Log KGdL Research Articles

A novel Gd3+ DTPA-bisamide complex with high relaxivity as an MRI contrast agent.

A novel Gd(III) complex-based magnetic resonance imaging (MRI) contrast agent GdL has been designed and synthesized, which exhibited a much higher relaxivity (7.8 mM-1 s-1) than the commercially used Magnevist® (3.5 mM-1 s-1), good water solubility (>100 mg mL-1), excellent thermodynamic stability (log KGdL = 17.21 ± 0.27), high biosafety and biocompatibility. In particular, the relaxivity of GdL increased to 26.7 mM-1 s-1 in a 4.5% bovine serum albumin (BSA) solution at 1.5 T, which was not significant in other commercial MRI contrast agents. The interaction sites and interaction types of GdL and BSA were further demonstrated by molecular docking simulations. Furthermore, the in vivo MRI behaviour was evaluated by using a 4T1 tumour-bearing mouse model. These results suggested that GdL is an excellent T1-weighted MRI contrast agent and has the potential to be applied in clinical diagnosis.

Underlining the Importance of Peripheral Protic Functional Groups to Enhance the Proton Exchange of Gd-Based MRI Contrast Agents

In this study, we report the synthesis and the equilibrium, kinetic, relaxation, and structural properties of two new GdIII complexes based on modified 10-(2-hydroxypropyl)-1,4,7,10-tetraazacyclododecane-1,4,7-triacetic acid (HPDO3A) designed to modulate the relaxivity at acidic and basic pH due to intra- and intermolecular proton exchange. The presence of a carboxylic or ester moieties in place of the methyl group of HPDO3A allowed differentiation of a protic and nonprotic functional group, highlighting the importance of the formation of an intramolecular hydrogen bond between the coordinated hydroxyl and the carboxylate groups for proton exchange (kH = 1.5 × 1011 M–1 s–1, kOH = 1.7 × 109 M–1 s–1). The determination of the thermodynamic stability and kinetic inertness of the GdIII complexes confirmed that the modification of peripheral groups does not significantly affect the coordination environment and thus the stability (log KGdL = 19.26, t1/2 = 2.14 × 107 hours, pH = 7.4, 0.15 M NaCl, 25 °C). The relaxivity (r1) was measured as a function of pH to investigate the proton exchange kinetics, and as a function of the magnetic field strength to extrapolate the relaxometric parameters (r1GdL1 = 4.7 mM–1 s–1 and r1GdL2 = 5.1 mM–1 s–1 at 20 MHz, 25 °C, and pH 7.4). Finally, the X-ray crystal structure of the complex crystallized at basic pH showed the formation of a tetranuclear dimer with alkoxide and hydroxide groups bridging the GdIII ions.

Pyclen-Based Ligands Bearing Pendant Picolinate Arms for Gadolinium Complexation.

We report the synthesis of two pyclen-based regioisomer ligands (pyclen = 3,6,9,15-tetraazabicyclo[9.3.1]pentadeca-1(15),11,13-triene) functionalized with picolinic acid pendant arms either at positions 3,9-pc2pa (L5) or 3,6-pc2pa (L6) of the macrocyclic fragment. The ligands were prepared by the regiospecific protection of one of the amine nitrogen atoms of the macrocycle using Boc and Alloc protecting groups, respectively. The X-ray structure of the Gd(III) complex of L5 contains trinuclear [(GdL5)3(H2O)3]3+ entities in which the monomeric units are joined by μ2-η1:η1-carboxylate groups. However, the 1H and 89Y NMR spectra of its Y(III) analogue support the formation of monomeric complexes in solution. The Tb(III) complexes are highly luminescent, with emission quantum yields of up to 28% for [TbL5]+. The luminescence lifetimes recorded in H2O and D2O solutions indicate the presence of a water molecule coordinated to the metal ion, as also evidenced by the 1H relaxivities measured for the Gd(III) analogues. The Gd(III) complexes present very different exchange rates of the coordinated water molecule (kex298 = 87.1 × 106 and 1.06 × 106 s-1 for [GdL5]+ and [GdL6]+, respectively). The very high water exchange rate of [GdL5]+ is associated with the steric hindrance originating from the coordination of the ligand around the water binding site, which favors a dissociatively activated water exchange process. The Gd(III) complexes present rather high thermodynamic stabilities (log KGdL = 20.47 and 19.77 for [GdL5]+ and [GdL6]+, respectively). Furthermore, these complexes are remarkably inert with respect to their acid-assisted dissociation, in particular the complex of L5.

