WO1993025243A2

WO1993025243A2 - Metal complexes formed with macrocyclic ligands for use in imaging techniques

Info

Publication number: WO1993025243A2
Application number: PCT/US1993/005532
Authority: WO
Inventors: Quintus Fernando; Michiko Inoue; Motomichi Inoue
Original assignee: Research Corporation Technologies, Inc.
Priority date: 1992-06-10
Filing date: 1993-06-10
Publication date: 1993-12-23
Also published as: WO1993025243A3

Abstract

Novel macrocyclic ligands with pendant carboxylic acid groups and their corresponding novel metal complexes are disclosed. Such metal complexes can be used for the enhancement imaging techniques.

Description

METAL COMPLEXES FORMED WITH MACROCYCLIC LIGANDS FOR

USE IN IMAGING TECHNIQUES

Cross-Reference To Related Application

The present application is a continuation-in-part of U.S. Patent Application No. 07/896,118 filed June 10, 1992.

Background of the Invention

The present invention relates to the field of macrocyclic ligands and their corresponding metal

complexes. More particularly, the invention relates to novel macrocyclic ligands with pendant carboxylic acid groups and their corresponding metal complexes which are useful in imaging techniques such as Magnetic Resonance Imaging (MRI), X-ray Contrast Imaging, Positron Emission Tomography (PET), and Single Photo Emission Computer Tomography (SPECT). If the ligands are complexed with a radioisotope and bound to a monoclonal antibody, they can be used in immuno-imaging and immuno-therapy.

In imaging techniques, in order to obtain a better contrast in the picture, nonradioactive or radioactive metals such as gadolinium or yttrium 90 are used.

Contrast enhancers are often needed when dealing with living subjects so that one can distinguish tissues which are histologically dissimilar but magnetically similar.

A problem arises because often these nonradioactive and radioactive metals are toxic to living subjects.

Therefore, it is desirable to incorporate the metals in a compound that will serve as a contrast agent, and at the same time, pass through the living subject and be excreted without releasing the metal. Ligands which can complex with nonradioactive and radioactive metals to form compounds which can serve as non-toxic contrast enhancers are needed.

Ligands which can complex with radioactive metals are also needed in the immuno-imaging and immuno-therapy fields. To be useful in these areas the macrocyclic ligand must be able to bind a radioisotope and also link to a monoclonal antibody. First, the macrocyclic ligand is functionalized, for example with a pendant aminoalkyl group and then linked by a bifunctional linker molecule to amino acid residues on a monoclonal antibody. These ligands can be directed with great selectivity to specific targeted sites in a living subject. This selectivity is achieved by using a monoclonal antibody that binds strongly to antigens that are associated with the targeted sites.

Summary of the Invention

Briefly stated, the present invention encompasses various macrocyclic ligands, their corresponding metal complexes, methods of using the complexes in imaging techniques and a process for synthesizing the ligands.

In accordance with one aspect of the invention, a macrocyclic ligand according to the following formula is provided:

wherein A is selected from the group consisting of:

-(CH₂)_x

-(CH₂)_x-NR₁- (CH₂)_y-

-(CH₂)_x-NR₂-(CH₂)_y-NR₃-(CH₂)_z-; B is selected from the group consisting of:

- ( CH₂) _v-

and wherein m, n, t, u, v, w, x, y, z are independently selected from the integers 1, 2, 3, 4;

w is selected to be the same as either m or n;

and R₁, R₂, R₃ is H or any alkyl group.

In accordance with another aspect of the invention, a macrocyclic ligand according to the following formula is provided:

wherein A is selected from the group consisting of

-(CH₂)_x-

-(CH₂)_x-NR₁-(CH₂)_y-

- (CH₂)_x-NR₂-(CH₂)_y-NR₃-(CH₂)_z-;

B is selected from the group consisting of

- (CH₂) _v-

w is selected to be the same as m or n; and R₁, R₂, R₃ is H or any alkyl group.

In accordance with still another aspect of the invention, a macrocyclic ligand according to the following formula is provided:

wherein A is selected from the group consisting of:

-(CH₂)_x-

-(CH₂)_x-NR₁-(CH₂)_y-

- (CH₂)_x-NR₂-(CH₂)_y-NR₃-(CH₂)_z-;

B is selected from the group consisting of:

-(CH₂)_v-

C is selected from the group consisting of:

- ( CH₂) _v-

and wherein m, n, t, u, v, w, x, y, z are independently selected from the integers 1, 2, 3, or 4;

w is selected to be the same as m or n; and

R₁, R₂, R₃ is H or any alkyl group In accordance with yet another aspect of the invention a macrocyclic ligand having the formula is provided:

In accordance with still another aspect of the invention a macrocyclic ligand having the following formula is provided:

In accordance with yet another aspect of the invention a macrocyclic ligand having the following formula is provided:

In accordance with still another aspect of the invention a metal selected from the group consisting of any metal ion in the +1, +2, +3 or +4 oxidation state is complexed with a macrocyclic ligand having the formula:

wherein A is selected from the group consisting of:

-(CH₂)_x- -(CH₂)_x-NR₁-(CH₂)_y-

- (CH₂)_x-NR₂-(CH₂)_y-NR₃-(CH₂)_z-; wherein B is selected from the group consisting of:

-(CH₂)_v-

w is selected to be the same as m or n; and

R₁, R₂, R₃ is H or any alkyl group.

wherein A is selected from the group consisting of:

-(CH₂)_x- -(CH₂)_x-NR₁-(CH₂)_y-

- (CH₂)_x-NR₂-(CH₂)_y-NR₃-(CH₂)_z-; B is selected from the group consisting of:

-(CH₂)_v-

w is selected to be the same as m or n; and

R₁, R₂, R₃ is H or any alkyl group.

In accordance with yet another aspect of the invention, a method for enhancing contrast in imaging techniques used on living subjects is provided. The method includes administering internally to the subject an effective amount of a contrast agent. The contrast agent comprises a complex of a metal selected from the group consisting of any metal ion that is in the +1, +2, +3 or +4 oxidation state and a macrocyclic ligand having the formula:

wherein A is selected from the group consisting of:

-(CH₂)_x-

-(CH₂)_x-NR₁-(CH₂)_y-

-(CH₂)_v-

w is selected to be the same as m or n; and

R₁, R₂, R₃ is H or any alkyl group.

wherein A is selected from the group consisting of:

-(CH₂)_x-

-(CH₂)_x-NR₁-(CH₂)_y-

- (CH₂) _v-

w is selected to be the same as m or n; and

R₁, R₁, R₂ is H or any alkyl group

In accordance with yet another aspect of the

invention, a method for synthesizing macrocyclic ligands with pendant carboxylic acid groups is provided.

The present invention, together with its attendant objects and advantages, will be best understood with reference to the detailed description below read in conjunction with the accompanying drawings.

Brief Description of the Drawings

FIGURE 1 shows the molecular structure of a

preferred ligand-metal complex of the present invention.

FIGURE 2 shows the crystal packing in a unit cell of the structure of FIGURE 1.

FIGURE 3 shows the molecular structure of a

preferred ligand-metal complex of the present invention.

FIGURE 4 shows the crystal packing in a unit cell of the structure of FIGURE 3.

FIGURE 5 shows the stereoscopic view of a preferred ligand-metal complex of the present invention.

FIGURE 6 shows the crystal packing in a unit cell of the structure of FIGURE 5.

FIGURE 7 shows the stereoscopic view of the

coordination geometry around the metal of the complex of FIGURE 5. FIGURE 8 shows the molecular structure of a

preferred ligand-metal complex of the present invention.

FIGURE 9 shows the tetradecahedron around the metal of the complex of FIGURE 8.

FIGURE 10 shows the structure of a preferred ligand-metal complex of the present invention.

FIGURE 11 shows the tetradecahedron around the metal of the complex of FIGURE 10.

Detailed Description

of the Preferred Embodiments

Macrocyclic ligands with pendant carboxylic acid groups can be prepared by condensation reactions between a polyalkylpolyaminopolycarboxylic dianhydride and a alkylpolyamine or a polyalkylpolyamine. The reaction occurs in a single step and the product is obtained in relatively high yield without the use of any template metal ions.

The metal complexes of these ligands will be formed readily, especially if the ligand has the same number of displaceable protons as the charge on the metal ion. The metal complexes of these ligands have unusual structures because the metal ions are coordinated not only to the nitrogen donors, but also to the pendant carboxylic acid groups.

When the ligands of the present invention are complexed with a radioactive or non-radioactive metal, the complexes are useful in imaging techniques such as Magnetic Resonance Imaging (MRI), X-Ray Contrast Imaging, Positron Emission Tomography (PET), Single Photo Emission Computer Tomography (SPECT) and Dual X-Ray Absorptiometry (DEXA).

When the ligands of the present invention are complexed with a radioisotope and a targeting molecule such as a monoclonal antibody or a fragment of an

antibody, the complexes are useful in immuno-therapy and immuno-imaging. Any metal ion having a +1, +2, +3 or +4 oxidation number can be used to form a complex with the ligands of the present invention. The preferred metals are

copper(II), lead(II), manganese (II), gadolinium(III), yttrium (III) iron (III) and cobalt (II).

In accordance with one embodiment of the invention macrocyclic ligands of the following formula are

provided:

wherein A is selected from the group consisting of:

-(CH₂)_x-

-(CH₂)_x-NR₁-(CH₂)_y-

-(CH₂)_x-NR₂-(CH₂)_y-NR₃-(CH₂)_z-;

Bz is selected from the group consisting of:

- (CH₂) _v-

wherein m, n, t, u, v, w, x, y, z are independently selected from the integers 1, 2, 3, 4;

w can be either m or n;

R₁, R₂, R₃ is H or any alkyl group. Preferably, A = (CH₂)_x

and B= (CH₂)_v or

Most preferably

m = 1, A = (CH₂)_x, B = (CH₂)_v, v = 2 and

x = 2. This provides a 12-membered ligand with two pendant carboxylic acid groups, which is denoted as L(12).

