Gd Complexes of DO3A-(Biphenyl-2,2′-bisamides) Conjugates as MRI Blood-Pool Contrast Agents

Abstract

We report the synthesis of DO3A derivatives of 2,2′-diaminobiphenyl (<b>1a</b>,<b>b</b>) and their Gd complexes of the type [Gd­(<b>1</b>)­(H₂O)]·<i>x</i>H₂O (<b>2a</b>,<b>b</b>) for use as new MRI blood-pool contrast agents (BPCAs) that provide strong and prolonged vascular enhancement. Pharmacokinetic inertness of <b>2</b> compares well with that of structurally related Dotarem, a DOTA-based MRI CA currently in use. The <i>R</i>₁ relaxivity in water reaches 7.3 mM^–1 s^–1, which is approximately twice as high as that of Dotarem (<i>R</i>₁ = 3.9 mM^–1 s^–1). They show interaction with HSA to give association constants (<i>K</i>_a) in the order of two (∼10²), revealing the existence of the blood-pool effect. The in vivo MR images of mice obtained with <b>2</b> 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