Unexpected Trends in the Stability and Dissociation Kinetics of Lanthanide(III) Complexes with Cyclen-Based Ligands across the Lanthanide Series.

We report a detailed study of the thermodynamic stability and dissociation kinetics of lanthanide complexes with two ligands containing a cyclen unit, a methyl group, a picolinate arm, and two acetate pendant arms linked to two nitrogen atoms of the macrocycle in either cis (1,4-H3DO2APA) or trans (1,7-H3DO2APA) positions. The stability constants of the Gd3+ complexes with these two ligands are very similar, with log KGdL values of 16.98 and 16.33 for the complexes of 1,4-H3DO2APA and 1,7-H3DO2APA, respectively. The stability constants of complexes with 1,4-H3DO2APA follow the usual trend, increasing from log KLaL = 15.96 to log KLuL = 19.21. However, the stability of [Ln(1,7-DO2APA)] complexes decreases from log K = 16.33 for Gd3+ to 14.24 for Lu3+. The acid-catalyzed dissociation rates of the Gd3+ complexes differ by a factor of ∼15, with rate constants (k1) of 1.42 and 23.5 M-1 s-1 for [Gd(1,4-DO2APA)] and [Gd(1,7-DO2APA)], respectively. This difference is magnified across the lanthanide series to reach a 5 orders of magnitude higher k1 for [Yb(1,7-DO2APA)] (1475 M-1 s-1) than for [Yb(1,4-DO2APA)] (5.79 × 10-3 M-1 s-1). The acid-catalyzed mechanism involves the protonation of a carboxylate group, followed by a cascade of proton-transfer events that result in the protonation of a nitrogen atom of the cyclen unit. Density functional theory calculations suggest a correlation between the strength of the Ln-Ocarboxylate bonds and the kinetic inertness of the complex, with stronger bonds providing more inert complexes. The 1H NMR resonance of the coordinated water molecule in the [Yb(1,7-DO2APA)] complex at 176 ppm provides a sizable chemical exchange saturation transfer effect thanks to a slow water exchange rate of (15.9 ± 1.6) × 103 s-1.

Gadolinium Complexes of Highly Rigid, Open-Chain Ligands Containing a Cyclobutane Ring in the Backbone: Decreasing Ligand Denticity Might Enhance Kinetic Inertness.

In an effort to explore novel ligand scaffolds for stable and inert lanthanide complexation in magnetic resonance imaging contrast agent research, three chiral ligands containing a highly rigid (1S,2S)-1,2-cyclobutanediamine spacer and different number of acetate and picolinate groups were efficiently synthesized. Potentiometric studies show comparable thermodynamic stability for the Gd3+ complexes formed with either the octadentate (L3)4- bearing two acetate or two picolinate groups or the heptadentate (L2)4- analogue bearing one picolinate and three acetate groups (log KGdL = 17.41 and 18.00 for [Gd(L2)]- and [Gd(L3)]-, respectively). In contrast, their dissociation kinetics is revealed to be very different: the monohydrated [Gd(L3)]- is considerably more labile, as a result of the significant kinetic activity of the protonated picolinate function, as compared to the bishydrated [Gd(L2)]-. This constitutes an uncommon example in which lowering ligand denticity results in a remarkable increase in kinetic inertness. Another interesting observation is that the rigid ligand backbone induces an unusually strong contribution of the spontaneous dissociation to the overall decomplexation process. Thanks to the presence of two inner-sphere water molecules, [Gd(L2)]- is endowed with high relaxivity (r1 = 7.9 mM-1 s-1 at 20 MHz, 25 °C), which is retained in the presence of large excess of endogenous anions, excluding ternary complex formation. The water exchange rate is similar for [Gd(L3)]- and [Gd(L2)]-, while it is 1 order of magnitude higher for the trishydrated tetraacetate analogue [Gd(L1)]- (kex298 = 8.1, 10, and 127 × 106 s-1, respectively). A structural analysis via density functional theory calculations suggests that the large bite angle imposed by the rigid (1S,2S)-1,2-cyclobutanediamine spacer could allow the design of ligands based on this scaffold with suitable properties for the coordination of larger metal ions with biomedical applications.