Also most preferably

m = 1, A = (CH₂)_x, B = (CH₂)_v, x = 3 and

v = 2. This provides a 13-membered ligand with two pendant carboxylic acid groups, which is denoted as L(13).

Also most preferably

A=(CH₂)_x,

and m=1, x=2, v=2, t=2, and w=1.

This provides a 15-membered ligand with three pendant carboxylic acid groups, which is denoted as L(15).

Also most preferably in this aspect

A=(CH₂)_x,

and m = 1, x = 3, v = 2, w = 1 and t = 2.

This provides a 16-membered ligand with three pendant acetate groups, denoted as L(16). In accordance with a second aspect of the invention, macrocyclic ligands of the following formula are

provided:

wherein A is selected from the group consisting of

-(CH₂)_x-

-(CH₂)_x-NR₁-(CH₂)_y-

-(CH₂)_x-NR₂-(CH₂)_y-NR₃-(CH₂)_z-;

B is selected from the group consisting of

- ( CH₂) _v-

w is selected to be the same as m or n;

and R₁, R₂, R₃ is H or any alkyl group.

Preferably

A = (CH₂)_x and B = (CH₂)_v.

Most preferably, m = 1, A = (CH₂)_x,

B = (CH₂)_v, x = 2 and v = 2.

This provides a 24-membered ligand with 4 pendant carboxylic acid groups, which is denoted as L(24). In accordance with a third aspect of the invention, macrocyclic ligands of the following formula are

provided:

wherein A is selected from the group consisting of:

-(CH₂)_x-

-(CH₂)_x-NR₁-(CH₂)_y-

-(CH₂)_x-NR₂-(CH₂)_y-NR₃-(CH₂)_z-;

B is selected from the group consisting of:

-(CH₂)_v-

C is selected from the group consisting of:

-(CH₂)_v-

and wherein m, n, t, u, v, w, x, y, z are independentlt selected from the integers 1, 2, 3, 4;

w is selected to be the same as m or n; and

R₁, R₂, R₃ Is H or any alkyl group. Figures 1-11 are various views of the presently preferred metal complexes of the presently preferred macrocyclic ligands of the instant invention.

Figure 1 shows the molecular structure of

CuL(12).4H₂O and Figure 2 shows the crystal packing in the unit cell of CuL (12).4H₂O. Table 1 summaries the crystal data. Tables 2 and 3 show the selected bond distances and bond angles. Table 4 shows the positional parameters of the non-hydrogen atoms. L(12) consists of a 12-membered ring with amide bonds and contains two pendant carboxylic acid groups. Each copper atom is coordinated to an amine nitrogen atom Nl (Cu-N=2.088 Å), an amide oxygen atom 05 (Cu-O=1.988 Å), a carboxylato oxygen atom 03 (Cu-O=1.996 Å) and another carboxylato oxygen atom 01 that belongs to the neighboring metal chelate (Cu-O=1.936 Å). In addition to these four atoms which form a plane around copper, an amine nitrogen atom N2 and a

carboxylato oxygen atom 02 are weakly coordinated to copper with Cu-N=2.485 Å and Cu-O=2.334 A and form an elongated octahedron around the copper. One of the amide groups is not coordinated to the metal ion. The 12-membered ring is too small to involve the metal ion inside its macrocyclic cavity. Water molecules are hydrogen-bonded to each other and are not coordinated to copper. One of the features of the structure is that one of the acetate groups is coordinated to two copper atoms forming a one-dimensional -Cu-O-C-O=Cu- chain.

Figure 3 shows the structure and Figure 4 shows the crystal packing in the unit cell of Mn₂L(24).8H2O.

Table 5 shows the positional parameters of the non- hydrogen atoms. The bond distances and the bond angles are collected in Tables 6 and 7. L(24) has a 24-membered ring and four pendant carboxylic acid groups. Each ligand is coordinated to two manganese ions. The

resulting manganese chelate molecule has C₂ symmetry, the symmetry axis of which coincides with the crystal C₂ axis and passes perpendicular to the averaged molecular plane of the macrocyclic ring. The manganese atoms within a chelate molecule are, therefore, crystallographically equivalent to each other. Each metal atom is coordinated to four oxygen atoms and two nitrogen atoms with bond distances of 2.111-2.445 A; two oxygen atoms 01 and 03 from two carboxylato groups (Mn-O=2.184 A), a water molecule (denoted OW1, Mn-O=2.137 A) and two amine nitrogen atoms N1 and N2 (Mn-N1=2.445 and Mn-N2=2.358 A). The Mn-O distances of 2.111-2.212 A are significantly shorter than the Mn-N distance of 2.358-2.445 A. An additional weak bond is formed between a Mn atom and an amide oxygen atom 06 with a distance of 2.686 Å. Thus, a distorted seven-coordination geometry is established around the metal atoms.

The 24-membered macrocyclic ligand was obtained as an amorphous powder, whereas its Mn(II) complex was obtained in a crystalline form. Chelate formation with metal ions makes the ring rigid and results in a well- defined configuration of the chelate ring. The

structural integrity of the metal chelate rings leads to the formation of crystals of the metal chelate.

Extensive hydrogen bonding occurs in the crystal lattice structure and defines the arrangement of the metal chelate molecules in the crystal. A water molecule (OW2) occupies a special position on the crystal C₂ axis that coincides with the C₂ axis of the metal chelate ring.

This water molecule forms strong hydrogen bonds with two water molecules (OW1) coordinated to Mn and also with two amide oxygen atoms that are weakly bonded to Mn. These hydrogen bonds firmly link the two Mn ions within a chelate ring and define the molecular structure of the metal chelate.

Figure 5 shows a stereoscopic view of PbL(13). The crystal packing diagram is shown in Figure 6. Figure 7 shows a stereoscopic view of the coordination geometry around the Pb(II) ion. Table 8 shows the bond distances and angles. Table 9 shows the fractional coordinates and equivalent isotropic temperature factors. L(13) forms a non-ionic neutral Pb(II) complex. A ligand molecule is coordinated to a Pb(II) ion with two carboxylato oxygen atoms, O(3) and O(5), two amide oxygen atoms, O(1) and O(2), and two amine nitrogen atoms, N(1) and N(2). All these donor atoms are located in half the coordination sphere because the ligand is unable to occupy all the positions in the coordination sphere of the metal ion. The remaining coordination positions are occupied by a water oxygen atom (OW1) and a carboxylato oxygen atom O(4') from the adjacent metal chelate. If the very long Pb-O(4') distance of 3.223 Å is considered to be a Pb-0 bond, the resulting molecule is a binuclear chelate. The water molecule (OW1), that is coordinated to the Pb(II) ion forms a hydrogen bond with O(3') of the adjacent metal chelate, thereby stabilizing the binuclear chelate. Other hydrogen bonds with the O-O distance less than 2.9 Å are found for OW1-O(6), OW2-O(4) and OW3-O(6) atomic pairs.

The coordination geometry around the Pb(II) ion that includes the two distant atoms O(2) and O(4) can be described as a highly distorted dodecahedron. For example, the O(4)-O(5) distance (3.836 Å) in the

polyhedron is much longer than the O(1)-N(l) distance (2.803 Å); these distances would be equal in a regular dodecahedron with D_2d symmetry. In addition, the O(2)-OW1 and O(3)-N(2) distances are quite different from each other: O(2)-OW1=5.017Å and O(3)-N(2)=3.358Å. This extreme distortion is caused by the nature of the ligand. The -C-CO-N-C- atoms in each amide group are on the same plane; the largest deviation from the averaged plane is 0.09Å for the amide N(4)HC (2) O(1), and 0.014Å for

N(3)HC(6) O(2). This planarity makes the macrocyclic ring inflexible. Moreover, the macrocycle cannot extend itself to occupy all the coordination positions around the Pb(II) ion. These geometrical constraints of the ligand and the coordination of the amide oxygen atoms result in novel coordination geometry around the Pb(II) atom.

Figure 8 shows the stereoview of GdL (15).8H20, the atoms are shown at a 20% probability level. Figure 9 shows the tetradecahedron around the Gd ion in Gd

L(15).8H₂O. Table 10 summarizes the crystal data.

Table 11 shows the positional parameters of GdL (15).8H₂O. Table 12 shows the positional parameters of YL(15).8H₂O. Table 13 shows the M-X and C-O bond distances. Table 14 shows the bond angles. The X-ray results show that the 15-membered macrocyclic ligand has three pendant

carboxylic acid groups and that the ligand forms a neutral non- ionic metal chelate. Each ligand molecule is coordinated to two Gd ions and each metal ion has nine coordination bonds with: two carboxylato oxygen atoms O(3) and O(5), an amide oxygen atom O(1) and two amine nitrogen atoms N(l) and N(2) from one ligand molecule; a carboxylato oxygen atom O(7), an amide oxygen atom O(2) and an amine nitrogen atom N(3) from the second ligand molecule and a water oxygen atom (OW1). Two metal ions are located between two ligand molecules, forming a binuclear metal chelate, in which the averaged molecular planes of the two macrocyclic rings are parallel to each other. The resulting metal chelate molecules have an inversion center with the result that the two metal ions are crystallographically equivalent to each other.

Figure 10 shows the structure of GdL (16).4H2O, the atoms are shown at a 50% probability level. Figure 11 shows the tetradecahedron around the Gd ion. Table 10 summarizes the crystal data. Table 15 shows the

positional parameters for GdL(16).4H₂O. Table 16 shows the bond distances and angles. Each metal ion has nine coordination bonds with: two amide oxygen atoms O(1) and O(2), three carboxylato oxygen atoms O(3), O(5) and O(7) and three amine nitrogen atoms N(1), N(2) and N(3) from a single ligand molecule, and a water oxygen atom (OW1). Therefore, the ligand molecule occupies all the coordination sites around the Gd(II) ion jointly with a water molecule.

The Gd(III) complexes of L(15) and L(16) both have M-O bond distances significantly shorter than M-N

distances, a water molecule is strongly coordinated to a metal ion, and the amide oxygen atoms are coordinated to metal ions, whereas none of the amide nitrogen atoms is bonded to a metal ion.

However, there are significant differences between the structures of the GdL(15) and GdL(16) complexes.

