Cationic Lanthanide Complexes of N,N'-Bis(2-pyridylmethyl)ethylenediamine-N,N'-diacetic Acid (H(2)bped).

A series of monocationic lanthanide complexes containing the ligand N,N'-bis(2-pyridylmethyl)ethylenediamine-N,N'-diacetate(2-) (bped(2)(-)) have been prepared and isolated as either the hexafluorophosphate or perchlorate salts. The complexes have been characterized by (1)H and (13)C NMR, +LSIMS, IR, and elemental analysis. Complex formation constants have been measured in water at 25 degrees C (&mgr; = 0.16 M (NaCl)). log K (Ln(bped)](+)) (log K([Ln(bped)(OH)])): Ln = La, 10.81 (0.06); Ln = Nd, 11.99 (1.45); Ln = Gd, 12.37 (2.10); Ln = Ho, 12.31 (3.00); Ln = Yb, 13.42 (4.43). The stability constants for [M(bped)](+) increase from La(III) to Nd(III), plateau to Ho(III), and increase again to Yb(III), while the formation constants for [Ln(bped)(OH)] increase almost linearly with atomic number. The solution structures of the [Ln(bped)](+) complexes have been probed by multinuclear NMR ((1)H, (13)C, (17)O) studies, and these indicate only one isomer present in solution; this isomer has 2-fold symmetry and is rigid at 20 degrees C on the NMR time scale. (17)O NMR studies of the paramagnetic lanthanides indicate that the hydration number is 3, [Ln(bped)(H(2)O)(3)](+), and that an overall coordination number of 9 is maintained across the lanthanide series.

Effect of Pyridyl Donors in the Chelation of Aluminum(III), Gallium(III), and Indium(III).

A new preparation of N,N'-bis(2-pyridylmethyl)ethylenediamine-N,N'-diacetic acid (H(2)bped) is reported, and its properties of complexation with Al(III), Ga(III), In(III), and Co(III) are investigated. The molecular structure of the cobalt(III) complex [Co(bped)]PF(6).CH(3)CN.H(2)O (C(20)H(25)CoF(6)N(5)O(5)P) has been solved by X-ray methods; the complex crystallizes in the triclinic space group P&onemacr;, with a = 10.611(2) Å, b = 12.720(2) Å, c = 9.868(1) Å, alpha = 102.70(1) degrees, beta =93.60(1) degrees, gamma = 106.96(1) degrees, and Z = 2. The structure was solved by direct methods and was refined by full-matrix least-squares procedures to R = 0.041 (R(w) = 0.038) for 4312 reflections with I > 3sigma(I). The Co(III) ion is coordinated in a distorted octahedral geometry with an N(4)O(2) donor atom set. The carboxylato oxygen atoms are coordinated trans, while the pyridyl nitrogen atoms are coordinated cis. The largest distortion from octahedral geometry is the N(pyridyl)-Co-N(pyridyl) angle of 107 degrees. Complex formation constants have been measured at 25 degrees C (&mgr; = 0.16 M (NaCl)). log K([M(bped)](+)) (log K([M(bped)(OH)])): M = Al, 10.85 (6.37); M = Ga, 19.89 (15.62); M = In, 22.6 (15.44). A protonated complex was also detected, [Ga(Hbped)](2+), log K = 21.79. The order of stability is In(III) > Ga(III) > Al(III) for the binary species, [M(bped)](+). The solution structures of the complexes have been probed in multinuclear NMR ((1)H, (13)C, (27)Al) studies, and these solution structures are compared with the solid state structure of the cobalt(III) complex. The complexes [In(bped)](+) and [In(bped)(OH)] are proposed to contain 7-coordinate In(III) with water and hydroxide completing the respective coordination spheres. The gallium complexes are proposed to be 6-coordinate: the [Ga(Hbped)](2+) complex contains a nondeprotonated carboxylic acid group which is not coordinated, and [Ga(bped)(OH)] contains a coordinated hydroxide which displaces a carboxylato donor. The [Al(bped)(OH)] complex may be 5-coordinate on the basis of its downfield (27)Al NMR chemical shift, 54 ppm.

Glucose-lowering properties of vanadium compounds: comparison of coordination complexes with maltol or kojic acid as ligands.

Bis(kojato)oxovanadium(IV) [abbreviated VO(ka)2], a close chemical analog of the insulin-mimetic lead compound bis(maltolato)oxovanadium(IV)--abbreviated BMOV or VO(ma)2--is reported and its reaction chemistry and insulin-mimetic properties are presented. VO(ka)2 [log K1 = 7.61(10), log K2 = 6.89(6), log beta 2 = 14.50(16)] has a reaction chemistry which directly parallels that of VO(ma)2. In aqueous solution it is more slowly oxidized by molecular oxygen to [VO2(ka)2]- than is VO(ma)2 to [VO2(ma)2]-. Variable pH electrochemistry and variable pH 51V NMR of solutions of VO(ka)2 are presented and contrasted with the corresponding results for VO(ma)2. Time course studies (24 hr) in STZ-diabetic rats following the oral or i.p. administration of VO(ka)2, VO(ma)2, VO2+ (vanadyl) as vanadyl sulfate (VOSO4), and [VO2(ma)2]- as its [NH4]+ salt have been performed, as have chronic oral studies comparing VO(ka)2 and VO(ma)2 over a six week period. In all studies, the most potent form of vanadium was the neutrally charged, water soluble, complex VO(ma)2.