Effect of Ligand Chirality and Hyperconjugation on the Thermodynamic Stability of a Tris(aquated) GdIII Complex: Synthesis, Characterization, and T1‐Weighted Phantom MR Image Study

The hexadentate chiral alanine‐based ligand, Li3cbda, in a reaction with hydrated GdCl3 at pH ~ 6.5 provided the corresponding nine‐coordinated, neutral GdIII complex (1). The hydration state (q) of complex 1 was 3.1 ± 0.1, as determined by luminescence decay time measurements of TbIII congener in H2O and D2O. Complex 1 exhibited thermodynamic stability, log KGdL = 14.64 in 0.15 m NaCl solution at 25 °C. At 1.41 T, pH ≈ 7.4, and 25 °C, the complex offered longitudinal relaxivity, r1 = 10.95 mm–1 s–1, which was in accordance with three inner‐sphere water molecules. While, the relaxivity value remained unaffected in the pH range of 4.0 to 7.4, under basic conditions (pH ≥ 10) a reduction in the relaxivity value to 6.68 mm–1 s–1 was observed. A similar phenomenon was also realized in the presence of endogenous anions (100 equivalents of F– and HCO3–), which implied the removal of coordinated‐water molecules under the conditions. Phantom MR imaging under the clinical scanner at 1.5 T showed the enhancement in the image intensity with increasing concentration of the complex. As expected, the image intensity of 1 mm complex 1 was about three times compared to 1 mm MultiHance® solution.

Expanding the Family of Pyclen-Based Ligands Bearing Pendant Picolinate Arms for Lanthanide Complexation.

We report a detailed characterization of lanthanide complexes with two azaligands based on the pyclen macrocycle containing two picolinate and one acetate pendant arms. The two picolinate arms are attached to either opposite (L3) or adjacent (L4) amine nitrogen atoms of the macrocyclic platform. The X-ray structures of the Yb3+ complexes show nine coordination of the ligand to the metal ion, a situation that is also observed for EuL4 in the solid state. The EuL3 complex forms centrosymmetric dimers in the solid state joined by μ2-η1:η1 carboxylate groups, which results in 10-coordinate Eu3+ ions. The emission spectra of EuL3 measured in H2O and D2O solution reveal the presence of a hydration equilibrium involving a nine-coordinate species lacking inner-sphere water molecules and a monohydrated 10-coordinate species. The Eu3+ complexes present modest emission quantum yields in buffered aqueous solution (Φ = 16 and 22% for EuL3 and EuL4, 0.1 M tris buffer, pH 7.4), while the corresponding Tb3+ complexes present very high emission quantum yields under the same conditions (∼90%). 1H NMR studies show that the complexes of L3 present a fluxional behavior in D2O solution, while those of L4 are more rigid. The analysis of the Yb3+-induced NMR shifts of YbL4 indicates that the complex presents a structure in solution similar to that observed in the solid state. The Gd3+ complexes present very high thermodynamic stability constants (log KGdL = 23.56(2) and 23.44(2) for GdL3 and GdL4, respectively). The corresponding pGd values (pGd = -log[Gd3+]free with cL = 1 × 10-5 M and cGd = 1 × 10-6 at pH 7.4) of 20.69 (GdL3) and 21.83 (GdL4) are higher than that of Gd(dota)- (pGd = 19.21). The Gd3+ complexes also show remarkable inertness with respect to their proton-assisted dissociation, with dissociation half-life times of 50 min (GdL3) and 20 h (GdL4) in 1 M HCl.

Coordination Properties of GdDO3A-Based Model Compounds of Bioresponsive MRI Contrast Agents.

