Ernö Brücher

Kinetic Stabilities of Gadolinium(III) Chelates Used as MRI Contrast Agents

Equilibrium calculations indicate that the Gd3+ chelates used as contrast agents in MRI may partly dissociate in the body fluids. However, the results of the kinetic studies point to the proton, Cu2+ and Zn2+ assisted dissociation of Gd3+ complexes being slow at pH > 5. The excretion of these contrast agents from the body is relatively fast so that the system is far from the equilibrium and the extent of in vivo dissociation is very low.

EQUILIBRIUM AND KINETIC STUDIES ON COMPLEXES OF 10-2,3-DIHYDROXY-(1-HYDROXYMETHYL)-PROPYL-1,4,7,10-TETRAAZACYCLODODECANE-1,4,7-TRIACETATE

Complexation properties of the ligand 10-[2,3-dihydroxy-(1-hydroxymethyl)-propyl]-1,4,7,10-tetraazacyclododecane-1,4,7-triacetatic acid (DO3A-B) were studied and compared with those of 10-(2-hydroxypropyl)-1,4,7,10-tetraazacyclododecane-1,4,7-triacetic acid (HP-DO3A) and 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA). The protonation constants of DO3A-B (KiH) and the stability constants (K) of the complexes formed with Ca2+, Sr2+, Ba2+, Zn2+, Cu2+, Fe3+, Ce3+, Nd3+, Eu3+, Gd3+, Dy3+, Tm3+ and Lu3+ were determined in different media (I = 0.1 M; 25°C). The first protonation constants (log K1H) in Me4NCl, KCl and NaCl were found to be 11.75, 11.27 and 9.46, respectively, indicating the formation of Na+ and weaker K+ complexes. The complexes of lanthanides, alkaline earths and Zn2+ form slowly and the complexation equilibria could be studied by means of an out-of-cell technique. The stabilities of the complexes Ln(DO3A-B) increase from La to Eu while the log K values are practically constant for the heavier lanthanides. The stability constants of the DO3A-B complexes of Ce, Gd and Lu are 1–2 orders of magnitude lower than those of the HP-DO3A complexes. The coordinated alcoholic hydroxy groups dissociate at relatively low pH. The dissociation constant (Kd) obtained pH-metrically for Gd(DO3A-B) (pKd=9.48) is about 100 times higher than that for Gd(HP-DO3A) (pKd=11.36), indicating the higher basicity of the alcoholic oxygen in HP-DO3A, which may contribute to the larger stability constants of the complexes formed with HP-DO3A. The kinetic stability of the complexes Gd(DO3A-B) and Gd(HP-DO3A) were studied by spectrophotometry in the pH range 3.2–5.3 by following the exchange reactions between the complexes and Eu3+. The rates of the exchange reactions proved to be linearly proportional to the H+ concentration. This was interpreted in terms of the rate-determining role of the rearrangement and dissociation of the monoprotonated complexes. The rate constants obtained for the proton-assisted dissociation of Gd(DO3A-B) and Gd(HP-DO3A) were (2.8 ± 0.1) × 10−5 and (2.6 ± 0.1) × 10−4 M−1 s−1, respectively.

Stability constants of the lanthanide(III)-1,4,7,10-tetraazacyclododecane-N,N′,N″,N‴-tetraacetate complexes

Abstract The stability constants of the LnDOTA - complexes have been determined by spectrophotometry at 37 °C in 1.0 M NaCl. The log K values of CeDOTA − and EuDOTA − were obtained by a direct method using the UV absorption of Ce 3+ and Eu 3+ . For the other lanthanides log K values were obtained from the study of the competition reaction between the Ln 3+ ion and the Ce 3+ or Eu 3+ ion for DOTA. The stability constants increase with the decrease in the ionic size between La 3+ and Eu 3+ , while for the heavier lanthanides the log K values are practically constant.

Solution Structures, Stabilities, Kinetics, and Dynamics of DO3A and DO3A−Sulphonamide Complexes

