Lanthanide Chelates Containing Pyridine Units with Potential Application as Contrast Agents in Magnetic Resonance Imaging

Abstract

A new pyridine-containing ligand, N,N'-bis(6-carboxy-2-pyridylmethyl)ethylenediamine-N,N'-diacetic acid (H(4)L), has been designed for the complexation of lanthanide ions. (1)H and (13)C NMR studies in D(2)O solutions show octadentate binding of the ligand to the Ln(III) ions through the nitrogen atoms of two amine groups, the oxygen atoms of four carboxylates, and the two nitrogen atoms of the pyridine rings. Luminescence measurements demonstrate that both Eu(III) and Tb(III) complexes are nine-coordinate, whereby a water molecule completes the Ln(III) coordination sphere. Ligand L can sensitize both the Eu(III) and Tb(III) luminescence; however, the quantum yields of the Eu(III)- and Tb(III)-centered luminescence remain modest. This is explained in terms of energy differences between the singlet and triplet states on the one hand, and between the 0-phonon transition of the triplet state and the excited metal ion states on the other. The anionic [Ln(L)(H2O)]- complexes (Ln=La, Pr, and Gd) were also characterized by theoretical calculations both in vacuo and in aqueous solution (PCM model) at the HF level by means of the 3-21G* basis set for the ligand atoms and a 46+4 f(n) effective core potential for the lanthanides. The structures obtained from these theoretical calculations are in very good agreement with the experimental solution structures, as demonstrated by paramagnetic NMR measurements (lanthanide-induced shifts and relaxation-rate enhancements). Data sets obtained from variable-temperature (17)O NMR at 7.05 T and variable-temperature (1)H nuclear magnetic relaxation dispersion (NMRD) on the Gd(III) complex were fitted simultaneously to give insight into the parameters that govern the water (1)H relaxivity. The water exchange rate (k(298)(ex)=5.0 x 10(6) s(-1)) is slightly faster than in [Gd(dota)(H2O)]- (DOTA=1,4,7,10-tetrakis(carboxymethyl)-1,4,7,10-tetraazacyclododecane). Fast rotation limits the relaxivity under the usual MRI conditions.

H4octapa: Highly Stable Complexation of Lanthanide(III) Ions and Copper(II)

“…This is consistent with the relaxivity value published earlier for this complex, 7 as well as with its X-ray crystal structure. 8 The stability constant determined using this method (Table 2) showed a large discrepancy with the value reported previously by Chatterton et al 8 Thus, the stability constant of the [Gd(octapa)]…”

“…The ligand was isolated with an overall yield of 59% over the two steps, which represents an important improvement with respect to the previously reported procedure in which the alkylation reaction was conducted in refluxing acetonitrile (21%). 7 The use of milder alkylation conditions requires longer reaction times (several days), but improves considerably the yield of the reaction most likely minimizing the formation of lactams and quaternary ammonium salts as a result of polyalkylation. A recent synthesis of H 4 octapa reported by Orvig starting from tert-butyl ester derivative of 1 proceeded with an overall yield of 71%.…”

“…The stability constants determined for the complexes with La 3+ , Gd 3+ , and Lu 3+ using relaxometric methods are log K LaL = 20.13 (7), log K GdL = 20.23 (4), and log K LuL = 20.49(5) (I = 0.15 M NaCl). High stability constants were also determined for the complexes formed with divalent metal ions such as Zn 2+ and Cu 2+ (log K ZnL = 18.91(3) and log K CuL = 22.08(2)).…”

Structure, Stability, Dynamics, High‐Field Relaxivity and Ternary‐Complex Formation of a New Tris(aquo) Gadolinium Complex

“…Assume that pÀ1 complexes (1 p n) are bound to B at the different sites i 1 , i 2 , …, i pÀ1 (1 i 1 n, …, 1 i pÀ1 n) to form the definite (pÀ1)-adduct B(i 1 ,…,i pÀ1 )C pÀ1 . The binding of another complex C at a vacant site i p of B to form the definite p-adduct B(i 1 , …, i p )C p satisfies the formation equilibrium defined by Equation (27):…”

Synthetic Approaches to Heterocyclic Ligands for Gd-Based MRI Contrast Agents

“…Reaction of 9 with 2,2-dimethoxyacetaldehyde in the presence of NaBH 3 CN, followed by treatment in acidic medium yielded compound 11, which by condensation with 9 or 10 under the mentioned conditions and subsequent basic hydrolysis, afforded the chelating ligands 7 and 8. Pyridine derivatives 12a-c, also based on ethylendiamine backbone, were recently reported by Platas-Iglesias et al (Scheme 2) [16]. Compounds 12a-c were synthesized from 2,6-pyridinedicarboxylic acid dimethyl ester by reduction of one of the ester groups using NaBH 4 in MeOH, followed by oxidation of the corresponding alcohol yielding compound 13.…”