We report a detailed characterization of the thermodynamic stability and dissociation kinetics of Gd3+ complexes with DO3A derivatives containing a (methylethylcarbamoylmethylamino)acetic acid (L1), (methylpropylcarbamoylmethylamino)acetic acid (L2), 2-dimethylamino- N-ethylacetamide (L3), or 2-dimethylamino- N-propylacetamide (L4) group attached to the fourth nitrogen atom of the macrocyclic unit. These ligands are model systems of Ca2+- and Zn2+-responsive contrast agents (CA) for application in magnetic resonance imaging (MRI). The results of the potentiometric studies ( I = 0.15 M NaCl) provide stability constants with log KGdL values in the range 13.9-14.8. The complex speciation in solution was found to be quite complicated due to the formation of protonated species at low pH, hydroxido complexes at high pH, and stable dinuclear complexes in the case of L1,2. At neutral pH significant fractions of the complexes are protonated at the amine group of the amide side chain (log KGdL×H = 7.2-8.1). These ligands form rather weak complexes with Mg2+ and Ca2+ but very stable complexes with Cu2+ (log KCuL = 20.4-22.3) and Zn2+ (log KZnL = 15.5-17.6). Structural studies using a combination of 1H NMR and luminescence spectroscopy show that the amide group of the ligand is coordinated to the metal ion at pH ∼8.5, while protonation of the amine group provokes the decoordination of the amide O atom and a concomitant increase in the hydration number and proton relaxivity. The dissociation of the complexes occurs mainly through a rather efficient proton-assisted pathway, which results in kinetic inertness comparable to that of nonmacrocyclic ligands such as DTPA rather than DOTA-like complexes.

Approaching the Kinetic Inertness of Macrocyclic Gadolinium(III)-Based MRI Contrast Agents with Highly Rigid Open-Chain Derivatives.

A highly rigid open-chain octadentate ligand (H4 cddadpa) containing a diaminocylohexane unit to replace the ethylenediamine bridge of 6,6'-[(ethane-1,2 diylbis{(carboxymethyl)azanediyl})bis(methylene)]dipicolinic acid (H4 octapa) was synthesized. This structural modification improves the thermodynamic stability of the Gd(3+) complex slightly (log KGdL =20.68 vs. 20.23 for [Gd(octapa)](-) ) while other MRI-relevant parameters remain unaffected (one coordinated water molecule; relaxivity r1 =5.73 mm(-1) s(-1) at 20 MHz and 295 K). Kinetic inertness is improved by the rigidifying effect of the diaminocylohexane unit in the ligand skeleton (half-life of dissociation for physiological conditions is 6 orders of magnitude higher for [Gd(cddadpa)](-) (t1/2 =1.49×10(5) h) than for [Gd(octapa)](-) . The kinetic inertness of this novel chelate is superior by 2-3 orders of magnitude compared to non-macrocyclic MRI contrast agents approved for clinical use.

H4octapa: highly stable complexation of lanthanide(III) ions and copper(II).

The acyclic ligand octapa(4-) (H4octapa = 6,6'-((ethane-1,2-diylbis((carboxymethyl)azanediyl))bis(methylene))dipicolinic acid) forms stable complexes with the Ln(3+) ions in aqueous solution. The stability constants determined for the complexes with La(3+), Gd(3+), and Lu(3+) using relaxometric methods are log KLaL = 20.13(7), log KGdL = 20.23(4), and log KLuL = 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 KZnL = 18.91(3) and log KCuL = 22.08(2)). UV-visible and NMR spectroscopic studies and density functional theory (DFT) calculations point to hexadentate binding of the ligand to Zn(2+) and Cu(2+), the donor atoms of the acetate groups of the ligand remaining uncoordinated. The complexes formed with the Ln(3+) ions are nine-coordinated thanks to the octadentate binding of the ligand and the presence of a coordinated water molecule. The stability constants of the complexes formed with the Ln(3+) ions do not change significantly across the lanthanide series. A DFT investigation shows that this is the result of a subtle balance between the increased binding energies across the 4f period, which contribute to an increasing complex stability, and the parallel increase of the absolute values of the hydration free energies of the Ln(3+) ions. In the case of the [Ln(octapa)(H2O)](-) complexes the interaction between the amine nitrogen atoms of the ligand and the Ln(3+) ions is weakened along the lanthanide series, and therefore the increased electrostatic interaction does not overcome the increasing hydration energies. A detailed kinetic study of the dissociation of the [Gd(octapa)(H2O)](-) complex in the presence of Cu(2+) shows that the metal-assisted pathway is the main responsible for complex dissociation at pH 7.4 and physiological [Cu(2+)] concentration (1 μM).

