Cu(II), suggesting the formation of a trimetallic (Gd/Cu₂) complex in situ. Such a relaxivity increase is almost negligible with Zn(II) and other endogenous ions such as Na(I), K(I), Mg(II), and Ca(II). In vivo MR images and the signal-to-noise ratio (SNR) obtained with an aqueous mixture of 2b and Cu(II) ion in an 1:2 ratio demonstrate the potentiality of 2 as a copper responsive MRI CA.