Development of intravascular contrast agents for MRI using gadolinium chelates

Two MRI contrast agents (CAs) composed of Gd-DO3A conjugated to amino acid building blocks derived from glutamic acid (CA1) and lysine (CA2) have been synthesized by using novel alkyne and propionate linkers, and subsequently characterized. Invitro cell viability assays showed insignificant cytotoxicity of both CAs at low concentrations up to 0.2mM. The longitudinal relaxivities (r₁) of CA1 and CA2 measured at 9.4T are 6.4 and 5.4mM^-1s^-1 in H₂O at 25°C, respectively. Both r₁ values are higher than those of CAs in clinical use: Gd-DTPA (Magnevist, Bayer Schering, Germany) and Gd-DOTA (Dotarem, Guerbet, France). Invivo imaging in Wistar rats demonstrated considerable signal enhancement (∼50%) in the brain artery by CA2, but lower signal enhancement (∼30%) by CA1. In contrast to Dotarem, which showed a similar signal enhancement as CA2, the enhancement by CA2 remained high (∼30%), even at 52min post-injection. This demonstrates that CA2 has a much longer blood half-life (68.1min), which could be advantageous for angiography and tissue targeting. Image this! Herein we describe the preparation and characterization of Gd^III chelates CA1 and CA2, which use novel linkers to connect the cyclen to the amino acid residue. Invivo imaging in Wistar rats demonstrated considerable signal enhancement and long blood retention time in the brain artery for CA2.