Lower Denticity Leading to Higher Stability: Structural and Solution Studies of Ln(III)–OBETA Complexes

The heptadentate ligand OBETA (2,2'-oxybis(ethylamine)-N,N,N',N'-tetraacetic acid) was reported to form complexes with Ln(3+) ions more stable than those formed by the octadentate and more popular congener EGTA (ethylene glycol O,O'-bis(ethylamine)-N,N,N',N'-tetraacetic acid). The structural features leading to this puzzling coordination paradox were investigated by X-ray diffraction, solution state NMR, molecular modeling, and relaxometric studies. The stability constant of Gd(OBETA) (log KGdL = 19.37, 0.1 M KCl) is 2 orders of magnitude higher than that of the higher denticity analogue Gd(EGTA) (log KGdL = 17.66, 0.1 M KCl). The half-lives (t1/2) for the dissociation reactions of Gd(OBETA) and Gd(EGTA) ([Cu(2+)]tot = 0.2 mM, [Cit(3-)]tot = 0.5 mM, [PO4(3-)]tot = 1.0 mM, and [CO3(2-)]tot = 25 mM at pH = 7.4 and 25 °C in 0.1 M KCl solution) are 6.8 and 0.63 h, respectively, reflecting the much higher inertness of Gd(OBETA) near physiological conditions. NMR studies and DFT calculations using the B3LYP functional and a large-core ECP indicate that the [Gd(OBETA)(H2O)2](-) complex most likely exists in solution as the Δ(λλ)(δδδδ)A/Λ(δδ)(λλλλ)A enantiomeric pair, with an activation free energy for the enantiomerization process of ∼40 kJ·mol(-1). The metal ion is nine-coordinate by seven donor atoms of the ligand and two inner-sphere water molecules. The X-ray crystal structure of [C(NH2)3]3[Lu(OBETA)(CO3)]·2H2O is in agreement with the predictions of DFT calculations, the two coordinated water molecules being replaced by a bidentate carbonate anion. The (1)H NMRD and (17)O NMR study revealed that the two inner-sphere water molecules in Gd(OBETA) are endowed with a relatively fast water exchange rate (kex(298) = 13 × 10(6) s(-1)). The higher thermodynamic stability and inertness of Ln(OBETA) complexes, peaking in the center of the 4f series, combined with the presence of two coordinated water molecules suggests that Gd(OBETA) is a promising paramagnetic probe for MRI applications.

QSPR prediction of the stability constants of gadolinium(III) complexes for magnetic resonance imaging.

Gadolinium(III) complexes constitute the largest class of compounds used as contrast agents for Magnetic Resonance Imaging (MRI). A quantitative structure-property relationship (QSPR) machine-learning based method is applied to predict the thermodynamic stability constants of these complexes (log KGdL), a property commonly associated with the toxicity of such organometallic pharmaceuticals. In this approach, the log KGdL value of each complex is predicted by a graph machine, a combination of parametrized functions that encodes the 2D structure of the ligand. The efficiency of the predictive model is estimated on an independent test set; in addition, the method is shown to be effective (i) for estimating the stability constants of uncharacterized, newly synthesized polyamino-polycarboxylic compounds and (ii) for providing independent log KGdL estimations for complexants for which conflicting or questionable experimental data were reported. The exhaustive database of log KGdL values for 158 complexants, reported for potential application as contrast agents for MRI and used in the present study, is available in the Supporting Information (122 primary literature sources).