First the L(15) ligand is coordinated to two Gd(III) ions resulting in a binuclear chelate, whereas the L(16) ligand is coordinated to single metal ion and forms a mononuclear molecule. The coordination geometries in both Gd(III) chelates are described as tricapped trigonal prisms. However, the sequences of the coordinated atoms in the tetradecahedrons are quite different from each other. The tetradecahedron in the GdL(15) chelate is highly distorted from the ideal D_3h geometry. The

dihedral angle between the O(1).N(1).O(7) and the

O(3) .N(2) .N(3) planes is 22.4°, and 4.9° between the O(2) .O(5) . (OW1) and the O(3) .N(2) .N(3). The three planes are parallel in the regular tetradecahedron. The

corresponding dihedral angles in the GdL (16) chelate are 5.6° between the O(5) .O(7) .N(2) and the N(1) .N(3) .OW1 planes and 7.3° between the O(1) .O(2) .O(3) and the

N(1) .N(3) .OW1 planes. The GdL(16) chelate forms a less distorted coordination geometry.

Examples

The following examples are provided by way of explanation and illustration. As such, these examples are not to be viewed as limiting the scope of the invention as defined by the appended claims.

Example 1-Synthesis of L(12)H₂

In a three-neck flask assembled with a condenser, a dropping funnel and a nitrogen-inlet tube, 2.05g (8.0 mmol) of ethylenediaminetetraacetic dianhydride (from Aldrich Chemical Co.) was suspended in 350 ml of dry dimethylformamide (DMF) with stirring under a nitrogen atmosphere. To the suspension was added dropwise a DMF solution (50 ml) containing 0.48g (8.0 mmol) of

ethylenediamine (supplied from Aldrich Chemical Co.) through the dropping funnel for a period of 2 hours. The resulting reaction mixture was heated at 60° for 3 hours and left to stand at room temperature overnight. The precipitate formed was removed by filtration. The filtrate was concentrated by the use of a rotary

evaporator at a temperature below 60°C and 10 ml of water was added to the resulting viscous liquid. The finely divided solid that was formed was separated by

filtration, washed with tetrahydrofuran (THF) and dried in vacuum; this product was L(12)H₂. Yield: 0.6g. Anal. Calcd. for C₁₂H₂₀N₄O₆: C,45.56; H,6.37; N,17.71%. Found: C45.23; H.6.31; N, 16.97%.

Example 2-Synthesis of Metal Complex of L(12)

L(12)H₂ from Example 1 was suspended in water and was reacted with a large excess of copper (II)

hydroxycarbonate (from J.T.Baker Chemical Co.) at ca.

45°C with stirring overnight. Unreacted solids were removed by filtration. Evaporation of the solvent at ca. 40°C yielded a vitreous solid, which was repeatedly purified by crystallization from water. Light blue needle-like crystals suitable for an X-ray crystal analysis were grown from an aqueous solution by slow evaporation.

Example 3 -Synthesis of L(24)H₄

The filtrate from Example 1 was concentrated in a rotary evaporator, and the resulting viscous solution was mixed with a large amount of THF. The colorless solid that precipitated was the 24-membered ligand. The product was collected on a glass filter, washed with THF and dried in vacuum overnight. The yield was 1.2 g. The Anal. Calcd. for C₂₄H₄₀N₈O₁₂.H₂O: C,44.30: H,6.51; N, 17.22%. Found: C,44.67; H,6.89; N,16.69%.

Example 4-Synthesis of Metal Complex of L(24)

L(24)H₄ from Example 3 was suspended in water and reacted with manganese (II) carbonate (from J.T.Baker Chemical Co.) in the mole ratio of 1:2 at 45°C with stirring overnight. The unreacted solids were removed by filtration. The filtrate was concentrated at 45°C. When the resulting solution was mixed with a large amount of ethanol, a colorless solid was obtained. Repeated recrystallization of the product from water by slow evaporation yielded needle-like colorless crystals.

The cobalt (II) complex of L(24) was obtained by the reaction of 81 mg of L(24)H₄ and 40 mg of cobalt (II) carbonate (from Alfa Products) in 10 ml of water,

followed by filtration and concentration. In two weeks, pink needle-like crystals suitable for an X-ray crystal analysis were grown from an aqueous solution.

Example 5-X-Ray Crystal Analyses of Metal Complexes of L(12) and L(24)

Data collection was performed on a Syntex P2₁ diffractometer with Crystal Logic automatic system. The cell parameters were determined using 25 reflections in the range of 20<2Θ<30°. Crystal data are summarized in

Table 1. The Θ-2Θ scan method was used. For CuL(12).4H₂O,

2368 reflections were collected in the scan range

0<2Θ≤55°; 2343 reflections were unique. The 1807

reflections with I>3σ_I were used in the refinements. For

Mn₂L(24).8H₂O, 5592 reflections were collected in the range of 0<2Θ≤50° of which 1804 were unique. The 1510 reflections with I>3σ_I were used for refinements. Metal atoms were located by direct methods and the remaining atoms were placed at calculated positions and were included in the refinement. All calculations were performed on a VAX computer with a SPD/VAX program.

Example 6-Synthesis of L(15)H₃

To 2.45 g of diethylenetriaminepentaacetic

dianhydride (from Aldrich Chemical Co.) that was

suspended in 350 ml of dry dimethylformamide (DMF) was added dropwise a 50 ml of DMF containing 0.413 g of ethylenediamine (from Aldrich Chemical Co.) in a period of 4 hours with vigorous stirring under a nitrogen atmosphere. The reaction mixture was heated at 50°C for 3 hours and then left to stand for ca. 16 hours at room temperature. The precipitate formed was removed by filtration. Concentration of the filtrate at a

temperature below 40°C resulted in the formation of a light yellow solid and a viscous liquid. To this

reaction mixture, a small amount of water was added to dissolve the solid. When the resulting solution was mixed with tetrahydrofuran, the ligand was obtained as a colorless solid. The yield was 1.9 g. The Anal. Calc. for C₁₆H₂₇N₅O₈.1.5H₂O is C,43.24; H,6.80 and N,15.76%. The actual percentages were C,43.15; H,6.79; and N, 15.42%.

Example 7-Synthesis of Metal Complexes of L(15)

0.4 grams of the ligand produced in Example 6 was suspended in a small amount of water and 0.2 g of

gadolinium (III) carbonate (supplied from Rare Earth Products) was added with stirring. The resulting mixture was heated at ca. 40°C with stirring, overnight. From the resulting solid, the product was extracted with water at ca. 40°C. By evaporation of water, Gd(III) L(15).8H₂O was obtained as colorless crystals. The corresponding yttrium(III) complex, YL(15).8H₂O, was obtained in a similar manner by using yttrium(III) carbonate (from Aldrich Chemical Co). Example 8-X-ray Analysis

A crystal of each complex was sealed in a glass capillary together with the mother liquor for X-ray analyses; the crystals were found to readily effloresce. Table 10 summarizes the crystal data and the data

collections of the Gd(III) and Y(III) complexes. An empirical absorption correction based on a series of φ scans was applied to the data. Each structure was solved by the Patterson heavy-atom method, which revealed the position of the metal atom. The remaining atoms were located in succeeding difference Fourier syntheses.

Hydrogen atoms associated with the water molecules were located from the Fourier synthesis while other hydrogen atoms were placed at calculated positions.

Example 9 -Synthesis of L(13)H₂

To 2.0 g (8 mmol) of ethylenediaminetetraacetic dianhydride (from Aldrich Chemical Co.) suspended in 350 ml of dry dimethylformamide (DMF) was added dropwise a DMF solution (50 ml) containing 0.58 g (8 mmol) of 1,3-diaminopropane (from Aldrich Chemical Co.) with stirring under a nitrogen atmosphere for a period of 2 hours. The resulting reaction mixture was heated at 60°C for 3 hours and left to stand at room temperature overnight. The precipitate formed was removed by filtration. The filtrate was concentrated by the use of a rotary

evaporator at a temperature below 50°C, and the resulting viscous solution was mixed with a large amount of THF. The colorless solid that was formed was separated by filtration, washed with THF, and dried in vacuum. Anal. Calcd. for C₁₃H₂₂N₄O₆: C,47.27; H,6.67; N, 16.97. Found: C47.56; H,6.76; N, 16.91.

Example 10-Synthesis of Metal Complex of L(13)

The ligand L(13)H₂ produced in example 9 was

suspended in a small amount of water and was added to an equivalent amount of lead (II) carbonate (from Mallinckrodt Chemical Works) at 45°C with stirring overnight. The unreacted solid was removed by

filtration. When ethanol was added to the filtrate, the lead (II) complex was precipitated as a colorless solid. A block crystal suitable for X-ray analysis was grown from an aqueous solution by slow evaporation.

Example 11-X-ray Crystal Analysis of Metal Complex of L(13)

A colorless crystal from example 10 with approximate dimensions of 0.38 × 0.35 × 0.22 mm was sealed in a glass capillary. The data collection was performed with monochromated Mo Kα (λ - 0.71073 A) on an Enraf-Nonius CAD4 diffractometer. The cell constants were determined from 25 reflections in the range 26 < 20 < 36°. From the systematic absences (hOℓ, ℓ - 2n + 1; OkO, k = 2n + 1) the space group was determined to be P2₁/c (No. 14). The data were collected using w-20 scan method at a rate of 1-7° min^-1 in the range 0 < 20 ≤ 50° (h-0 to 10; k = 0 to 27; ℓ↼ =11 to 11): (sinΘ)/λ≤ 0.5940 Å^-1. Three standard reflections were monitored every 60 min, and were

constant within experimental error. A total of 3567 reflections were collected, 3245 of which were unique and not systematically absent. μ=92.6 cm^-1. An empirical absorption correction based on a series of Ψ-scans were applied to the data. Relative transmission coefficients ranged from 0.552 to 0.998 with an average value of

0.852. The structure was solved by the Patterson heavy-atom method which revealed the position of the Pb atom. The remaining atoms were located in succeeding difference Fourier syntheses. Hydrogen atoms were included in the refinement but constrained to ride on the atom to which they were bonded. Non-hydrogen atoms were

anisotropically refined. The full-matrix least-squares refinements were carried out using 2829 reflection with I > 3σ : where Σw(|F_o| - |F_c|)² was minimized; w was

calculated from 4F_o ²/σ²(F_o ²). Scattering factors used were from Cromer and Waber (1974). The anomalous dispersion effects were included in F_c, the values for Δf' and Δf" were those of Cromer (1974). The final agreement factors for 244 variables were: R=∑|F_o - F_c|/ΣF_o = 0.026 and R_w = [Σw(F_o - F_c)²/ΣwF_o ²]^1/2 = 0.038. The standard derivation of an observation of unit weight was 1.57. The ratio of Δ_max/σ was less than 0.01. The highest peak in the final difference Fourier was found near the Pb atom with a height of 1.1 (1)e- Å^-3; the minimum negative peak had a height of -0.3 (1) e- Å^-3. All calculations were performed on a VAX computer with a MolEN (Enraf-Nonius) program.

