Gd complexes of DO3A-(biphenyl-2,2′-bisamides) conjugates as MRI blood-pool contrast agents

We report the synthesis of DO3A derivatives of 2,2′-diaminobiphenyl (1a,b) and their Gd complexes of the type [Gd(1)(H₂O)]·xH ₂O (2a,b) for use as new MRI blood-pool contrast agents (BPCAs) that provide strong and prolonged vascular enhancement. Pharmacokinetic inertness of 2 compares well with that of structurally related Dotarem, a DOTA-based MRI CA currently in use. The R₁ relaxivity in water reaches 7.3 mM ^-1 s^-1, which is approximately twice as high as that of Dotarem (R₁ = 3.9 mM^-1 s^-1). They show interaction with HSA to give association constants (K_a) in the order of two (∼10²), revealing the existence of the blood-pool effect. The in vivo MR images of mice obtained with 2 are coherent, showing strong signal enhancement in both heart, abdominal aorta, and small vessels. Furthermore, the brain tumor is vividly enhanced for an extended period of time.