Physicochemical Properties of the High-Field MRI-Relevant [Gd(DTTA-Me)(H2O)2]− Complex

To study the physicochemical properties of the DTTA chelating moiety (H4DTTA = diethylenetriaminetetraacetic acid = N,N'-[iminobis(ethane-2,1-diyl)]bis[N-(carboxymethyl)glycine]), used in several compounds proposed as magnetic resonance imaging (MRI) contrast agents, the methylated derivative H4DTTA-Me (N,N'-[(methylimino)bis(ethane-2,1-diyl)]bis[N-(carboxymethyl)glycine]) was synthesized. Protonation constants of the ligand were determined in an aqueous solution by potentimetry and (1)H NMR pH titration and compared to various DTTA derivatives. Stability constants were measured for the chelates formed with Gd(3+) (log K(GdL) = 18.60 +/- 0.10) and Zn(2+) (log K(ZnL) = 17.69 +/- 0.10). A novel approach of determining the relative conditional stability constant of two paramagnetic complexes in a direct way by (1)H NMR relaxometry is presented and was used for the Gd(3+) complexes [Gd(DTTA-Me)(H2O)2](-) (L1) and [Gd(DTPA-BMA)(H2O)] (L2) [K(L1/L2)*(at pH 8.3, 25 degrees C) = 6.4 +/- 0.3]. The transmetalation reaction of the Gd(3+) complex with Zn(2+) in a phosphate buffer solution (pH 7.0) was measured to be twice as fast for [Gd(DTTA-Me)(H2O)2](-) in comparison to that for [Gd(DTPA-BMA)(H2O)]. This can be rationalized by the higher affinity of Zn(2+) toward DTTA-Me(4-) if compared to DTPA-BMA(3-). The formation of a ternary complex with L-lactate, which is common for DO3A-based heptadentate complexes, has not been observed for [Gd(DTTA-Me)(H2O)2](-) as monitored by (1)H NMR relaxometric titrations. From the results, it was concluded that the heptadentate DTTA-Me(4-) behaves similarly to the commercial octadentate DTPA-BMA(3-) with respect to stability. The use of [Gd(DTTA-Me)(H2O)2](-) as an MRI contrast agent in vitro and in animal studies is conceivable, mainly at high magnetic fields, where an increase of the inner-sphere-coordination water actually seems to be the most certain way to increase the relaxivity.

H5EPTPACH2OH: Synthesis, Relaxometric Characterization and 1H NMR Spectroscopic Studies on the Solution Dynamics of Its LnIII Complexes

AbstractThe synthesis and characterization of a new metal chelator, 4‐(S)‐hydroxymethyl‐3,6,10‐tri(carboxymethyl)‐3,6,10‐triazadodecanedioic acid (H5EPTPACH2OH), is reported. Protonation constants for the ligand H5EPTPACH2OH and for the previously reported H5EPTPAC16 have been determined by potentiometry, which reveals that both ligands display slightly higher protonation constants relative to that of the ligand DTPA5–. The stability constant for the [Gd(EPTPACH2OH)(H2O)]2– complex has also been determined by potentiometry. The obtained value (log KGdL = 16.7) is two orders of magnitude lower than that for the [Gd(EPTPA)(H2O)]2– complex, which indicates the destabilizing effect of the pendant hydroxymethyl group at the EPTPA backbone. The microscopic protonation scheme has been deduced from the pH dependence of the 1H NMR spectra of both H5EPTPACH2OH and H5EPTPAC16 ligands. The first two protonations occur exclusively at the backbone nitrogen atoms – the first protonation occurs preferentially at the more basic central nitrogen atom. The second proton distributes preferentially between the two terminal nitrogen atoms with the favoring of the trimethylene nitrogen atom over the ethylene nitrogen atom. The LnIII complexes of the ligand H5EPTPACH2OH have been prepared and their solution dynamics studied by 1H NMR spectroscopy. Two sets of resonances of very different intensities from two isomeric complexes have been observed. Relaxometric investigations (17O NMR and 1H NMRD) demonstrate that the [Gd(EPTPACH2OH)(H2O)]2– complex displays an accelerated water‐exchange rate (kex = 87.6 × 106 s–1) that is close to the theoretically derived optimal value. However, the kinetic stability of this complex in phosphate‐buffered solutions towards Zn2+ transmetallation is quite low, but higher than that of the corresponding methyl derivative.(© Wiley‐VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2007)