Example 12-Synthesis of L(16)H₃

To 2.45 g of diethylenediaminepentaacetic

dianhydride (from Aldrich Chemical Co.) that was

suspended in 350 mL of dry dimethylformamide (DMF) was added dropwise a DMF solution (50 mL) containing

propylenendiamine (from Aldrich Chemical Co.) for a period of 4 hours with vigorous stirring under a nitrogen atmosphere. The reaction mixture was heated at 50°C for 3 hours and then left to stand for ca. 16 hours at room temperature. The precipitate formed was removed by filtration. The filtrate was concentrated and purified by precipitation from a concentrated aqueous solution by the addition of ethanol. Anal. Calcd. for

C₁₇H₂₉N₅O₈.C₂H₅₀H.2H₂O: C,44.43; H,7.65; N, 13.64. Found:

C,45.05; H,7.21; N, 12.97.

Example 13-Metal Complex of L(16)

To 0.4 g of L(16) suspended in a small amount of water, 0.2 g of gadolinium(III) carbonate (supplied from Rare Earth Products) was added with stirring. The resulting mixture was heated at ca. 40°C with stirring overnight. The product was purified by adding ethanol to the aqueous solution. Single crystals suitable for X-ray analyses were obtained as a tetrahydrate by diffusion of acetone into an aqueous solution of the complex in a narrow bore tube.

TABLE 1

Summary of Crystal Data for CuL(12) ·4H₂O(I) and Mn₂L(24) ·8H₂O (II) complex I II

empirical formula CuC₁₂H₂₆N₄O₁₀ Mn₂C₂₄H₅₂N₈O₂₀

F.W. 449.90 882.60

T/°C 23 23

λ/Å (monochromated 0.71073 1 0.71073

Mo Ka)

F(000) 940 1386

crystal 0.30×0. 18×0 .17 0.48×0.37×0.25 dimensions/mm

space group orthorhombic hexagonal

P2₁2₁2₁ (No. 19) P6₂ (No.171)^a

Cell parameters

a/Å 10.070 (1) 18.072 (3)

b/Å 18.832 (2) 18.072 (3)

c/Å 9.425 (1) 10.195 (2)

V/Å³ 1787.3 (6) 2884 (2)

Z 4 3

dcalcd/^g cm^-3 1.67 1.56

μ/cm^-1 12.8 7.2

R(F_o) 0.040 0.036

R_w(F_o ²) 0.050 0.055

aRepresented by one of the space groups of a chiral pair (P6₂ and P6₄) TABLE 2

Selected Bond Distances (Å) in CuL(12)·4H₂O.

Atom 1 Atom 2 Distance Atom 1 Atom 2 Distance

Cu O1 1.936(4) 01 C4 1.277(6)

Cu O2 2.334(3) 02 C4 1.233(6)

Cu O3 1.996(4) 03 C6 1.274(6)

Cu O5 1.988(4) 04 C6 1.248(6)

Cu N1 2.088(4) 05 C8 1.254(6)

Cu N2 2.485(4) 06 C10 1.249(8)

TABLE 3 Selected Bond Angles (in Degrees) in CuL(12)·4H₂·.

Atom Atom Atom Angle Atom Atom Atom Angle 1 2 3 1 2 3

01 Cu O2 99.8(1) O2 Cu N2 142.9(1)

01 Cu O3 91.3(2) O3 Cu O5 177.1(2)

01 Cu O5 88.6(2) O3 Cu N1 97.7(2)

01 Cu N1 168.7(2) O3 Cu N2 74.5(1)

01 Cu N2 108.5(1) O5 Cu N1 82.7(2)

02 Cu O3 81.4(1) O5 Cu N2 102.7(1)

02 Cu O5 101.5(1) N1 Cu N2 80.7(1)

02 Cu N1 75.0(1)

TABLE 4

Positional Parameters and Their Estimated Standard Deviations of Non-hydrogen Atoms of CuL (12)·4H₂O.

Atom X y z B (Å²)

Cu 0.49178(5) 0.23571(3) 0.57602(6) 1.557(8)

O1 0.4096(3) 0.2862(2) 0.4202(4) 2.26(7)

O2 0.2060(3) 0.2777(2) 0.5147(4) 2.05(7)

O3 0.0711(4) 0.1746(2) 0.3494(4) 2.17(7)

O4 0.0181(4) 0.0660(2) 0.2751(5) 3.42(9)

O5 -0.0955(4) 0.3526(2) 0.4923(4) 2.17(7)

O6 -0.3238(5) 0.3716(3) 0.0667(5) 4.6(1)

N1 0.0861(4) 0.3346(2) 0.854(4) 1.51(7)

N2 -0.1333(4) 0.2370(2) 0.2034(5) 1.84(7)

N3 -0.1356(5) 0.4626(2) 0.4059(5) 2.67(9)

N4 -0.3233(4) 0.3571(3) 0.3047(5) 2.54(9)

C1 0.0183(5) 0.3370(3) 0.1451(5) 2.2(1)

C2 -0.0338(5) 0.2642(3) 0.1021(5) 2.22(9)

C3 0.2282(4) 0.3136(3) 0.2722(6) 1.85(9)

C4 0.2831(5) 0.2911(3) 0.4166(6) 1.97(9)

C5 -0.1271(6) 0.1585(3) 0.2108(6) 2.6(1)

C6 -0.0028(6) 0.1312(3) 0.2823(5) 2.27(9)

C7 0.0767(5) 0.4048(3) 0.3569(6) 2.1(1)

C8 -0.0598(5) 0.4067(3) 0.4248(6) 2.09(9)

C9 -0.2713(5) 0.2556(3) 0.1593(6) 2.4(1)

C10 -0.3075(5) 0.3344(3) 0.1749(6) 2.5(1)

C11 -0.2743(6) 0.4621(3) 0.4549(7) 3.1(1)

C12 -0.3621(6) 0.4301(3) 0.3404(8) 3.4(1)

OW1 0.6732(7) 0.6359(3) 0.3121(6) 6.6(2)

OW2 0.3457(7) 0.5026(3) 0.5139(8) 7.5(2)

OW3 0.5991(7) 0.9556(4 0.4053(8) 7.9(2)

OW4 0.5758(6) 0.0684(3 0.2318(8) 7.9(2) TABLE 4 CONT' D

.Anisotropically refined atoms are given in the form of the isotropic equivalent displacement parameter defined as:

(4/3) [a²·B(1.1) + b²·B(2,2) + c²·B(3,3) + ab(cos γ)-B(1,2) + ac(cos β)·B(1,3) + bc(cos α)·B(2,3)]

TABLE 5

Positional Parameters and Their Estimated Standard Deviations of Non-hydrogen Atoms of Mn₂L(24)·8H_·O.

Atom x y z B (Å²)

Mn 0.41960(5) 0.15747(4) 0.311 2.16(1)

O1 0.3105(2) 0.1395(3) 0.1896(4) 3.5(1)

O2 0.2128(2) 0.1761(3) 0.1542(5) 3.39(9)

O3 0.4970(3) 0.2705(2) 0.2046(4) 3.2(1)

O4 0.6163(3) 0.3950(3) 0.1965(5) 4.2(1)

O5 0.3787(2) 0.0524(2) 0.4508(5) 3.28(9)

O6 0.5609(2) 0.1619(2) 0.4042(4) 2.73(8)

N1 0.3103(3) 0.1572(2) 0.4530(5) 2.30(9)

N2 0.4974(2) 0.2622(2) 0.4714(5) 2.12(9)

N3 0.3031(3) -0.0148(2) 0.6286(5) 2.7(1)

N4 0.6172(3) 0.1702(3) 0.6056(5) 2.8(1)

C1 0.3528(3) 0.2167(3) 0.5630(6) 2.6(1)

C2 0.4390(3) 0.2911(3) 0.5200(6) 2.6(1)

C3 0.2592(3) 0.1830(3) 0.3730(6) 3.0(1)

C4 0.2608(3) 0.1639(3) 0.2278(6) 2.7(1)

C5 0.5708(3) 0.3337(3) 0.4047(6) 2.6(1)

C6 0.5599(3) 0.3341(3) 0.2583(6) 2.6(1)

C7 0.2590(3) 0.0681(3) 0.4981(6) 2.7(1)

C8 0.3185(3) 0.0342(3) 0.5249(6) 2.2(1)

C9 0.5280(3) 0.2297(3) 0.5779(6) 2.5(1)

C10 0.5717(3) 0.1843(3) 0.5205(5) 2.1(1)

C11 0.3559(3) -0.0532(3) 0.6582(7) 3.0(1)

C12 0.6679(4) 0.1299(3) 0.5726(8) 3.4(1)

OW1 0.4231(3) 0.0717(2) 0.1705(4) 3.8(1)

OW2 0.000 0.500 0.9678(7) 3.1(1)

OW3 0.1784(3) 0.3009(3) 0.2365(6) 5.1(1)

OW4 0.3423(4) 0.4387(4) 0.2455(6) 5.8(2)

OW5 0.0416(7) 0.0803(7) 0.052(1) 5.0 TABLE 5 CONT'D

When OW5 was refined by assuming a fixed isotropic thermal

parameter, an occupancy of approximately 0.5 was obtained.

