Gd-DTPA derivatives

Provided the interactions between a contrast agent and an enzyme are sufficiently strong, a large increase in relaxivity will be observed due to the increased rotational correlation time of the adduct. This behavior was observed for a Gd-DTPA derivative substituted by an arylsulfonamide pendant arm [116]. 

Scheme 9. Activation of a Gd-DTPA derivative by alkaline phosphatase...

Caravan, P., Amedio, J.C. Jr, Dunham, S.U., et al. (2005) When are two waters worse than one Doubling the hydration number of a Gd-DTPA derivative decreases relaxivity. Chemistry - A European Journal, 11, 5866-5874. 

Kabalka GW, Davis MA, Moss TH, Buonocore E, Hubner K, Hoknberg E, Maruyama K, Huang L (1991) Gadohnimn-labeled liposomes containing various amphiphilic Gd-DTPA derivatives targeted MRl contrast enhancement agents for the liver. Magn Reson Med 19(2) 406-415... 

As an example of behavior of a typical Gd-complex and Gd-macromolecule we discuss here the NMRD profiles of a derivative of Gd-DTPA with a built-in sulfonamide (SA) and the profile of its adduct with carbonic anhydrase (see Fig. 37) 100). Other systems are described in Chapter 4. The profile of Gd-DTPA-SA contains one dispersion only, centered at about 10 MHz, and can be easily fit as the sum of the relaxation contributions from two inner-sphere water protons and from diffusing water molecules. Both the reorientational time and the field dependent electron relaxation time contribute to the proton correlation time. The fit performed with the SBM theory, without... 

The ligation of Ln3+ by DTPA, DTPA-BPA, DTPA-BGLUCA, and DTPA-BEN-GALAA has been derived from Nd3+-C distances as evaluated from Nd3+-induced 13C relaxation rate enhancements [5-8]. The distances obtained are in agreement with those observed in crystal structures of this class of compounds. H NMR studies on various paramagnetic [Ln(DTPA)]2 complexes [9,10] and 13C relaxation rate measurements on the diamagnetic [La(DTPA)] 2 confirm this mode of coordination [11]. A detailed X-ray absorption spectroscopy study of [Gd(DTPA)2-] also showed that the local structure around the Gd3+ ion in aqueous solution is similar to that in crystals [12]. 

Linear copolymers of Gd(DTPA-bisamide) or Gd(EGTA-bisamide) units with poly(ethylene-glycol) (PEG) or polyalkyl (-(CH2)n- n = 6,10 and 12) spacers also had water exchange kinetics similar to that of the corresponding monomer chelate [60-62]. An 170 NMR study on the micellar system formed in aqueous solution of the amphiphilic DOTA-derivative [Gd(D0TA-C12)(H20)] also showed that the water exchange is not altered by the micellar structure [63]. 

The Gd3+ complex MS-325 formed with a diphenylcyclohexyl derivative of DTPA, proved to be kinetically more stable than Gd(DTPA)2 in a metal-exchange reaction with Zn2+ [41]. 

The rates of the exchange reactions between several complexes Ln(DTPA)2 (Ln = La, Nd, Gd, Ho and Lu) and Eu3+ have been studied by spectrophotometry on the charge-transfer band of Eu3+ [20, 31]. Similar studies were carried out with the Gd3+ complexes of some other DTPA derivatives DTPA-BMA,DTPA-N-MA and DTPA-N -MA. The progress of the exchange reactions between the complexes and Eu3+ and Cu2+ was followed by spectrophotometry, while when Zn2+ was used as exchanging ion, the longitudinal relaxation rates of water pro-... 

The rate constants k and k2 furnish information on the role of the proton-assisted dissociation of the Gd3+ complexes. However, under physiological conditions the H+ concentration is very low and the rate of proton-assisted dissociation is therefore also very low. The values obtained for the DTPA derivative complexes do not differ considerably. Only the kj value characterizing the dissociation of Gd(DTPA-BMA) is larger, but, because of the relatively low protonation constant value (KGdHL < 2 [43]), the concentration of the protonated complex Gd(HDTPA-BMA)+ is also low, and thus the rate of dissociation of Gd(DTPA-BMA) is comparable with those of the other DTPA derivative complexes. 

The rate of proton-assisted dissociation of Gd(DTPA-BMEA), studied by Rothermel et al., does not differ considerably from that of Gd(DTPA-BMA) (Table 2), indicating that the kinetic stabilities of the complexes of the different DTPA-bis(amide) derivatives are similar [42]. 

The iron(III) complex of the microbial siderophore desferrioxamine B (DF, Fig. 16) was investigated as a MRI contrast agent [142],but the rapid injection of this agent may result in a precipitous drop in blood pressure [143]. For this reason, the primary amine on Fe-DF was conjugated with polyethylene-glycol to form Fe-PEG-DF (Fig. 16) [143, 144]. The new derivative has a Rj value of 1.35 mM-1 s-1 and R2 value of 1.67 mM-1 s 1 at 20 MHz and 37 °C, both values are similar to those of Fe-DF under the same conditions [143]. The LD50 for Fe-PEG-DF in mice is 7.7 mmol kg-1 and no blood pressure drops were observed after injection of Fe-PEG-DF. The enhancement of dog kidneys after injection of 0.2 mmol kg1 Fe-PEG-DF was similar to the enhancement profile caused by Gd-DTPA [143]. 

Another strategy for selective delivery of CA s at cancer cells exploits the intrinsic overexpression of sialic acid in them. Upon incubation of cancer cells with peracetylated N-levulinoylmannosamine the sialoside biosynthetic pathway affords N-levulinoyl sialic acid, the ketone group of which can be a target for an Gd + complex of an aminooxy-functionalized DTPA derivative [165]. 

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