The Gd(3+)-DO3A-arylsulphonamide (DO3A-SA) complex is a promising pH-sensitive MRI agent. The stability constants of the DO3A-SA and DO3A complexes formed with Mg(2+), Ca(2+), Mn(2+), Zn(2+), and Cu(2+) ions are similar, whereas the logKLnL values of Ln(DO3A-SA) complexes are 2 orders of magnitude higher than those of the Ln(DO3A) complexes. The protonation constant (log KMHL) of the sulphonamide nitrogen in the Mg(2+), Ca(2+), Mn(2+), Zn(2+), and Cu(2+) complexes is very similar to that of the free ligand, whereas the logKLnHL values of the Ln(DO3A-SA) complexes are lower by about 4 logK units, indicating a strong interaction between the Ln(3+) ions and the sulphonamide N atom. The Ln(HDO3A-SA) complexes are formed via triprotonated *Ln(H3DO3A-SA) intermediates which rearrange to the final complex in an OH(-)-assisted deprotonation process. The transmetalation reaction of Gd(HDO3A-SA) with Cu(2+) is very slow (t1/2 = 5.6 × 10(3) h at pH = 7.4), and it mainly occurs through proton-assisted dissociation of the complex. The (1)H and (13)C NMR spectra of the La-, Eu-, Y-, and Lu(DO3A-SA) complexes have been assigned using 2D correlation spectroscopy (COSY, EXSY, HSQC). Two sets of signals are observed for Eu-, Y-, and Lu(DO3A-SA), showing two coordination isomers in solution, that is, square antiprismatic (SAP) and twisted square antiprismatic (TSAP) geometries with ratios of 86-14, 93-7, and 94-6%, respectively. Line shape analysis of the (13)C NMR spectra of La-, Y- , and Lu(DO3A-SA) gives higher rates and lower activation entropy values compared to Ln(DOTA) for the arm rotation, which indicates that the Ln(DO3A-SA) complexes are less rigid due to the larger flexibility of the ethylene group in the sulphonamide pendant arm. The fast isomerization and the lower activation parameters of Ln(DO3A-SA) have been confirmed by theoretical calculations in vacuo and by using the polarizable continuum model. The solid state X-ray structure of Cu(H2DO3A-SA) shows distorted octahedral coordination. The coordination sites of Cu(2+) are occupied by two ring N- and two carboxylate O-atoms in equatorial position. The other two ring N-atoms complete the coordination sphere in axial positions. The solid state structure also indicates that a carboxylate O atom and the sulphonamide nitrogen are protonated and noncoordinated.

NMR and potentiometric studies of 1,4,7-triazacyclononane-N,N′,N″-tris(methylenephosphonate monoethylester) and its complexes with metal ions

Abstract 1,4,7-Triazacyclononane- N , N ′, N ″-tris(methylene-phosphonate monoethylester) (NOTPME) and its complexes with the trivalent lanthanide cations and divalent calcium, magnesium, zinc and cadmium have been examined by potentiometry and NMR. The 31 P NMR spectra of the lanthanide-NOTPME complexes show single resonances characteristic of symmetrical chelated species at low concentrations (below 0.1 mM) but multiple resonances at higher concentrations. This tendency of the neutral complexes to form unsymmetrical, perhaps oligomeric, species is dependent upon the size of the Ln 3+ and the solution pH. The alkaline earth and divalent transition metal cation complexes do not show this same behavior. The stability constants of the Ln(NOTPME) complexes were found to be considerably smaller than their respective Ln(NOTA) complexes.

Equilibrium study of the systems of aluminium(III), gallium(III) and indium(III) with mercaptoacetate, 3-mercaptopropionate and 2-mercaptobenzoate

Abstract Equilibrium studies were carried out by pH-potentiometry on the systems of aluminium(III), gallium(III) and indium(III) with mercaptoacetate (MerAc2−), 3-mercaptopropionate (MerPr2−) and 2-mercaptobenzoate (MerBe2−). It was found that the complex-forming properties of the Al3+ ion towards these mercaptocarboxylic acid ligands differ from those of Ga3+ and Al3+. Under the conditions of the study, Al3+ forms only hydroxo complexes, while Ga3+ and In3+ form relatively stable complexes involving the simultaneous coordination of the carboxylate and the deprotonated mercapto group. In all cases the equilibrium systems can be described without the assumption of polynuclear complexes. The complexes Ga(MerAc)2 and Ga(MerBe)2 show marked stability; this was interpreted in terms of back-coordination and of interaction between the d10 electrons of the Ga3+ ion and the empty d orbitals of the S donor atom. Complexes of composition MLi are not formed in the Ga3+-MerPr2− system; this points to the importan roles of the number of atoms in the chelate ring and the higher stability of the Ga(III)-hydroxo complexes.

TUNING WATER-EXCHANGE RATES ON (CARBOXYMETHYL)IMINOBIS-(ETHYLENENITRILO)TETRAACETATE (DTPA)-TYPE GADOLINIUM(III) COMPLEXES

A variable-temperature and -pressure, multiple-field 17 O NMR study has been performed on the gadolinium(III) complexes of an ethoxybenzyl (L 1 ) and symmetric (L 2 ) and asymmetric (L 3 ) mono(methylamide) derivatives of (carboxymethyl)iminobis(ethylenenitrilo)tetraacetate (dtpa) in order to study water exchange and rotational dynamics. Electronic relaxation parameters were obtained from EPR measurements. The water-exchange rates on the [GdL 2 (H 2 O)] - and [GdL 3 (H 2 O)] - complexes [k ex 298 = (1.9 ± 0.1) × 10 6 and (1.3 ± 0.1) × 10 6 s -1 ] are smaller than that observed for [Gd(dtpa)(H 2 O)] 2- ; that of the ethoxybenzyl derivative [GdL 1 (H 2 O)] - is k ex 298 = (3.6 ± 0.1) × 10 6 s -1 . High positive activation volumes have been obtained for all three complexes studied (ΔV ‡ = 10.6 –12.7 cm 3 mol -1 ), indicating dissociatively activated water exchange. As a general rule, when amide groups substitute for carboxylates in gadolinium(III) polyaminopolycarboxylate complexes, the water-exchange rate is decreased by about a factor of 4 per substituted carboxylate, but the mechanism of the process is not affected. However, no influence on the water exchange is observed as a result of the introduction of large groups on the carbon backbone of the ligand, outside the first co-ordination sphere.