Anisotropically refined atoms are given in the form of the

isotropic equivalent displacement parameter defined as:

(4/3) [a ²·B(1.1) + b²·B(2,2) + c²·B(3,3) + ab(cos γ) ·B(1,2) + ac(cosβ)-B(1,3) + bc(cos α) -B(2,3)]

TABLE 6

Selected Bond Distances (A) in Mn₂L(24) ·8H₂O

Atom 1 Atom 2 Distance Atom 1 Atom 2 Distance

Mn O1 2.212(5) O1 C4 1.244(9)

Mn O3 2.111(4) O2 C4 1.248(8)

Mn O5 2.184(4) O3 C6 1.268(6)

Mn O6 2.686(4) O4 C6 1.235(6)

Mn OW1 2.137(5) O5 C8 1.226(7)

Mn N1 2.445(5) O6 C10 1.237(7)

Mn N2 2.358(4) OW2 O6 2.767(5)

OW1 OW2 2.680(6)

TABLE 7

Selected Bond Angles (in Degrees) in Mn₂L(24)·8H₂O

Atom 1 Atom Atom Angle Atom Atom Atom Angle

2 3 1 2 3

01 Mn O3 87.9(2) O5 Mn 06 72.6(1)

01 Mn O5 110.4(1) O5 Mn OW1 85.8(2)

01 Mn O6 165.0(2) O5 Mn N1 72.1(2)

01 Mn OW1 82.2(2) O5 Mn N2 93.1(2)

01 Mn N1 70.8(2) O6 Mn OW1 83.4(2)

01 Mn N2 129.5(2) O6 Mn N1 123.2(2)

03 Mn O5 161.7(2) O6 Mn N2 63.7(2)

03 Mn O6 89.6(2) OW1 Mn N1 135.4(1)

03 Mn OW1 96.3(2) OW1 Mn N2 145.6(2)

03 Mn N1 116.8(2) N1 Mn N2 75.5(1)

03 Mn N2 74.9(2)

TABLE 8

Bond distances (Å) and Angles (°)

Pb-O(1)_amide 2 585 (3) N(1)-C(2) 1 468 (6) Pb-O(2)_amide 2 968 (4) N(1)-C(3) 1 487 (7)

Pb-O(3)_carboxylato 2 426 (4) N(1)-C(10) 1 476 (6) Pb-O(5)_carboxylato 2 .649 (4) N(2)-C(4) 1 469 (5)

Pb-N(1)_amine 2 .644 (3) N(2)-C(5) 1 491 (6) Pb-N(2)_amine 2 .594 (4) N(2)-C(12) 1 467 (7) Pb-O(w1)_water 2 .614 (4) N(3)-C(7) 1 478 (7) Pb-O(4')^a 3 .223 (4) N(4)-C(9) 1 .453 (7)

C(1) -O(1)_amide 1 .228 (5) C(1)-C(2) 1 .523 (7)

C(1) -N(4)_amide 1 .325 (6) C(3)-C(4) 1 .503 (7) C(6)-O(2)_amide 1 .232 (6) C(5)-C(6) 1 .520 (8) C(6) -N(3)_amide 1 .320 (6) C(7)-C(8) 1 .509 (7) C(11) -O(3)_carboxylato 1 .271 (6) C(8)-C(9) 1 .544 (8) C(11) -O(4)_carboxylato 1 .241 (6) C(10)-C(11) 1 .503 (6) C(13) -O(5)_carboxylato 1 .265 (9) C(12)-C(13) 1 .525 (8) C(13) -O(6)_carboxylato 1 .225 (8)

aO(4'): carboxylato oxygen from the adjacent metal chelate. O(1)-Pb-O(2) 60.4 (1) Pb-N(1)-C(10) 104.2 (3) O(1)-Pb-O(3) 129.1 (1) C(2)-N(1)-C(3) 111.7 (4) O(1)-Pb-O(4') 123.7 (1) C(2)-N(1)-C(10) 110.6 (4) O(l)-Pb-O(5) 138.3 (1) C(3)-N(1)-C(10) 109.8 (4) TABLE 8 CONT'D O(1)-Pb-O(wl) 80.1 (1) Pb-N(2)-C(4) 109. 4 (3)O(1)-Pb-N(1) 64.8 (1) Pb-N(2)-C(5) 110. 3 (3)O(1)-Pb-N(2) 83.8 (1) Pb-N(2)-C(12) 106. 8 (3)O(2)-Pb-O(3) 148.2 (1) C(4)-N(2)-C(5) 110. 4 (4)O(2)-Pb-O(4') 105.47 (9) C(4)-N(2)-C(12) 111. 4 (4)O(2)-Pb-O(5) 81.8 (1) C(5)-N(2)-C(12) 108 .3 (4)O(2)-Pb-O(wl) 127.9 (1) C(6)-N(3)-C(7) 123 .5 (5)O(2)-Pb-N(1) 111.3 (1) C(1)-N(4)-C(9) 123 .3 (4)O(2)-Pb-N(2) 66.1 (1) O(1)-C(1)-N(4) 123 .1 (5)O(3)-Pb-O(4') 92.5 (1) O(1)-C(1)-C(2) 120 .1 (4) O(3)-Pb-O(5) 75.3 (1) N(4)-C(1)-C(2) 116 .8 (4)O(3)-Pb-O(w1) 82.9 (1) N(1)-C(2)-C(1) 111 .5 (4) O(3)-Pb-N(1) 64.6 (1) N(1)-C(3)-C(4) 113 .1 (4) O(3)-Pb-N(2) 83.9 (1) N(2)-C(4)-C(3) 112 .6 (4) O(4')-Pb-O(5) 81.0 (1) N(2)-C(5)-C(6) 110 .3 (4) O(4')-Pb-O(w1) 68.1 (1) O(2)-C(6)-N(3) 125 .6 (5) O(4')-Pb-N(1) 139.2 (1) O(2)-C(6)-C(5) 117 .6 (4)O(4')-Pb-N(2) 144.4 (1) N(3)-C(6)-C(5) 116 .8 (5) O(5)-Pb-O(w1) 141.1 (1) N(3)-C(7)-C(8) 114 .1 (4) O(5)-Pb-N- (1) 120.7 (1) C(7)-C(8)-O(9) 118 .1 (4) O(5)-Pb-N(2) 63.8 (1) N(4)-C(9)-C(8) 116 .1 (5) O(w1)-Pb-N(1) 75.6 (1) N(1)-C(10)-C(11) 113 .3 (4) O(w1)-Pb-N(2) 145.4 (1) O(3)-C(11)-O(4) 123 .6 (4) TABLE 8 CONT'D

N(1)-Pb-N(2) 69.9 (1) O(3)-C(11)-C(10) 118.2 (4)

Pb-O(1)-C(1) 120.4 (3) O(4)-C(11)-C(10) 118.2 (4)

Pb-O(3)-C(11) 118.6 (3) N(2)-C(12)-C(13) 115.9 (5)

Pb-O(5)-C(13) 112.3 (3) O(5)-C(13)-O(6) 126.5 (6)

Pb-N(1)-C(2) 112.3 (3) O(5)-C(13)-C(12) 118.0 (5)

Pb-N(1)-C(3) 108.0 (2) O(6)-C(13)-C(12) 115.4 (6)

Hydrogen bonds

A B C A-B B-C A-C A-B-C

O(w1)-H(w1a)-O(3) 0.954 (4) 1.876 (3) 2.780 (5) 157.0 (3)

O(w1)-H(w1b)-O(6) 0.919 (4) 1.859 (4) 2.703 (5) 151.7 (3)

O(w2)-H(w2b)-O(4) 0.903 (5) 1.871 (4) 2.748 (6) 163.1 (3)

O(w3)-H(w3b)-O(6) 0.882 (6) 2.044 (6) 2.886 (8) 159.1 (4)

TABLE 9

Fractional coordinates and equivalent isotropic temperature factors.

x y z β_eq(Å²)

Pb 0.03928 (2) 0.10685 (1) 0.11590 (2) 1.920(4) O(1) 0.2813 (4) 0.1693 (2) 0.2529 (4) 2.71 (8) O(2) 0.0048 (5) 0.2344 (2) 0.1343 (4) 2.89 (8) O(3) -0.0309 (4) 0.0108 (2) 0.1786 (4) 2.60 (8) O(4) 0.0661 (5) -0.0774 (2) 0.2381 (5) 3.66 (9) O(5) -0.2688 (5) 0.1107 (2) 0.0556 (5) 3.5 (1) O(6) -0.4315 (4) 0.0680 (2) 0.1586 (6) 5.5 (1) O(w1) 0.2561 (4) 0.0498 (2) 0.0442 (4) 3.95 (9) O(w2) 0.7075 (5) 0.1595 (2) 0.7453 (5) 5.0 (1) O(w3) 0.4721 (6) 0.0544 (3) 0.8008 (5) 5.6 (1)

N(1) 0.2217 (4) 0.0640 (2) 0.3737 (4) 1.99 (8)

N(2) -0.0599 (4) 0.1398 (2) 0.3341 (4) 1.92 (8)

N(3) 0.1162 (5) 0.2667 (2) 0.3731 (4) 2.50 (9)

N(4) 0.4740 (5) 0.1892 (2) 0.4673 (5) 2.8 (1)

C(1) 0.3725 (5) 0.1537 (2) 0.3744 (5) 2.02 (9)

C(2) 0.3785 (6) 0.0902 (2) 0.4212 (6) 2.4 (1)

C(3) 0.1412 (6) 0.0723 (2) 0.4881 (5) 2.3 (1)

C(4) 0.0642 (5) 0.1307 (2) 0.4783 (5) 2.00 (9)

C(5) -0.1072 (5) 0.2020 (2) 0.3157 (6) 2.2 (1)

C(6) 0.0113 (6) 0.2372 (2) 0.2673 (5) 2.3 (1)

C(7) 0.2377 (6) 0.3036 (2) 0.3440 (6) 3.0 (1)

C(8) 0.3993 (6) 0.2959 (2) 0.4560 (6) 3.0 (1) TABLE 9 CONT'D

C(9) 0.5408 (6) 0.2477 (3) 0.4262 (6) 3.0 (1)

C(10) 0.2313 (6) 0.0015 (2) 0.3432 (6) 2.6 (1)

C(11) 0.0782 (6) -0.0238 (2) 0.2476 (6) 2.3 (1)

C(12) -0.1991 (6) 0.1048 (2) 0.3239 (7) 2.6 (1)

C(13) -0.3108 (6) 0.0941 (3) 0.1656 (7) 3.3 (1)

Anisotropic atoms are given in the form of:

B_eq - (4/3) [a²β_1,1 + b²β_2,2 + c²β_3,3 + ab(cos γ)β_1,2 + ac(cos β)β_1,3 + bc (cos α)β_2,3]

TABLE 10

Crystal Data and Data Collections for GdL(15)-8H₂O and GdL (16)-4H₂O.

