Synthesis and evaluation of novel macrocyclic and acyclic ligands as contrast enhancement agents for magnetic resonance imaging.

Novel chelates PIP-DT'PA, AZEP-DTPA, NETA, NPTA, and PIP-DOTA were synthesized and evaluated as potential magnetic resonance imaging (MRI) contrast enhancement agents. The T 1 and T 2 relaxivities of their corresponding Gd(III) complexes are reported. At clinically relevant field strengths, the relaxivities of the complexes are comparable to that of the clinically used contrast agents Gd(DTPA) and Gd(DOTA). The serum stability of the 153 Gd-labeled complexes, Gd(PIP-DTPA), Gd(AZEP-DTPA), Gd(PIP-DOTA), Gd-(NETA), and Gd(NPTA), was assessed by measuring the release of 153 Gd from the complexes. 153 Gd-(NETA), 153 Gd(PIP-DTPA), and 153 Gd(PIP-DOTA) were found to be stable in human serum for up to 14 days without any measurable loss of radioactivity. Significant release of 153 Gd was observed with the 153 Gd-(III) radiolabled NPTA. In vivo biodistribution of the 153 Gd-labeled complexes was performed to evaluate their in vivo stability. While Gd(AZEP-DTPA) and Gd(NPTA) were found to be unstable in vivo, Gd(NETA), Gd(PIP-DTPA), and Gd(PIP-DOTA) were excreted without dissociation. These results suggest that the Gd(III) complexes of the novel chelates NETA, PIP-DTPA, and PIP-DOTA possess potential as MRI contrast enhancement agents. In particular, the piperidine backboned chelates Gd(PIP-DTPA) and Gd(PIP-DOTA) displayed reduced kidney retention as compared to the nonspecific MRI contrast agent Gd(DOTA) at all time points, although the observed effects were relatively small at 0.5 h postinjection. Incorporation of the lipophilic piperidine ring appears to confer a moderate effect on the liver uptake of these two chelates.