DOTA-amide complexes

PARACEST agents with a response to enzymatic activity have also been reported. Pagel et al. used a Tm1 DOTA monoamide complex containing a peptide chain which is hydrolyzed by the Caspase-3 enzyme (204,205). Following enzymatic cleavage, the PARACEST effect originating from the amide proton disappears due to the hydrolysis of the amide bond. 

Lanthanide complexes of mono- and tetra-amide /1-cyclodextrin derivatives of DOTA have been characterized [140]. The proton NMR spectra of the Eu3+ complexes in methanol-d, show that, while the tetra-amide complex occurs in solution exclusively as a C4-symmetry SAP structure, the mono-amide complex, with less than C4-symmetry, occurs predominantly as two SAP isomers (A/XXXX and Al8885), with the presence of a small amount of the twisted SAP isomer. Luminescence and relaxivity measurements confirm that the Eu3+, Tb3+ and Gd3+ complexes of the eight-coordinate mono-amide ligand possess one bound water molecule, while the tetra-amide complexes have q = 0. The relaxivity of the /LCD mono-amide Gd3+ complex is enhanced when non-covalently bound to a second Gd3+ complex bearing two phenyl moieties (MS-325, AngioMARK , EPIX/Mallinckrodt). 

Although the water exchange rates on all, medically used Gd(III) chelates are similar (within the range of one order of magnitude), other Gd(III) complexes were found to have considerably lower (e.g. positively charged DOTA-amide derivatives) or considerably higher (e.g. the aqua ion) water exchange rates. In... 

Lin and co-workers described a multimodal contrast agent formed by the layer-by-layer deposition of Gd complexes and polymers on sihca nanoparticles containing [Ru(bipy)3] " ions as luminescence markers " (Figure 7.4). The doped silica particle was formed by the hydrolysis of TEOS in the presence of [Ru(bipy)3] ". Anionic gadolinium-DTPA complexes were then tethered to the surface with an appended trimethoxy silane chain. A layer-on-layer process followed with the addition of oligomeric cationic Gd(DOTA bis amide) complexes. SEM and TEM data showed silica particles of 37 nm diameter. 

X-ray structure of the yttrium complex of DOTA-amide (Heppeler et al. 2000). Reproduced by permission of Bentham Science Publishers Ltd... 

Another general method for the synthesis of these macrocycles is the reaction of amines with (active) esters of carboxylic acids leading to oxoderivatives of the cycles. The amides can be reduced to amines or directly used for further transformations or complexation of metal ions. Two cyclens 55 and 56, as intermediates for the synthesis of bifunctional DOTA derivatives, were obtained by condensation shown in Scheme 10 between appropriate diamine-amide and active ester of AT-BOC-iminodiacetic acid (BOC = /-butoxycarbonyl), followed by deprotection and reduction <2003NMB581>. 

Zhang, S., Kovacs, Z., Burgess, S., et al. (2001) DOTA-bis(amide) lanthanide complexes NMR evidence for differences in water-molecule exchange rates for coordination isomers. Chemistry - A European Journal, 1, 288-296. 

The direct coupling of a biomolecule by one acetic acid function of DOTA leads to a conversion of this group to an amide offering the carbonyl oxygen for potential complexation of the radiometal, which consequently may lead to a decrease in thermodynamic stability compared to the acid. The difference is in one order of magnitude (Good 2006 Heppeler et al. 2008). To prevent this problem, a special coupling moiety should be introduced into the macrocycle. 

NMR spectroscopy has confirmed that the chiral asymmetric structure of [Sm(ri -C5H4PPh2) (3,5-Me2pz)3BH I(THF)] is maintained in solution at low temperature and the B NMR spectrum was reported." and NMR spectroscopy, including EXSY, has been used to study conformation and water exchange in DOTA-bis(amide) lanthanide complexes." [ HB(3,5-... 

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