Chapter 5.2: The Future of Biomedical Imaging: Synthesis and Chemical Properties of the DTPA and DOTA Derivative Ligands and Their Complexes

The chelate complexes of lanthanides and some other trivalent metal ions are widely used in medical diagnosis and therapy (MRI contrast agents, Optical Imaging, Nuclear Medicine). The chelating agents are mostly aminopolycarboxylate ligands, the open-chain DTPA, the macrocyclic DOTA and their derivatives. This Chapter describes the most important synthetic methods used for the preparation of the ligands (including some bifunctional chelators) and their complexes. The behaviour of the metal complexes in biological systems strongly depends on their equilibrium and kinetic properties. A short review on the methods used to determine the protonation constants of ligands, the stability constants of the complexes and the stability data reported, help to understand the in vivo equilibrium behaviour of metal chelates. The safety of gadolinium based MRI contrast agents strongly depends on the kinetic inertness of the complexes which is characterized with the rate data reported for the transmetallation reactions occurring between the complexes and Zn²⁺ or Cu²⁺ ions. The summary on transmetallation kinetics of the complexes formed with DTPA and DOTA derivative ligands are also summarized in the current Chapter. The rate data obtained in the presence of the endogenous citrate are in harmony with the results of biodistribution studies, indicating that the amount of retained Gd is largest for the Gd(DTPA-BMA).