In vivo evaluation of gadolinium hydroxypyridonate chelates: initial experience as contrast media in magnetic resonance imaging.

The effect of ligand structure on the magnetic resonance (MR) imaging and biodistribution of six gadolinium (Gd) chelates based on a hydroxypyridonate-terephthalimide (HOPO-TAM) ligand design was investigated. Modifications to the molecular structure of the Gd-HOPO-TAM chelates (hydrophilicity and aromatic group substitution) significantly influence the efficacy of imaging and biodistribution. MR imaging was performed on female mice after intravenous (iv) injection of 100 micromol of Gd/kg of body weight of the different complexes. The biodistribution results indicate that the liver uptake of the complexes is enhanced by a short poly(ethyleneoxy) (PEO) chain, while blood pool localization is facilitated by a very long PEO chain. There is a direct correlation between the blood pool localization of the complexes and the signal intensity of blood vessels in the MRI. The imaging results are consistent with in vitro NMR measurements that indicate long PEO chains increase image enhancement capabilities in the presence of serum albumin.

Toward optimized high-relaxivity MRI agents: thermodynamic selectivity of hydroxypyridonate/catecholate ligands.

The thermodynamic selectivity for Gd(3+) relative to Ca(2+), Zn(2+), and Fe(3+) of two ligands of potential interest as magnetic resonance imaging (MRI) contrast agents has been determined by NMR spectroscopy and potentiometric and spectrophotometric titration. The two hexadentate ligands TREN-6-Me-3,2-HOPO (H(3)L2) and TREN-bisHOPO-TAM-EA (H(4)L3) incorporate 2,3-dihydroxypyridonate and 2,3-dihydroxyterephthalamide moieties. They were chosen to span a range of basicity while maintaining a structural motif similar to that of the parent ligand, TREN-1-Me-3,2-HOPO (H(3)L1), in order to investigate the effect of the ligand basicity on its selectivity. The 1:1 stability constants (beta(110)) at 25 degrees C and 0.1 M KCl are as follows. L2: Gd(3+), 20.3; Ca(2+), 7.4; Zn(2+), 11.9; Fe(3+), 27.9. L3: Gd(3+), 24.3; Ca(2+), 5.2; Zn(2+), 14.6; Fe(3+), 35.1. At physiological pH, the selectivity of the ligand for Gd(3+) over Ca(2+) increases with the basicity of the ligand and decreases for Gd(3+) over Fe(3+). These trends are consistent with the relative acidities of the various metal ions;- more basic ligands favor harder metals with a higher charge-to-radius ratio. The stabilities of the Zn(2+) complexes do not correlate with basicity and are thought to be more influenced by geometric factors. The selectivities of these ligands are superior to those of the octadentate poly(aminocarboxylate) ligands that are currently used as MRI contrast agents in diagnostic medicine.

Hetero-tripodal hydroxypyridonate gadolinium complexes: syntheses, relaxometric properties, water exchange dynamics, and human serum albumin binding.

The synthesis and relaxometric properties of hetero-tripodal hydroxypyridonate-terephthalamide gadolinium (Gd(3+)) chelates with differing structural features for probing human serum albumin (HSA) interactions are reported. The Gd(3+) complexes are divided into two series. The first series (3-5) features a benzyl derivative connected to the hydroxypyridonate (HOPO) moiety. The second series of complexes (6-10) has the common feature of a poly(ethylene glycol) (PEG) attached to the terephthalamide (TAM) moiety and is nonbenzylated. The water exchange of the complexes is in the fast exchange regime with rates (k(ex)) in the range 0.45-1.11 x 10(8) s(-1). The complexes have a moderate interaction with HSA with association constants (K(A)'s) in the range 0.7-8.6 x 10(3) M(-1). Protein binding results in an enhancement in proton relaxivity from 7.7-10.4 mM(-1) s(-1) (r(1p)) to 15-29 mM(-1) s(-1) (r(1p)(b)). It is concluded that the interaction of the complexes with HSA (i) is enhanced by the presence of benzyl groups, (ii) is entropically driven, and (iii) results in a lower hydration number (q).

Toward optimized high-relaxivity MRI agents: the effect of ligand basicity on the thermodynamic stability of hexadentate hydroxypyridonate/catecholate gadolinium(III) complexes.

The thermodynamic stabilities of the Gd(III) complexes of five hexadentate ligands, which incorporate the 2,3-dihydroxyterephthalamide and 2,3-hydroxypyridonate chelating moieties, have been determined by potentiometric and spectrophotometric titration. The ligands were chosen to span a range of basicities while maintaining a similar tripodal structural motif, facilitating a study of the effect of ligand basicity on the thermodynamic stability of the Gd(III) complexes. The relative stability of the five complexes is found to be highly pH dependent, with the most acidic ligands forming the most stable complexes at low pH and more basic ligands forming more stable complexes at high pH. The most stable Gd(III) complex at a physiological pH of 7.4 is formed with a ligand of intermediate basicity and is of stability comparable to that of Gd(III) complexes that feature eight-coordinate amino-carboxylate ligands and are currently used as magnetic resonance imaging contrast agents in diagnostic medicine. A single-crystal X-ray structure of the intermediate compound 3-hydroxy-6-methyl-2-oxo-1,2-dihydropyridine-4-carboxylic acid ethyl ester is described: This compound crystallizes in the triclinic space group P1 with a = 7.4801(3) A, b = 8.0671(3) A, c = 8.3457(4) A, alpha = 72.242(2) degrees, beta = 80.693(2) degrees, gamma = 69.943(3) degrees, V = 449.60(3) A(3), Z = 2, and R = 0.042.