GdL (15)·8H₂O GdL (16)·4H₂O chemical formula GdC₁₆H₄₀N₅O₁₆ GdC₁₇H₃₄N₅O₁₂

formula weight 715.8 657.74

crystal 0.46 × 0.30 × 0.22 0.50 × 0.37 × 0.34 dimensions/mm

T/°C 21 23

F(000) 2904 1324

space group orthorhombic monoclinic

Pbca (No. 61) P2₁/c (No. 14)

cell parameters

a/Å 18.205 (1) 8.246 (2)

b/Å 18.930 (1) 14.995 (3)

c/Å 15.609 (1) 19.367 (4)

β/deg 90.00 90.258 (2)

V/Å³ 5379 (1) 2395 (1)

Z 8 4

pcalcd/g cm^-3 1.77 1.82

μ/cm^-1 25.5 28.5

diffractometer used Enraf-Nonius CAD 4 Syntex P2₁

λ/Å (monochromated 0.71073 0.71073

Mo Kα)

scan method ω- 2θ θ-2θ TABLE 10 CONT'D

GdL (15) ·8H₂O GdL (16) ·4H₂O maximum 2θ 50° 50°

no. reflec collected 5269 4518 no. unique reflec 4741 4209 no. reflec with 3974 3661

I > 3.0σ_I

transmission 0.77 - 1.00 0.77 - 1.00 coefficient

R(F_o)^a 0.026 0.021

R(Fo²)^b 0.042 0.035 highest peak/e- Å^-3 0.79 (8) 0.49 (7) min. neg. peak/e- Å- -0.14 (8) -0.42 (7) computer and program VAX/MolEN VAX/MolEN used ^aR(Fo) = ∑|Fo-Fc|/ΣFo. ^bR(F_o ²) = [(∑w(Fo-Fc)²/ΣwFo²)]^1/2.

TABLE 11

Positional Parameters and Their Estimated Standard Deviations of GdL (15)·8H₂O.

Atom x y z B_eq(Å²)

Gd 0.42584(1) 0.45223(1) 0.30709(1) 2.163(4)

O(1) 0.5543(1) 0.4714(1) 0.3476(2) 2.63(5)

O(2) 0.6391(1) 0.5538(1) 0.5589(2) 2.62(5)

O(3) 0.4089(2) 0.4461(1) 0.1561(2) 3.27(6)

O(4) 0.4035(2) 0.4949(2) 0.0272(2) 3.54(6)

O(5) 0.3209(1) 0.5243(2) 0.2820(2) 3.14(5)

O(6) 0.2309(1) 0.5899(2) 0.3335(2) 4.16(6)

O(7) 0.5011(1) 0.6419(1) 0.7477(2) 3.24(5)

O(8) 0.4135(1) 0.7199(2) 0.7200(2) 3.71(6)

N(1) 0.4980(2) 0.5467(2) 0.2190(2) 2.59(6)

N(2) 0.4240(1) 0.5850(2) 0.3804(2) 2.24(5)

N(3) 0.5337(1) 0.6574(1) 0.5705(2) 2.28(5)

N(4) 0.6849(2) 0.5990(2) 0.4372(2) 2.96(6)

N(5) 0.6695(2) 0.4940(2) 0.3003(2) 2.92(6)

C(1) 0.5983(2) 0.4898(2) 0.2899(2) 2.45(6)

C(2) 0.5680(2) 0.5102(2) 0.2032(2) 2.77(7)

C(3) 0.5121(2) 0.6146(2) 0.2646(2) 2.84(7)

C(4) 0.4469(2) 0.6372(2) 0.3156(2) 2.73(7)

C(5) 0.4719(2) 0.5844(2) 0.4577(2) 2.39(6)

C(6) 0.4679(2) 0.6498(2) 0.5147(2) 2.46(6)

C(7) 0.6004(2) 0.6697(2) 0.5188(2) 2.53(7)

C(8) 0.6427(2) 0.6025(2) 0.5056(2) 2.32(6)

C(9) 0.7383(2) 0.5432(2) 0.4230(3) 3.29(8)

C(10) 0.7061(2) 0.4781(2) 0.3806(2) 3.02(7)

C(11) 0.4603(2) 0.5599(2) 0.1368(2) 2.98(7)

C(12) 0.4220(2) 0.4948(2) 0.1035(2) 2.74(7)

C(13) 0.3468(2) 0.5989(2) 0.4013(2) 2.76(7)

C(14) 0.2957(2) 0.5687(2) 0.3335(2) 2.72(7) TABLE 11 CONT'D

Atom x y z B_eq (Å²)

C(15) 0.5186(2) 0.7168(2) 0.6293(2) 2.72(7)

C(16) 0.4727(2) 0.6914(2) 0.7043(2) 2.88(7)

O(w1) 0.3343(1) 0.3623(2) 0.2829(2) 3.66(6)

O(w2) 0.1181(2) 0.3667(2) 0.4733(2) 4.69(7)

O(w3) 0.4857(2) 0.3137(2) 0.0768(2) 4.78(7)

O(w4) 0.3547(2) 0.1352(2) 0.4782(2) 5.94(8)

O(w5) 0.1803(2) 0.2127(2) 0.1090(3) 7.9(1)

O(w6) 0.2944(2) 0.3047(2) 0.1229(3) 8.1(1)

O(w7) 0.1991(2) 0.3315(3) 0.3323(3) 10.0(1)

O(w8) 0.3362(3) 0.1872(3) 0.2119(3) 8.9(1)

B_eq - (4/3) [a²B(1,1) + b²B(2,2) + c²B(3,3) + ab(cos γ)B(1,2) + ac(cos β)B(1,3) + bc(cos α)B(2,3)]

TABLE 12

Positional Parameters and Their Estimated Standard Deviations of YL(15)·8H₂O.

Atom x y z B_eq(Å²)

Y 0.42741(4) 0.45211(5) 0.30519(5) 2.39(1)

O(1) 0.5519(3) 0.4713(3) 0.3479(3) 2.6(1)

O(2) 0.6356(3) 0.5540(3) 0.5624(3) 2.6(1)

O(3) 0.4106(3) 0.4444(3) 0.1568(4) 3.2(1)

O(4) 0.4008(4) 0.4932(4) 0.0270(4) 3.6(1)

O(5) 0.3245(3) 0.5200(3) 0.2800(4) 3.3(1)

O(6) 0.2315(3) 0.5857(4) 0.3289(4) 4.2(2)

O(7) 0.5000(3) 0.6395(3) 0.7481(4) 3.2(1) O(8) 0.4116(3) 0.7173(3) 0.7224(4) 3.8(2)

N(1) 0.4975(4) 0.5459(4) 0.2179(4) 2.5(1)

N(2) 0.4237(4) 0.5836(4) 0.3786(4) 2.4(1)

N(3) 0.5314(4) 0.6564(4) 0.5715(4) 2.3(2)

N(4) 0.6828(4) 0.5980(4) 0.4396(4) 2.9(2)

N(5) 0.6684(4) 0.4932(4) 0.3009(4) 2.9(2)

C(1) 0.5960(5) 0.4896(5) 0.2910(5) 2.7(2)

C(2) 0.5679(5) 0.5105(5) 0.2032(5) 3.0(2)

C(3) 0.5110(5) 0.6128(5) 0.2635(5) 3.1(2)

C(4) 0.4451(4) 0.6363(4) 0.3137(5) 2.7(2)

C(5) 0.4715(4) 0.5831(4) 0.4560(5) 2.4(2)

C(6) 0.4668(5) 0.6486(5) 0.5141(5) 2.8(2)

C(7) 0.5973(5) 0.6692(5) 0.5210(6) 2.9(2)

C(8) 0.6400(4) 0.6010(5) 0.5080(5) 2.2(2)

C(9) 0.7358(4) 0.5432(5) 0.4263(6) 3.3(2)

C(10) 0.7035(5) 0.4761(5) 0.3829(6) 3.2(2)

C(11) 0.4601(5) 0.5589(5) 0.1363(5) 3.4(2)

C(12) 0.4211(5) 0.4934(5) 0.1041(5) 2.9(2)

C(13) 0.3462(4) 0.5970(5) 0.3992(5) 2.8(2)

C(14) 0.2986(5) 0.5660(5) 0.3314(5) 2.9(2) TABLE 12 CONT'D

Atom x y z B_eq (Å²)

C(15) 0.5162(5) 0.7162(5) 0.6297(5) 2.9(2)

C(16) 0.4717(5) 0.6889(5) 0.7051(5) 3.0(2)

O(w1) 0.3383(3) 0.3642(3) 0.2827(4) 3.5(1)

O(w2) 0.1211(3) 0.3681(4) 0.4741(4) 4.6(2)

O(w3) 0.4871(4) 0.3155(4) 0.0772(5) 5.3(2)

O(w4) 0.3588(5) 0.1361(5) 0.4749(5) 7.9(2)

O(w5) 0.1785(4) 0.2123(5) 0.1126(6) 7.9(3)

O(w6) 0.2946(4) 0.3090(5) 0.1217(5) 7.5(2)

O(w7) 0.2002(4) 0.3303(6) 0.3342(5) 8.3(3)

O(w8) 0.3398(6) 0.1888(6) 0.2084(7) 11.9(3)

