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This paper reports on the synthesis and relaxivity properties of tetraacetic DOTA-type chelating agents featuring one or two alkyne groups directly grafted on the tetraaza macrocyclic ring and available for "click" reactions with azide-bearing substrates. The racemic DOTAma ligand bearing one alkyne group was obtained by a bisaminal template route. The same approach was used to prepare ligand DOTAda substituted by two alkyne groups located on two adjacent carbon atoms. The S,S enantiomer of DOTAda was also prepared by a "crab-like" condensation. This ligand is the first example of a DOTA derivative featuring two reactive functions adjacent to each other on the macrocyclic ring. A triacetic monoalkyne ligand (DO3ma) was also synthesized for comparison purposes. NMR studies indicate that the Yb(III) chelates of DOTAma and DOTAda adopt two conformations in solutions in which the tetraaza ring is rigidified. The hydration state of the Eu(III) chelates was determined by luminescence spectroscopy, and the water exchange time of the Gd(III) complexes was measured by (17)O NMR. Ring substitution accelerates the water exchange. These data were used to interpret nuclear magnetic relaxation dispersion curves of the Gd(III) chelates. Two long aliphatic chains have been added to DOTAda by a "click" procedure to form the (C18)(2)DOTAda ligand. The corresponding Gd(III) complex forms micelles of unusually high relaxivity presumably because of the close proximity of the aliphatic chains on the macrocyclic ring that ensures a rigid double anchoring into the micelles.

The gadolinium(III) complex with a new DOTA-based ligand bearing a methanethiosulfonate group (MTS) was synthesized and its relaxivity properties were investigated. MTS-ADO3A is a triacid DOTA derivative with an amide arm substituted by an ethylmethanethiosulfonate function. This ligand was obtained in two steps: tri-tert-butyl 2,2',2''-(1,4,7,10-tetraazacyclododecane-1,4,7-triyl)triacetate was reacted with S-(2-aminoethyl)methanesulfonothioate and the tert-butyl groups were removed with trifluoroacetic acid. The Gd(III) MTS-ADO3A complex readily formed disulfide bonds with albumin (BSA) in its native and reduced forms and with thiolated silica particles. Four- to five-fold relaxivity increases at 20 MHz were measured on the isolated adducts. The EuMTS-ADO3A chelate was found to be monohydrated by fluorescence and the relaxivity parameters of the Gd(III) complex were obtained by (17)O NMR and by measuring the nuclear magnetic relaxation dispersion between 0.01 and 80 MHz. The water exchange time tau(m) is increased upon forming disulfide bonds with macromolecules and particles and the relaxivity gains of all the complexes are limited by the tau(m) factor. Forming covalent or hydrophobic/electrostatic bonds with BSA seems to bring about similar relaxivity changes but the covalent BSA adducts can be isolated and their properties can be directly studied. The addition of dithiothreitol or glutathione leads to the removal of the metal chelates from the macromolecules, as indicated by the relaxation times reverting to their values before binding. It is thus expected that the chelate will stay in the body long enough for imaging but will still be excreted through the kidneys., (Copyright 2007 John Wiley & Sons, Ltd.)

This paper presents the views of a coordination chemist on the synthesis and the properties of new contrast agents containing gadolinium. Attention is drawn to various macrocyclic complexes such as the polyaza polycarboxylic chelates, the cryptates as well as compounds obtained by template synthesis. The structural factors influencing the kinetic and thermodynamic stability of the gadolinium complexes are discussed with special emphasis on the polyaza polycarboxylic derivatives. Some of the macrocyclic complexes under investigation are more stable than Gd-DTPA.