Cationic assembly of metal complex aggregates: structural diversity, solution stability, and magnetic properties.

The tetradentate imino-carboxylate ligand [L](2)(-) chelates the equatorial sites of Ni(II) to give the complex [Ni(L)(MeOH)(2)] in which a Ni(II) center is bound in an octahedral coordination environment with MeOH ligands occupying the axial sites. Lanthanide (Ln) and Group II metal ions (M) template the aggregation of six [Ni(L)] fragments into the octahedral cage aggregates (M[Ni(L)](6))(x)(+) (1: M = Sr(II); x = 2,2: M = Ba(II); x = 2, 3: M = La(III); x = 3, 4: M = Ce(III); x = 3, 5: M = Pr(III); x = 3, and 6: M = Nd(III); x = 3). In the presence of Group I cations, however, aggregates composed of the alkali metal-oxide cations template various cage compounds. Thus, Na(+) forms the trigonal bipyramidal [Na(5)O](3+) core within a tricapped trigonal prismatic [Ni(L)](9) aggregate to give ((Na(5)O) subset [Ni(L)](9)(MeOH)(3))(BF(4))(2).OH.CH(3)OH, 7. Li(+) and Na(+) together form a mixed Li(+)/Na(+) core comprising distorted trigonal bipyramidal [Na(3)Li(2)O](3+) within an approximately anti-square prismatic [Ni(L)](8) cage in ((Na(3)Li(2)O) subset [Ni(L)](8)(CH(3)OH)(1.3)(BF(4))(0.7))(BF(4))(2.3).(CH(3)OH)(2.75).(C(4)H(10)O)(0.5), 8, while in the presence of Li(+), a tetrahedral [Li(4)O](2+) core within a hexanuclear open cage [Ni(L)](6) in ((Li(4)O) subset [Ni(L)](6)(CH(3)OH)(3))2ClO(4).1.85CH(3)OH, 9, is produced. In the presence of H(2)O, the Cs(+) cation induces the aggregation of the [Ni(L)(H(2)O)(2)] monomer to give the cluster Cs(2)[Ni(L)(H(2)O)(2)](6).2I.4CH(3)OH.5.25H(2)O, 10. Analysis by electronic spectroscopy and mass spectrometry indicates that in solution the trend in stability follows the order 1-6 > 7 > 8 approximately 9. Magnetic susceptibility data indicate that there is net antiferromagnetic exchange between magnetic centers within the cages.

The effect of ligand scaffold size on the stability of tripodal hydroxypyridonate gadolinium complexes.

The variation of the size of the capping scaffold which connects the hydroxypyridonate (HOPO) binding units in a series of tripodal chelators for gadolinium (Gd) complexes has been investigated. A new analogue of TREN-1-Me-3,2-HOPO (1) (TREN = tri(ethylamine)amine) was synthesized: TREN-Gly-1-Me-3,2-HOPO (2) features a glycine spacer between the TREN cap and HOPO binding unit. TRPN-1-Me-3,2-HOPO (3) has a propylene-bridged cap, as compared to the ethylene bridges within the TREN cap of the parent complex. Thermodynamic equilibrium constants for the acid-base properties of 2 and the Gd(3+) complexation strength of 2 and 3 were measured and are compared with that of the parent ligand. The most basic ligand is 2 while 3 is the most acidic. Both 2 and 3 form Gd(3+) complexes of similar stability (pGd = 16.7 and 15.6, respectively) and are less stable than the parent complex Gd-1 (pGd = 19.2). Two of the three complexes are more stable than the bis(methylamide)diethylenetriamine pentaacetate complex Gd(DTPA-BMA) (pGd = 15.7) while the other is of comparable stability. Enlargement of the ligand scaffold decreases the stability of the Gd(3+) complexes and indicates that the TREN scaffold is superior to the TRPN and TREN-Gly scaffolds. The proton relaxivity of Gd-2 is 6.6 mM(-)(1) s(-)(1) (20 MHz, 25 degrees C, pH 7.3), somewhat lower than the parent Gd-1 but higher than that of the MRI contrast agents in clinical practice. The pH-independent relaxivity of Gd-2 is uncharacteristic of this family of complexes and is discussed.

Template Assembly of Metal Aggregates by Imino-Carboxylate Ligands.

Lanthanide, main group, and transition metal ion templates provide different polynuclear cages from [M(L)] (M=Ni, Mn; (L)2-=CH2[CH2N=C(CH3)COO-]2). Templating with lanthanum results in a 12-coordinate LaIII ion encapsulated by six [Ni(L)] units, whereas with sodium four Na+ ions are trapped inside a tricapped trigonal prismatic [{Ni(L)}9] cage. With manganese, an octahedrally coordinated MnII ion is surrounded by six [Mn(L)] fragments in a twisted trigonal-prismatic configuration (see picture).