Equilibrium and NMR studies on GdIII, YIII, CuII and ZnII complexes of various DTPA–N,N″-bis(amide) ligands. Kinetic stabilities of the gadolinium(III) complexes

Three DTPA-derivative ligands, the non-substituted DTPA-bis(amide) (L(0)), the mono-substituted DTPA-bis(n-butylamide) (L(1)) and the di-substituted DTPA-bis[bis(n-butylamide)] (L(2)) were synthesized. The stability constants of their Gd3+ complexes (GdL) have been determined by pH-potentiometry with the use of EDTA or DTPA as competing ligands. The endogenous Cu2+ and Zn2+ ions form ML, MHL and M(2)L species. For the complexes CuL(0) and CuL(1) the dissociation of the amide hydrogens (CuLH(-1)) has also been detected. The stability constants of complexes formed with Gd3+, Cu2+ and Zn2+ increase with an increase in the number of butyl substituents in the order ML(0) < ML(1) < ML(2). NMR studies of the diamagnetic YL(0) show the presence of four diastereomers formed by changing the chirality of the terminal nitrogens of their enantiomers. At 323 K, the enantiomerization process, involving the racemization of central nitrogen, falls into the fast exchange range. By the assignment and interpretation of 1H and 13C NMR spectra, the fractions of the diastereomers were found to be equal at pH = 5.8 for YL(0). The kinetic stabilities of GdL(0), GdL(1) and GdL(2) have been characterized by the rates of the exchange reactions occurring between the complexes and Eu3+, Cu2+ or Zn2+. The rates of reaction with Eu3+ are independent of the [Eu3+] and increase with increasing [H+], indicating the rate determining role of the proton assisted dissociation of complexes. The rates of reaction with Cu2+ and Zn2+ increase with rising metal ion concentration, which shows that the exchange can take place with direct attack of Cu2+ or Zn2+ on the complex, via the formation of a dinuclear intermediate. The rates of the proton, Cu2+ and Zn2+ assisted dissociation of Gd3+ complexes decrease with increasing number of the n-butyl substituents, which is presumably the result of steric hindrance hampering the formation or dissociation of the intermediates. The kinetic stabilities of GdL(0) and GdL(1) at pH = 7.4, [Cu2+] = 1 x 10(-6) M and [Zn(2+)] = 1 x 10(-5) M are similar to that of Gd(DTPA)2-, while the complex GdL2 possesses a much higher kinetic stability.

Gd3+ chelates of interest in magnetic resonance imaging (MRI): studies using 17O NMR and EPR at several magnetic fields

Abstract The combination of 17 O NMR relaxation rate and chemical shift measurements and EPR linewidth measurements at several magnetic fields provides a powerful probe of water exchange, rotational dynamics and electronic relaxation in aqueous solutions of Gd 3+ complexes. This information is important for the understanding of the proton relaxivity of the complexes. Variable pressure measurements show a change of water exchange mechanism from associatively activated on [Gd(H 2 O) 8 ] 3+ and [Gd(PDTA)(H 2 O) 2 ] − to probably limiting dissociative on the MRI contrast agents [Gd(DTPA)(H 2 O)] 2− , [Gd(DOTA)(H 2 O)] and [Gd(DTPA-BMA)(H 2 )O)]. This leads to relatively slow water exchange rates on the latter three complexes. For [Gd(DTPA-BMA)(H 2 O)], the exchange rate is sufficiently slow to have an effect on the inner sphere proton relaxivity, and hence on the interpretation of NMRD profiles.

NOTPME: A 31P NMR probe for measurementof divalent cations in biological systems

1, 4, 7‐Triazacyclononame‐N, N′,N′‐tris(methylenephosphonate monoethylester) (NOTPME) has been synthesized, characterized and analyzed for use as a 31P NMR indicator of intracellular Mg2+ and Zn2+ ions. The 31P NMR spectrum of this chelate in the presence of metal ions shows characteristics resonances for the free chelate, Mg(NOTPME)−, Zn(NOTPME)− and Ca(NOTPME)−. The K ??? values indicate that this chelate has a 10‐fold higher affinity for Mg2+ than for Ca2+ at physiological pH values. In the presence of Mg2+, NOTPME is readily loaded into red blood cells. A 31P NMR spectrum of red cells taken after several washing shows resonances characteristics of entrapped NOTPME and the Mg(NOTPME)− complex, the relative areas of which report an intracellular free Mg2+ concentration of 0.32 mM. The 31P chemical shifts of the free chelate and its metal complexes are far downfield from the typical phosphorus‐containing metabolites observed in biological systems, thus making it possible to monitor intracellular cation concentration and cell energetics simultaneously.