TABLE 13

M-X and C-D Bond Distances (in A) in ML (15) -8H₂O

(M = Gd or Y)

Gd Y

M-O(1)_amide 2.449 (2) 2.403 (5)

M-O(2)_amide 2.406 (2) 2.370 (5)

M-O(3)_carboxylato 2.380 (3) 2.342 (5)

M-O(5)_carboxylato 2.381 (3) 2.320 (6)

M-O(7)_carboxylato 2.381 (3) 2.348 (6)

M-N(1)_amine 2.611 (3) 2.589 (7)

M-N(2)_amine 2.761 (3) 2.759 (7)

M-N (3)_amine 2.915 (3) 2.926 (7)

M-O(w1)_water 2.412 (3) 2.367 (6)

C(1)-O(1) 1.255 (4) 1.25 (1)

C(8)-O(2) 1.243 (4) 1.24 (1)

C(12)-O(3) 1.257 (5) 1.26 (1)

C(12)-O(4) 1.238 (4) 1.26 (1)

C(14)-O(5) 1.249 (5) 1.28 (1)

C(14)-O(6) 1.246 (4) 1.29 (1)

C(16)-O(7) 1.267 (4) 1.27 (1)

C(16)-O(8) 1.230 (5) 1.26 (1) TABLE 14

Bond Angles (in Degrees) around Metal in ML (15) 8H₂O

(M = Gd or Y)

Gd Y

0(1) -M-O(2) 104.59 (8) 103.1 (2)

0(1)-M-O(3) 112.72 (9) 114.1 (2)

0(1) -M-O(5) 136.35 (9) 137.1 (2)

0(1)-M-O(7) 70.75 (8) 71.0 (2)

0(1)-M-N(1) 63.51 (9) 64.6 (2)

0(1)-M-N(2) 76.67 (8) 76.7 (2)

0(1)-M-N(3) 72.24 (8) 71.4 (2)

0(1)-M-)(w1) 143.59 (9) 143.5 (2)

0(2)-M-O(3) 142.68 (9) 142.7 (2)

0(2)-M-O(5) 77.04 (9) 77.3 (2)

0(2)-M-O(7) 123.44 (8) 123.2 (2)

0(2)-M-N(1) 137.55 (8) 137.3 (2)

0(2)-M-N(2) 71.16 (8) 70.8 (2)

0(2)-M-N(3) 61.36 (8) 61.1 (2)

0(2)-M-O(w1) 76.28 (9) 76.0 (2)

0(3)-M-O(5) 76.18 (9) 76.1 (2)

0(3)-M-O(7) 71.36 (9) 71.2 (2)

0(3)-M-N(1) 64.96 (9) 65.7 (2) TABLE 14 CONT'D

O(3)-M-N(2) 116.94 (8) 117.7 (2) O(3)-M-N(3) 130.33 (8) 129.8 (2) O(3)-M-O(wl) 73.82 (9) 73.6 (2) O(5)-M-0(7) 144.88 (9) 144.6 (2) O(5)-M-N(1) 85.66 (9) 85.9 (2) O(5)-M-N(2) 62.40 (8) 62.8 (2) O(5)-M-N(3) 135.97 (8) 135.7 (2) O(5)-M-O(w1) 79.88 (9) 79.1 (2) O(7)-M-N(1) 92.42 (9) 92.7 (2) O(7)-M-N(2) 146.72 (8) 146.9 (2) O(7)-M-N(3) 64.00 (8) 63.9 (2) O(7)-M-O(w1) 78.58 (9) 79.1 (2) N(1)-M-N(2) 66.47 (9) 66.6 (2) N(1)-M-N(3) 134.87 (8) 135.0 (2) N(1)-M-O(w1) 138.5 (1) 138.9 (2) N(2)-M-N(3) 112.29 (8) 112.1 (2) N(2)-M-O(w1) 134.33 (8) 133.5 (2) N(3)-M-O(w1) 77.00 (8) 76.9 (2)

TABLE 15

Positional Parameters and Isotropic Thermal Parametersor GdL (16)·4H₂O.

Atom x y z B_eq/Å²

Gd 0.18531(2) 0.14340(1) 0.17534(1) 1.783(3)

O(1) 0.3071(2) 0.2896(2) 0.1528(1) 2.59(4)

O(2) -0.0280(2) 0.2527(1) 0.1539(1) 2.44(4)

O(3) 0.2354(3) 0.1406(2) 0.0549(1) 3.13(5)

O(4) 0.3865(3) 0.1159(2) -0.0373(1) 4.28(6)

O(5) 0.2757(3) -0.0037(2) 0.1825(1) 2.87(4)

O(6) 0.3601(4) -0.1218(2) 0.2411(2) 4.59(6)

O(7) 0.0206(2) 0.0792(2) 0.2636(1) 2.55(4)

O(8) -0.1099(3) 0.0816(2) 0.3632(1) 3.33(5)

N(1) 0.5058(3) 0.1441(2) 0.1371(1) 2.32(5)

N(2) 0.3788(3) 0.1159(2) 0.2807(1) 2.30(5)

N(3) 0.1149(3) 0.2554(2) 0.2777(1) 2.05(5)

N(4) -0.0123(3) 0.4018(2) 0.1377(1) 2.72(5)

N(5) 0.4187(4) 0.3522(2) 0.0582(2) 2.92(6)

C(l) 0.4198(4) 0.2956(2) 0.1097(2) 2.37(6)

C(2) 0.5639(4) 0.2353(2) 0.1199(2) 2.80(6)

C(3) 0.6033(4) 0.1053(3) 0.1934(2) 2.90(7)

C(4) 0.5475(4) 0.1426(2) 0.2626(2) 2.77(7)

C(5) 0.3277(4) 0.1705(3) 0.3409(2) 2.80(6)

C(6) 0.2647(4) 0.2613(2) 0.3214(2) 2.71(6)

C(7) 0.0711(4) 0.3431(2) 0.2486(2) 2.42(6)

C(8) 0.0035(3) 0.3295(2) 0.1762(2) 2.31(6)

C(9) -0.0293(4) 0.3987(3) 0.0630(2) 3.38(7)

C(10) 0.1222(5) 0.3640(2) 0.0270(2) 3.33(8)

C(11) 0.2789(4) 0.4132(2) 0.0476(2) 3.38(7)

C(12) 0.5042(4) 0.0897(2) 0.0740(2) 2.99(7)

C(13) 0.3673(4) 0.1180(2) 0.0263(2) 2.95(7)

C(14) 0.3739(4) 0.0193(2) 0.2975(2) 3.09(7) TABLE 15 CONT'D

Atom x y z B_eq/Å²

C(15) 0.3355(4) -0.0404(2) 0.2355(2) 2.89(6)

C(16) -0.0233(4) 0.2196(2) 0.3175(2) 2.43(6)

C(17) -0.0380(4) 0.1193(2) 0.3157(2) 2.31(6)

O(w1) -0.0326(3) 0.0590(2) 0.1163(1) 3.62(5)

O(w2) 0.6739(4) 0.1671(2) 0.9075(2) 5.57(7)

O(w3) 0.6665(3) 0.1605(2) 0.4542(1) 4.18(6)

O(w4) 0.9772(6) 0.0995(3) 0.9544(3) 12.1(1)

B,eq (4/3) [a ²·B(1,1) + b²B(2,2) + c²B(3,3) + ab(cos γ)B(1,2) + ac(cos β)B(1,3) + bc(cos α)B(2,3)]

TABLE 16

Selected Bond Distances (A) and Angles (°) In GdL(16)·4H₂O

2.748 (3)

Bond

Distances

2.451 (2) Gd-N(1)_amine

Gd- O(1)_amide

Gd- O(2)_amide 2.439 (2) Gd-N(2)_amine 2.618 (2) Gd- 2.371 (2) Gd-N(3)_amine 2.664 (2)

O(3)_carboxylato

Gd- 2.332 (2) Gd-N(w1)_water 2.474 (2)

O(5)_carboxylato

Gd- 2.391 (2)

O(7)_carboxylato

C(1)-O(1) 1.256 (4) C(15)-O(5) 1.264 (4) C(8)-O(2) 1.257 (4) C(15)-O(6) 1.242 (4) C(13)-O(3) 1.270 (4) C(17)-O(7) 1.272 (4) C(13)-O(4) 1.242 (4) C(17)-O(8) 1.234 (4)

Bond Angles

O(1)-Gd- 70.39 (7) O(1)-Gd- 76.55 (7)

O(2) O(3)

O(1)-Gd- 136.48 (7) O(1)-Gd- 136.23 (7) O(5) O(7)

O(1)-Gd- 63.47 (7) O(1)-Gd- 91.77 (7)

N(1) N(2)

O(1)-Gd- 70.11 (7) O(1)-Gd- 132.29 (8)

N(3) O(w1) TABLE 16 CONT'D

O(2)-Gd- 88.44 (8) O(2)-Gd- 151.15 (7)

O(3) O(5)

O(2)-Gd- 88.92 (7) O(2)-Gd- 130.20 (7)

O(7) N(1)

O(2)-Gd- 132.50 (8) O(2)-Gd- 62.87 (7)

N(2) N(3)

O(2)-Gd- 75.14 (7) O(3)-Gd- 89.11 (8)

O(w1) O(5)

O(3)-Gd- 142.98 (8) O(3)-Gd- 64.09 (8)

O(7) N(l)

O(3)-Gd- 131.00 (8) O(3)-Gd- 141.52 (8)

N(2) N(3)

O(3)-Gd- 70.46 (8) O(5)-Gd- 76.06 (8)

O(wl) O(7)

O(5)-Gd- 73.26 (7) O(5)-Gd- 67.12 (8)

N(1) N(2)

O(5)-Gd- 128.50 (8) O(5)-Gd- 76.96 (8)

N(3) O(w1)

O(7)-Gd- 138.10 (7) O(7)-Gd- 74.04 (7)

N(1) N(2)

O(7)-Gd- 66.13 (7) O(7)-Gd- 73.18 (8)

N(3) O(w1)

N(1)-Gd- 68.11 (8) N(1)-Gd- 114.28 (7)

N(2) N(3)

N(1)-Gd- 125.08 (8) N(1)-Gd- 69.70 (8)

O(w1) N(3)

N(2)-Gd- 135.93 (8) N(3)-Gd- 120.42 (7)

O(w1) O(w1)

Claims

CLAIMS :

1. A macrocyclic ligand according to the following formula:

wherein A is selected from the group consisting of:

-(CH₂)_x-

-(CH₂)_x-NR₁-(CH₂)_y-

- (CH₂) _x-NR₂-(CH₂)_y-NR₃-(CH₂)_z-;

B is selected from the group consisting of:

- (CH₂) _v-

w is selected to be the same as either m or n;

and R₁, R₂, R₃ is H or any alkyl group.