Dinuclear, Bishydrated GdIII Polyaminocarboxylates with a Rigid Xylene Core Display Remarkable Proton Relaxivities

Two novel dinuclear Gd(III) complexes have been synthesized, based on a xylene core substituted with diethylenetriamine-N,N,N'',N''-tetraacetate (DTTA) chelators in para or meta position. The complexes [Gd2(pX(DTTA)2)(H2O)4]2- and [Gd2(mX(DTTA)2)(H2O)4]2- both exhibit high complex stability (log K(GdL) = 19.1 and 17.0, respectively), and a good selectivity for Gd(III) against Zn(II), the most abundant endogenous metal ion (log K(ZnL) = 17.94 and 16.19). The water exchange rate is identical within experimental error for the two isomers: k(ex)298 = (9.0 +/- 0.4) x 10(6) s(-1) for [Gd2(pX(DTTA)2)(H2O)4]2- and (8.9 +/- 0.5) x 10(6) s(-1) for [Gd2(mX(DTTA)2)(H2O)4]2-. It is very similar to the k(ex)298 of the structural analogue, bishydrated [Gd(TTAHA)(H2O)2]3-, and about twice as high as that of the monohydrated [Gd(DTPA)(H2O)]2- (TTAHA(6-) = N-tris(2-aminoethyl)amine-N',N',N'',N'',N''',N'''-hexaacetate; DTPA(5-) = diethylenetriamine-N,N,N',N'',N''-pentaacetate). This relatively fast water exchange can be related to the presence of two inner sphere water molecules which decrease the stereorigidity of the inner sphere thus facilitating the water exchange process. At all frequencies, the water proton relaxivities (r1 = 16.79 and 15.84 mM(-1) s(-1) for the para and meta isomers, respectively; 25 degrees C and 20 MHz) are remarkably higher for the two dinuclear chelates than those of mononuclear commercial contrast agents or previously reported dinuclear Gd(III) complexes. This is mainly the consequence of the two inner-sphere water molecules. In addition, the increased molecular size as compared to monomeric compounds associated with the rigid xylene linker between the two Gd(III) chelating subunits also contributes to an increased relaxivity. However, proton relaxivity is still limited by fast molecular motions which also hinder any beneficial effect of the increased water exchange rate.

Synthesis, Crystal Structure, and Potentiometry of Pyridine-Containing Tetraaza Macrocyclic Ligands with Acetate Pendant Arms

Tetraazamacrocycles containing the pyridine moiety as part of the cyclic backbone and acetate pendant arms were prepared. The resulting products were characterized by high resolution NMR (‘H and I3C) spectroscopy and single-crystal X-ray diffraction. Single-crystal X-ray diffraction data were obtained for the following compounds: py[l2]aneN4*HC1, C I I H I ~ N ~ C ~ , orthorhombic Pnma (No. 62), a = 10.304(6) A, b = 9.160(2) A, c = 13.552(2) A, Z = 4, Mo Ka, ;1 = 0.710 69, R = 0.037, R, = 0.036; and BP2A.2HC1-3H20, C18H22N404c ~ ~ . ~ H ~ o , triclinic pi (NO. 21, u = 10.201(0) A, b = i3.267(3) A, c = 8.612(6) A, a = 97.676(2)”, p = 105.821(0)”, I. = 86.363(7)”, Z = 2, Mo Ka, = 0.710 69, R = 0.039, R , = 0.038. In addition, protonation constants (log KH~L) and metal ion stability constants (log KML) for BP2A (log KH,-L = 9.57, 5.99, 2.59, 2.22; log KMgL = 8.9; log K c ~ L = 10.0; log KGdL = 14.5) and PC2A (log KH,-~L = 12.5, 5.75, 3,28, 2.38, -1; log KMgL = 8.4, log Kc& = 10.0, log KGdL = 16.6) were determined using potentiometric and NMR pH titrations. These values agree well with previously reported literature values for analogous ligand systems.