Complexes of Ga³⁺and In³⁺with the N,N″-bis(butylamide) derivative of diethylenetriaminepentaacetic acid: stability constants and nuclear magnetic resonance studies in aqueous solution

Abstract

Potentiometric titrations showed that the sum of the first three protonation constants of diethylenetriaminepentaacetate N,N"-bis( butylamide) ( L1) decreases by 6.6 units when compared to the diethylenetriaminepentaacetate (dtpa), and that the complexes of Ga3+ and In3+ of L1 have stability constants 6.1 -6.3 log units lower than those of dtpa. The decreased basicity of the bis(amide) derivative thus correlates with the lower stability of its complexes. However, at pH 7.4 the lower overall basicity of L1 compared to dtpa partly compensates the lower stability of its complexes, thus causing their conditional stability constants to be comparable to those of the dtpa complexes. The efficacy of L' in binding Ga3+ and In3+ under physiological conditions is discussed by comparing pM values at pH 7.4, showing that this compound can withstand the competition of transferrin for In3+ in biological media relevant to medical applications. The 13C and l H NMR shifts were measured for the complexes of A13+, Ga3+, In3+ and Y3+ with L1 and compared with 13C shifts for the dtpa complexes. The complexes of A13+ and Ga3+ are hexadentate, possibly of octahedral geometry, and form various structural isomers, whereas those of In3+ and Y3+, with a single structural isomer of eight-co-ordination, are very similar to the lanthanide complexes. The complexes of A13+ and Ga3+ of L1 have considerable populations of isomers with bound amide groups, whereas the single structural isomer of the complexes of In3+ and Y3+ with both amide groups co-ordinated yield a variety of enantiomers in solution. studies on complexes of La3+ and Lu3+ with the corresponding bis(propy1amide) H3L2,22*23 as well as with our studies and literature data on complexes of A13+, G a 3 + , In3+, Y 3 + , La3+ and Lu3+ with dtpa.'9,25*30 ExperimentalReagents.-All chemicals were of analytical grade, used as received unless specifically noted, and obtained from the following sources: diethylenetriaminepentacetic acid dianhydride, pentasodium and di-sodium or -potassium salts of H,dtpa (Sigma); butylamine, aluminium nitrate hydrate, gallium nitrate hydrate, indium nitrate pentahydrate, yttrium chloride (Aldrich); solvents (Prolabo). Other materials are cited under specific sections.Synthesis and Characterization of the N,N "-Bis(buty1amide) of H,dtpa, H3L'.-Butylamine (0.327 cm3, 3 mmol) was added dropwise with stirring to a solution of diethylenetriaminepentaacetic acid dianhydride (0.536 g, 1.5 mmol) in dry dimethylformamide (50 cm3, 40 "C). The colourless reaction mixture was stirred (4OoC, 1 h) and filtered. Chloroform (50 cm3) was added and, after cooling at 4 "C for 2 h, the white solid was filtered off, washed with diethyl ether (100 cm3) and dried at 40 "C overnight. The compound was recrystallized, from hot ethanol-hexane (1 10: 110 cm3), after cooling at 4 "C overnight. The white crystals were filtered off, washed with acetone (10 cm3) and diethyl ether (10 cm3) and dried overnight at 40 "C.

153Sm3+ and 111In3+ DTPA derivatives with high hepatic specificity: in vivo and in vitro studies

“…2c) In -L and Sm -L give, at pH 7, an octanol / intensities for each proton. This is in agreement with 1 1 31 water log P value of 21.65 and 21.15, indicating a low previous studies of In -DTPA-bis(amides) [18]. 31 lipophilicity for these complexes.…”

“…They are main factor determining the excretion pathway of a sharp but quite different, indicating structural differences. three aromatic groups in its chelates, but this value was [15][16][17][18] ture for each type of proton. The chirality in the benzyloxIn -L and 97% for In -L .…”

Lanthanide(III) Chelates of DTPA Bis(amide) Glycoconjugates: Potential Imaging Agents Targeted at the Asyaloglycoprotein Receptor

“…[36,39] With this assumption, the minimum of seven low-frequency-shifted resonances observed for the Sm III complex at high temperature (Figure 3), resulting from two ethylenic protons, confirms that several of the four possible isomers are present in solution. This is also in agreement with the observation of a mini-mum of ten high-frequency-shifted resonances in the Eu III complex at high temperature (out of a maximum of sixteen) for these two ethylenic protons (Figure 4) [35,41] show the presence of four diastereoisomeric pairs, while for bis-(amides) containing long (C 14 to C 18 ) aliphatic chains only two pairs have been detected in solution. [42] Water Proton Relaxation (NMRD) Studies of Gd IIIDTPALac 2 The efficiency of a contrast agent is given by its proton relaxivity, defined as the paramagnetic enhancement of the longitudinal water proton relaxation rate at a concentration of 1 mm (r 1 , in s -1 mm -1 ).…”

Synthesis, Characterization, and Relaxivity of Two Linear Gd(DTPA)−Polymer Conjugates

“…In the DTPA-HMD polymer only a single set of broad signals was observed, which can be explained by the fast exchange between the isomers on the NMR time scale. Figure 4 shows the proton decoupled 13 C NMR spectra of the two polymers, which were assigned on the basis of the pH dependence of their chemical shifts and previous work on small DTPA-bisamides (34). For the DTPA-CHD polymer, we see two sets of resonances for carbons a-f.…”