Molecular factors that determine Curie spin relaxation in dysprosium complexes.

Dysprosium complexes can serve as transverse relaxation (T(2)) agents for water protons through chemical exchange and the Curie spin relaxation mechanism. Using a pair of matched dysprosium(III) complexes, Dy-L1 (contains one inner-sphere water) and Dy-L2 (no inner-sphere water), it is shown that the transverse relaxation of bulk water is predominantly an inner-sphere effect. The kinetics of water exchange at Dy-L1 were determined by (17)O NMR. Proton transverse relaxation by Dy-L1 at high fields is governed primarily through a large chemical shift difference between free and bound water. Dy-L1 forms a noncovalent adduct with human serum albumin which dramatically lengthens the rotational correlation time, tau(R), causing the dipole-dipole component of the Curie spin mechanism to become significant and transverse relaxivity to increase by 3-8 times that of the unbound chelate. These findings aid in the design of new molecular species as efficient r(2) agents.

The Gd(3+) complex of a fatty acid analogue of DOTP binds to multiple albumin sites with variable water relaxivities.

The 20 MHz water relaxivity (r(1)) of gadolinium(III) complexes formed with two fatty acid analogues of 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetrakis(methylene phosphonate) were shown to increase substantially in the presence of albumin. The r(1) values of Gd(C(8)-DOTP)(5-) and Gd(C(11)-DOTP)(5-) in water were similar to that of the parent GdDOTP(5-), a q = 0 complex known to relax water very efficiently via an outer-sphere mechanism. Neither fatty acid analogue formed apparent aggregates or micelles in water up to 20 mM, but both showed dramatic increases in r(1) upon addition of albumin. Further ultrafiltration studies of Gd(C(11)-DOTP)(5-) in the presence of non-defatted HSA showed that the complex binds at a minimum of five high-affinity fatty acid sites with stepwise binding constants ranging from 1.27 x 10(5) to 2.7 x 10(3) M(-1). The 20 MHz relaxivity of Gd(C(11)-DOTP)(5-) in the presence of excess HSA was 23 mM(-1) s(-1) at 25 degrees C. The NMRD curve showed a broad maximum 20-30 MHz which fitted well to standard theory for a q = 0 complex with rapid outer-sphere water exchange. The r(1b) of Gd(C(11)-DOTP)(5-) bound at the tightest site on HSA was approximately 40 mM(-1) s(-1) at 5 degrees C, an extraordinarily high value for an outer-sphere complex. However, the r(1b) of Gd(C(11)-DOTP)(5-) bound at the weaker sites on HSA was considerably lower, approaching the relaxivity of the free complex in water. This suggests that the complex bound in the highest affinity fatty acid site is less mobile than the same complex bound at the weaker affinity fatty acid sites. This combined ultrafiltration and relaxivity study demonstrates that the common assumption of a single r(1b) value for a Gd(3+) complex bound at several protein sites is not a valid approximation.

Thermodynamic stability and kinetic inertness of MS-325, a new blood pool agent for magnetic resonance imaging.

Stability constants were measured for complexes formed between a modified DTPA ligand and the metal ions Gd(III), Eu(III), Fe(III), Ca(II), Cu(II), and Zn(II) at 25 degrees C in 0.1 M NaClO4. The gadolinium complex of this ligand is MS-325, a novel blood pool contrast agent for magnetic resonance imaging currently undergoing clinical trials. Stability constants were determined by 4 different methods: direct pH titration, pH titration with competition by EDTA, competition with DTPA using an HPLC-MS detection system, and competition with Eu(III) by monitoring equilibrium by luminescence spectroscopy. The 1:1 stability constants, log beta101, are the following: Gd, 22.06 (23.2 in 0.1 M Me4NCl); Eu, 22.21; Fe, 26.66; Ca, 10.45; Cu, 21.3; Zn, 17.82. The exchange kinetics of the Gd complex, MS-325, with the radioactive tracer (152,154)Eu were studied at 25 degrees C in 0.1 M NaClO4. The exchange reaction has acid-dependent and acid-independent terms. The rate expression is given by the following: R = k(a)[GdL][H]2 + kb[GdL][Gd][H] + kc[GdL][Gd]. The rate constants were determined to be the following: k(a) = 1.84 x 10(6) M(-2) x min(-1), kb = 2.87 x 10(3) M(-2) x min(-1), kc = 3.72 x 10(-3) M(-1) x min(-1). MS-325 is 2-3 times more stable than GdDTPA at pH 7.4 and is 10-100 times more kinetically inert.