2. The macrocyclic ligand of claim 1 wherein m=l, A=(CH)_x, and B=(CH₂)_v or

3. The macrocyclic ligand of claim 1 wherein m=l, A=(CH₂)_x, B=(CH₂)_v, v=2 and x=2.

4. The macrocyclic ligand of claim 1 wherein m=1, A=(CH₂)_x, B=(CH₂)_v, x=3 and v=2.

5. The macrocyclic ligand of claim 1 wherein A=(CH₂)_x,

m=1, x=2, v=2, t=2, and w=1.

6. The macrocyclic ligand of claim 1 wherein A=(CH₂)_x

m=1, x=3, v=2, w=1, and t=2.

7. A macrocyclic ligand according to the following formula:

wherein A is selected from the group consisting of

-(CH₂)_x-

-(CH₂)_x-NR₁-(CH₂)_y-

- (CH₂)_x-NR₂-(CH₂)_y-NR₃-(CH₂)_C-; B is selected from the group consisting of

-(CH₂)_v-

w is selected to be the same as m or n;

and R₁, R₂, R₃ is H or any alkyl group.

8. The macrocyclic ligand of claim 7 wherein A =(CH₂)_x and B =(CH₂)_v.

9. The macrocyclic ligand of claim 7 wherein m=1, A=(CH₂)_x, B=(CH₂)_v, x=2 and v=2.

10. A macrocyclic ligand according to the following formula:

wherein A is selected from the group consisting of:

-(CH₂)_x-

-(CH₂)_x-NR₁-(CH₂)_y-

- (CH₂)_x-NR₂-(CH₂)_y-NR₃-(CH₂) -; B is selected from the group consisting of:

-(CH₂)_v-

C is selected from the group consisting of:

-(CH₂)_v-

w is selected to be the same as m or n; and

R₁, R₂, R₃ is H or any alkyl group.

11. A macrocyclic ligand according to the following formula:

12 . A macrocyclic ligand according to the following formula :

13. A macrocyclic ligand according to the following formula:

14. A macrocyclic ligand according to the following formula:

15. A macrocyclic ligand according to the following formula:

16. A complex of a metal selected from the group consisting of any metal ion that is in the +1, +2, +3, or +4 oxidation state with a macrocyclic ligand having the formula:

wherein A is selected from the group consisting of:

-(CH₂)_x-

-(CH₂)_x-NR₁-(CH₂)_y-

- (CH₂)_x-NR₂-(CH₂)_y-NR₃-(CH₂)_z-;

wherein B is selected from the group consisting of:

-(CH₂)_v-

w is selected to be the same as m or n; and

R₁, R₂, R₃ is H or any alkyl group.

17. The complex of claim 16 wherein m=1, A=(CH₂)_x, B=(CH₂)_v, x=2, and v=2.

18. The complex of claim 17 wherein the metal is any divalent metal ion.

19. The complex of claim 17 wherein the metal is copper (II).

20. The complex of claim 16 wherein m=1, A=(CH₂)_x, B=(CH₂)_v, x=3 and v=2.

21. The complex of claim 20 wherein the metal is any divalent metal ion.

22. The complex of claim 20 wherein the metal is manganese (II).

23. The complex of claim 20 wherein the metal is lead (II).

24. The complex of claim 16 wherein

A=(CH₂)_x

m=1, v=2, x=2, w=1, and t=2.

25. The complex of claim 24 wherein the metal is any trivalent metal ion.

26. The complex of claim 25 wherein the metal is gadolinium(III).

27. The complex of claim 25 wherein the metal is yttrium(III).

28. The complex of claim 16 wherein A=(CH₂)_x

m=1, x=3, v=2, w=1, and t=2.

29. The complex of claim 28 wherein the metal is any trivalent metal ion.

30. The complex of claim 28 wherein the metal is gadolinium(III).

31. A complex of a metal selected from the group consisting of any metal ion that is in the +1, +2, +3 or +4 oxidation state with a macrocyclic ligand having the formula:

wherein A is selected from the group consisting of:

-(CH₂)_x-

-(CH₂)_x-NR₁-(CH₂)_y-

- (CH₂)_x-NR₂-(CH₂)_y-NR₃-(CH₂)_z-;

B is selected from the group consisting of:

-(CH₂)_v-

w is selected to be the same as m or n; and

R₁, R₂, R₃ is H or any alkyl group.

32. The complex of claim 31 wherein m=1, A=(CH₂)_x, B=(CH₂)_v, x=2 and v=2.

33. The complex of claim 32 wherein the metal is any divalent metal ion.

34. The complex of claim 32 wherein the metal is manganese (II).

35. The complex of claim 32 wherein the metal is cobalt (II).

36. A method for enhancing contrast in imaging techniques used on living subjects, which includes administering internally to the subject an effective amount of a contrast agent which comprises a complex of a metal selected from the group consisting of any metal ion that is in the +1, +2, +3 or +4 oxidation state and a macrocyclic ligand having the formula:

wherein A is selected from the group consisting of:

-(CH₂)_x-

-(CH₂)_x-NR₁-(CH₂)_y-

-(CH₂)_x-NR₂-(CH₂)_y-NR₃-(CH₂)_z-;

B is selected from the group consisting of:

-(CH₂)_v-

w is selected to be the same as m or n; and

R₁, R₂, R₃ is H or any alkyl group.

37. The method of claim 36 wherein m=1,

A=(CH₂)_x, B=(CH₂)_v, v=2 and x=2.

38. The method of claim 37 wherein the metal is any divalent metal ion.

39. The method of claim 37 wherein the metal is copper (II).

40. The method of claim 36 wherein m=1, A=(CH₂)_x, B=(CH₂)_v, x=3, and v=2.

41. The method of claim 40 wherein the metal is any divalent metal ion.

42. The method of claim 40 wherein the metal is lead(II).

43. The method of claim 40 wherein the metal is manganese (II).

44. The method of claim 36 wherein A=(CH₂)_x

m=1, x=2, w=1, t=2 and v=2.

45. The method of claim 44 wherein the metal is any trivalent metal ion.

46. The method of claim 44 wherein the metal is gadolinium(III).

47. The method of claim 44 wherein the metal is yttrium(III).

48. The method of claim 36 wherein

A=(CH₂)_x

m=1, x=3, t=2, w=1 and v=2.

49. The method of claim 48 wherein the metal is any trivalent metal ion.

50. The method of claim 48 wherein the metal is gadolinium (III).

51. A method for enhancing contrast in imaging and diagnostic techniques used on living subjects, which includes administering internally to the subject an effective amount of a contrast agent which comprises a complex of a metal selected from the group consisting of any metal ion that is in the +1, +2, +3 or +4 oxidation state and a macrocyclic ligand having the formula:

wherein A is selected from the group consisting of:

-(CH₂)_x-

-(CH₂)_x-NR₁-(CH₂)_y-

-(CH₂)_v-

w is selected to be the same as m or n; and

R₁, R₁, R₂ is H or any alkyl group.

52. The method of claim 51 wherein m=1, A=(CH₂)_x, B=(CH₂)_v, x=2, and v=2.

53. The method of claim 52 wherein the metal is any divalent metal ion.

54. The method of claim 52 wherein the metal is manganese (II).

55. The method of claim 52 wherein the metal is cobalt (II).

56. A method for synthesizing macrocyclic ligands with pendant carboxylic acid groups comprising the steps of:

providing a polyalkylpolyaminopolycarboxylic dianhydride;

providing an alkylpolyamine or polyalkylpolyamine; reacting the polyalkylpolyaminopolycarboxylic dianhydride and the polyalkylpolyamine under conditions sufficient to cause the synthesis of the macrocyclic ligands with pendant carboxylic acid groups.

57. The method of claim 56 wherein the

polyalkylpolyaminopolycarboxylic dianhydride is

ethylenediaminetetraacetic dianhydride and the

alkylpolyamine or polyalkylpolyamine is ethylenediamine.

58. The method of claim 56 wherein the

polyalkylpolyaminopolycarboxylic dianhydride is

ethylenediaminetetraacetic dianhydride and the

alkylpolyamine or polyalkylpolyamine is

1,3-diaminopropane.

59. The method of claim 56 wherein the

alkylpolyamine or polyalkylpolyaminopolycarboxylic dianhydride is diethylenetriaminepentaacetic dianhydride and the polyalkylpolyamine is ethylenediamine.

60. The method of claim 56 wherein the

polyalkylpolyaminopolycarboxylic dianhydride is

diethylenetriaminepentaacetic dianhydride and the

alkylpolyamine or polyalkylpolyamine is propylenediamine.

61. The complex of claim 16 wherein two of said metal ions complex with two of said ligands.

62. The complex of claim 16 wherein two of said metal ions complex with one of said ligands.

63. A complex of two metal ions selected from the group consisting of metal ions that are in the +1, +2, +3 or +4 oxidation state with two macrocyclic ligands having the following formula:

64. The complex of claim 63 wherein the metal ions are selected from the group consisting of

gadolinium(III) and yttrium (III).

65. The complex of claim 31 wherein two of said metal ions complex with two of said ligands.

66. The complex of claim 31 wherein two of said metal ions complex with one of said ligands.

67. A complex of two metal ions selected from the group consisting metal ions that are in the +1, +2, +3 or +4 oxidation state with a macrocyclic ligand having the following formula:

68. The complex of claim 67 wherein the metal ions are manganese (II),