DOTA complexes

The high in vivo stability of DOTA complexes makes it a desirable ligand framework for BFCAs relative to acyclic analogs however, complex formation with DOTA and its analogs can be slow. The slow kinetics of complex formation with DOTA-type ligands does not pose problems with nuclides such as 177Lu (t /2 6.64 d) however, improved reaction conditions may... 

This effect of the position of the lone pair is relevant not only in the case of phthalocyaninato ligands, but also can be a clue to the intriguing behaviour of the [Dy(DOTA)] complex, where the rotation of a water molecule changes the magnetic properties [13]. A PCE or an REC model cannot account for the effect of such a rotation, but an LPEC model would predict a dramatic effect, since the change in the position of the lone pair effectively means a completely different geometry. 

Giant field dependence of the low temperature relaxation of the magnetization in a dysprosium(III)-DOTA complex. Chem. Commun., 47, 3751-3753 (b) Cucinotta, G., Perfetti, M., Luzon,... 

Values for nota are also documented in Ref. (237) values for nota and dota complexes of several M2+ ions are given in Clarke, E. T. Martell, A. E. Inorg. Chim. Acta 1991,190, 27-36, for M3+ ions in Clarke, E. T. Martell, A. E. Inorg. Chim. Acta 1991, 190, 37-46. 

Apromising new class of stable Gd3+ complexes based onTREN-Me- 3,2 -HOPO shows relatively fast water exchange rates. The water soluble tris(2-hydroxymethyl)-TREN-Me-3,2-HOPO complex is eight-coordinate with two water molecules in the first coordination sphere (234). The water exchange rate is more than one order of magnitude faster than on DTPA and DOTA complexes and the mechanism is proposed to be a-activated. 

Both the DTPA- and DOTA-Gd(III) complexes are thermodynamically very stable (Table V), but DOTA complexes have a higher kinetic stability. The stabilities are highly pH dependent. For example, log K for [Gd(DTPA)] falls by a factor of about 4 when the pH drops from 7.4 to 5. This could be significant in some biological compartments, e.g., lysosomes, where the pH can be as low as 5. 

The DTPA and DOTA complexes currently in clinical use act as extracellular markers which are associated with changes in blood... 

Paramagnetic amphiphilic complexes embedded in micelles have their hydrophilic head and thus the paramagnetic ion in contact with the surrounding water. If the complex has only one hydrophobic chain, the access of water to the ion should be easy but when two hydrophobic chains are involved like in DTPA bisamides complexes, the incorporation of both chains in the micellar structure could reduce either the accessibility of water to the ion or the water exchange rate. It has been reported that micellar Gd-DOTA complexes substituted by one hydrophobic chain are characterized by a water residence time similar to that of Gd-DOTA 200 ns) and that their enhanced relax-... 

Ln3+ induced water 170 shifts of [Ln(DOTA)] solutions show that the hydration number of the complexes is one across the lanthanide series [59]. The substantial pseudocontact contribution to its LIS indicated that this water ligand has a preferred location in the complex. Two sets of peaks have been observed in H and 13C NMR spectra of [Ln(DOTA)] complexes at room temperature showing the presence of two slowly interconverting structural isomers [60-63]. In the spectra of the paramagnetic complexes, one isomer has larger LIS values than the other. These structural features have been confirmed by luminescence studies [51, 64]. The temperature dependence of the H and 13C NMR spectral features of both the dia- and paramagnetic Ln3+ complexes indicates that the... 

Fig. 2. Schematic representation of the structures and dynamics of [Ln(DOTA)]- complexes, looking down along the Ln-water O bond. The water molecule is omitted for clarity...

The H NMR spectra of the related [La(THED)]3+ as a function of temperature reveal a dynamic process at room temperature similar to that observed for [Ln(DOTA)] complexes [143]. At ambient temperature, the 13C NMR spectra (methanol-d, ) consists of two sharp resonances assigned to the pendant arms and one broad resonance attributed to the ethylene ring carbons, which sharpens as the fast exchange limit is approached (ca. 50°C). Likewise, at -20°C the broad resonance resolves into two peaks. The increased flexibility observed for [La(THED)]3+ as compared to DOTA complexes suggests that the pendant groups contribute to the structural rigidity of the macrocyclic ring. 

Another method to increase the number of metals associated with each macromolecule is to attach them, in a chelated form, to a carrier molecule with many sites of attachment. An example of this can be found in the work of Meade [29], His group has synthesized a fi-cyclodcxtrin from which seven Gd-DOTA complexes were attached using highly efficient click chemistry. The contrast agent was observed to accumulate in primary cancers but then localize in secondary metastases over the subsequent 48 hours. This is a particularly valuable property as one of the main problems with cancer treatment is the inability to detect these small secondary tumours in their early stages. 

The most thermodynamically stable and kinetically inert complexes of the trivalent lanthanides are those of the ligand DOTA (1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetate) (42, 43). Our search for lanthanide macrocyclic complexes that would remain intact for longer time periods led us to examine derivatives of DOTA. There are two potential difficulties with the use of DOTA complexes of the trivalent lanthanides for RNA cleavage. First, the overall negative charge on the complex is not conducive to anion binding for example, Gd(DOTA)-does not bind hydroxide well (44). Second, DOTA complexes of the middle lanthanides Eu(III) and Gd(III) have only one available coordination site for catalysis. The previous lanthanide complexes that we used, e.g., Eu(L1)3+, were good catalysts and had at least two available coordination sites. 

The rate of conversion of [Ln(H2L)(H20)s]+(aq) into [Ln(D0TA)(H20)] is pH-dependent and ranges from 7.2 x 1(T4 to 7. 9 x 10 2 for Ln = Eu as the pH is raised from 3.8 to 5.8 similar values are obtained for Ln = Gd. Dissociation of the Gd-DOTA complex is also very slow and its half-life in a 0.1 M solution of hydrochloric acid is larger than one month. The usual dose for an experiment is 0.1 mmol kg-1, there are few side effects and excretion is reasonably fast (75% in three hours). 

An elaborate supramolecular sensor has been engineered by attaching a permethylated cyclodextrin to a terbium-DOTA complex. The cyclodextrin acts as a scavenger for... 

Fig. 4.45. Luminescent sensor for polyaromatic hydrocarbons (e.g. anthracene) based on a derivatised Tb(III)-DOTA complex. Redrawn from D. Parker et al., J. Chem. Soc., Perkin Trans. 2,1329, 2000.

---