A novel albumin-binding macrocyclic Gd-HPDO3A complex bearing a deoxycholic acid residue: the role of the hydration state, water exchange and local dynamics in the observed relaxivity†

Gd-HPDO3A (ProHance, Bracco) appears to be one of the MRI contrast agents with the lowest level of gadolinium retention in the body. Recently, we reported the synthesis and characterization of a Gd-HPDO3A derivative with good binding affinity to human serum albumin whose MR contrast efficiency was limited by the slow exchange rate of the coordinated water molecule and reduced hydration state of the albumin-bound complex. Here, we report the results on a strictly related analogue, Gd-HIBDO3A-DCA, which contains an additional methyl group on the hydroxyl arm. The minor structural modification resulted in the stabilization of the TSAP isomer (85%) (as clearly assessed by means of the ¹H-NMR spectroscopy of the europium complex). Gd-HIBDO3A-DCA displayed an enhanced water exchange rate (τ_M = 53 ns), by maintaining the stability of the parent Gd-HPDO3A complex. The expected high relaxivity of the supramolecular adduct with HSA is partly “quenched” by the flexibility of the spacer joining the Gd(III) chelate and the deoxycholic acid moiety. The high HSA binding capacity (three bound complexes) yields an excellent agent with good contrasting ability as shown in in vivo images acquired on a preclinical MRI scanner operating at 1T in a murine breast tumor model. Gd-HIBDO3A-DCA, administered at a half-dose (0.05 mmol kg⁻¹) with respect to the conventional clinical dose, yielded more than two fold signal enhancement compared to ProHance in the tumor region. Moreover, the very high liver signal enhancement makes this complex a promising candidate for liver imaging in hepatic diseases.