Lanthanide complexes of tetraamide derivatives of DOTA are of interest today because of their application as chemical exchange saturation transfer (CEST) agents for magnetic resonance imaging (MRI). The protonation constants of some simple tetraamide derivatives of DOTA and the stability constants of the complexes formed with some endogenous metal ions, namely Mg 2+ , Ca 2+ , Cu 2+ , Zn 2+ , and lanthanide(III) ions, have been studied. These complexes were found to be considerably less stable than the corresponding [M(DOTA)] 2− complexes, largely due to the lower basicity of the tetraamide ligands. The Mg 2+ and Ca 2+ complexes are well described by formation of only ML species at equilibrium while the Zn 2+ and Cu 2+ complexes exhibit one and two additional deprotonation steps above a pH of around 6, respectively. The extra deprotonation that occurs at high pH for the [Zn{DOTA-(amide) 4 }] 2+ complexes has been assigned to an amide deprotonation by 1 H NMR spectroscopy. The first deprotonation step for the Cu 2+ complexes was traced to formation of the ternary hydroxo complexes ML(OH) (by UV/Vis spectrophotometry) while the second step corresponds to deprotonation of an amide group to form ML(OH)H −1 -type complexes. The trends in the stability constants of the [Ln{DOTA-(amide) 4 }] 3+ complexes follow similar trends with respect to ion size as those reported previously for the corresponding [Ln(DOTA)] − complexes, but again, the stability constants are about 10-11 orders of magnitude lower. A kinetic analysis of complex formation has shown that complexes are directly formed between a Ln 3+ cation and fully deprotonated L without formation of a protonated intermediate. [Ln{DOTA-(MeAm) 4 }] 3+ complex formation occurs at a rate that is two to three orders of magnitude slower than those of the corresponding [Ln(DOTA)] − complexes, while the variation in complex formation rates with Ln 3+ ion size is opposite to that observed for the corresponding [Ln(DOTA)] − complexes. The Ce 3+ and Correspondence to: Gyula Tircsó; A. Dean Sherry. Supporting information for this article is available on the WWW under http://www.eurjic.org or from the author. Eu 3+ complexes of DOTA-(MeAm) 4 are kinetically inert with respect to acid-catalyzed dissociation, which suggests that these complexes may potentially be safe for use in vivo.

A bifunctional version of PCTA (3,6,9,15-tetraazabicyclo[9.3.1]pentadeca-1(15),11,13-triene-3,6,9,-triacetic acid) that exhibits fast complexation kinetics with the trivalent lanthanide(III) ions was synthesized in reasonable yields starting from N, N′, N″-tristosyl-(S)-2-(p-nitrobenzyl)-diethylenetriamine. pH-potentiometric studies showed that the basicities of p-nitrobenzyl-PCTA and the parent ligand PCTA were similar. The stability of M(NO 2 -Bn-PCTA) (M = Mg 2+ , Ca 2+ , Cu 2+ , Zn 2+ ) complexes was similar to that of the corresponding PCTA complexes while the stability of Ln 3+ complexes of the bifunctional ligand is somewhat lower than that of PCTA chelates. The rate of complex formation of Ln(NO 2 -Bn-PCTA) complexes was found to be quite similar to that of PCTA, a ligand known to exhibit the fastest formation rates among all lanthanide macrocyclic ligand complexes studied to date. The acid catalyzed decomplexation kinetic studies of the selected Ln (NO 2 -Bn-PCTA) complexes showed that the kinetic inertness of the complexes was comparable to that of Ln(DOTA) chelates making the bifunctional ligand NO 2 -Bn-PCTA suitable for labeling biological vectors with radioisotopes for nuclear medicine applications.

Tissue hypoxia occurs in pathologic conditions such as cancer, ischemic heart disease and stroke when oxygen demand is greater than oxygen supply. An imaging method that can differentiate hypoxic versus normoxic tissue could have an immediate impact on therapy choices. In this work, the gadolinium complex of 1,4,7,10-tetraaza-1,4,7,10-tetraacetate (DOTA) having a 2-nitroimidazole attached to one carboxyl group via an amide linkage was prepared, characterized and tested as a hypoxia-sensitive MRI agent. A control complex, Gd(DO3A-monobutylamide), was also prepared in order to test whether the nitroimidazole side-chain alters either the water proton T1 relaxivity or the thermodynamic stability of the complex. The stabilities of these complexes were lower than that of Gd(DOTA)− as expected for mono-amide derivatives. The water proton T1 relaxivity (r1), bound water residence lifetime (τM) and rotational correlation time (τR) of both complexes was determined by relaxivity measurements, variable temperature 17O NMR and proton nuclear magnetic relaxation dispersion (NMRD) studies. The resulting parameters (r1 = 6.38 mm−1s−1 at 20 MHz, τM = 0.71 µs, τR = 141 ps) determined for the nitroimidazole derivative closely parallel those of other Gd(DO3A-monoamide) complexes of similar molecular size. In vitro MR imaging experiments using 9L rat glioma cells maintained under nitrogen (hypoxic) versus oxygen (normoxic) gas showed that both agents enter cells but only the nitroimidazole derivative is trapped in cells maintained under N2 as evidenced by ~2-fold decrease in T1 measured for hypoxic cells versus normoxic cells exposed to this agent. These results suggest that the nitroimidazole derivative may serve as a molecular reporter for discriminating hypoxic versus normoxic tissues by MRI.

Lanthanide complexes of two tris-(amide) derivatives of PCTA were synthesized and characterized. The relaxometric and luminescence properties of their lanthanide complexes were investigated as bimodal magnetic resonance (MR) and optical imaging agents. Luminescence studies show that one of the Tb III complexes dimerizes in solution at low millimolar concentrations while the other may have a higher than expected coordination number in solution. The corresponding Gd III complexes display unusually high T 1 relaxivities and enhanced kinetic inertness compared to GdPCTA. These features suggest that these new chelates may be suitable for in vivo applications. The fast water exchange rates observed for these complexes make them unsuitable as paramagnetic chemical exchange saturation transfer (PARACEST) agents.