HRP970139A2 - New ternary radiopharmaceutical complexes - Google Patents

Description

This application is related to the still pending patent application of U.S.S.N. 08/415,908, which is a continuation of U.S.S.N. 08/218,861 which is a continuation of U.S.S.N. 08/040,336 filed Mar. 30, 1993, the contents of which are incorporated herein by reference.

The field of technology

This invention relates to novel radiopharmaceuticals useful as contrast agents, imaging agents for diagnosing cardiovascular disorders, infectious diseases and cancer, and kits (accessories) useful in their preparation. Radiopharmaceuticals consist of technetium-99m bound to a heterocycle containing nitrogen labeled hydrazino or diazino modified biologically active molecules that are selectively localized at the sites of the disease and therefore enable imaging at these sites by means of gamma scintigraphy.

State of the art

Today, there is a need for new procedures (methods) of non-invasive diagnostics of various diseases such as thromboembolic disease, atherosclerosis, infection and cancer. Radiopharmaceuticals, which consist of radionuclides that emit gamma rays and label biologically active molecules, can meet this need. Biologically active molecules are used to place radionuclides at disease sites and thus enable visualization (showing) of these sites by gamma scintigraphy. Molecules can be proteins, antibodies, antibody particles, peptides or polypeptides or peptidomimetics. The molecules interact with a receptor or binding site expressed at sites of disease or with a receptor or binding site on an endogenous blood component, such as platelets or leukocytes, that accumulate at those sites. This interaction leads to the selective localization of a certain percentage of the injected radiopharmaceutical while the rest is cleared, leaving, either by the renal or hepatobiliary system. The localized radiopharmaceutical is then visualized externally using gamma scintigraphy. The relative rates of sequestration, clearance, and radionuclide decay determine the quality of the visualization, which is often expressed as a target-to-background ratio. Often, only certain parts of biologically active molecules bind to receptors; these parts are called sequences or recognition units.

Numerous radiopharmaceuticals consisting of radionuclide-labeled proteins, antibodies, and antibody particles are being developed, but only one of them has been approved by the US Food and Drug Administration to date. This small number of approved radiopharmaceuticals is the result of a combination of factors that make obtaining such radiopharmaceuticals very difficult, including problems with production and quality control, suboptimal sequestration and clearance ratios, and the occurrence of antigenic or aphergic reactions to radiopharmaceuticals. These problems are mainly related to the macromolecular nature of proteins, antibodies and antibody particles. Their high molar weight makes simple and direct chemical production difficult, and therefore they must be synthesized by recombinant or cloning techniques, which are characteristically low-yielding and require extensive isolation and purification procedures. Their molar weight can slow down their localization ratios and prevent their clearance by active elimination mechanisms via the kidney or liver, leading to their prolonged retention in the bloodstream resulting in a high background level during imaging (imaging). Also, the body's immune system usually recognizes larger amounts of the exogenous species more effectively.

The use of peptides, polypeptides or peptidomimetics of lower molar weight for biologically active molecules prevents a large part of these problems. These molecules can be directly synthesized using classical solution chemistry or an automated peptide synthesizer. They can be obtained in larger quantities and require less complex purification procedures. They are usually cleared from the bloodstream more quickly by active elimination, leading to lower background levels in images. They are also not immunogenic. Recently, the US Department of Food and Drugs (Food and Drugs Administration) approved the first radionuclide-labeled polypeptide radiopharmaceutical.

There are two main methods of labeling biologically active molecules with radionuclides so that they can be used as radiopharmaceuticals, and they are called direct and indirect labeling. Direct labeling includes binding of radionuclides to atoms of biologically active molecules; while the indirect method involves the binding of radionuclides by means of chelators. The chelator can either be bound to the biologically active molecule prior to reaction with the radionuclide, or the radionuclide-labeled chelator medium can be bound to the biologically active molecule. Several recent articles describe these labeling procedures and are incorporated herein by reference: S. Jurisson et. al., Chem. Rev., 1993, 93, 1137; A. Verbruggen, Eur. J. Nuc. Med., 1990, 17, 346; and M. Derwanjee, Semin. Nuc. Med., 1990, 20, 5.

The use of hydrazines and hydrazides as chelators to modify proteins for radionuclide labeling was recently described by Schwartz et al., U.S. Patent 5,206,370. For labeling with technetium-99m, the hydrazine-modified protein was introduced into the reaction with the reduced species of technetium, obtained by the reaction of pertechnetate with a reducing agent in the presence of a dioxygen ligand acting as a chelator.

Technetium binds to the protein via what is believed to be a hydrazido or diazenido bond with a coordination sphere complete with ancillary dioxygen ligands. Examples of ancylamic dioxygen ligands include glucoheptonate, gluconate, 2-hydroxyisobutyrate, and lactate. Recently, certain dioxygen ligands have been reported to be particularly suitable for labeling hydrazine-modified proteins with technetium-99m. Bridger et al., U.S. Patent 5,350,837 discloses a series of functionalized aminocarboxylates whose application is said to improve the labeling process of hydrazine-modified macromolecules such as monoclonal antibodies. Improvements manifest as shorter reaction times and higher specificity of activity. Examples of these improved dioxygen ligands include hydroxyalkyl substituted derivatives of glycine such as tricine.

In a pending U.S. patent application Serial No. 08/218,861 (equivalent to WO 94/22494), filed Mar. 28, 1994, describes the synthesis of novel radiolabeled platelet IIb/IIIa receptor antagonists as contrast agents (imaging agents) for thromboembolic disorders. These reagents contain radionuclide-labeled chelator-modified cyclic compounds. A preferred chelator for modifying cyclic compounds is a hydrazino or diazenido group.

Preferred reagents are used for the synthesis of binary complexes consisting of a hydrazido or diazenido moiety and one of a number of ancylam ligands.

Presentation of the essence of the invention

The present invention provides novel radiopharmaceuticals that are useful as contrast agents (imaging agents) for diagnosing cardiovascular disorders, such as thromboembolic disease or atherosclerosis, infectious disease and cancer. Radiopharmaceuticals consist of technetium-99m bound to a nitrogen-labeled heterocyclic hydrazino or diazino-modified biologically active molecule that selectively accumulates at the sites of disease and therefore enables imaging (displaying) of these sites using gamma scintigraphy. This invention also provides methods of using said radiopharmaceuticals as contrast agents (imaging agents) for diagnosing thromboembolic disease or atherosclerosis, infectious disease or cancer. He also brings kits (accessories) for the preparation of the respective radiopharmaceuticals.

Short description of the pictures

Figure 1. Data from a canine arteriovenous "shunt" (junction) model for the radiopharmaceutical from Example 1 (150 μCi/kg, i.v.), compared with 111In-platelets, 125I-fibrinogen and 99mTc-albumin.

Detailed description of the invention

This invention relates to new radiopharmaceuticals for diagnosing cardiovascular disorders, such as thromboembolic disease or atherosclerosis, infectious disease or cancer of the formula [(Q)d,Ln-Ch-]x - Mt(AL1)y(AL2)z, procedures for applying the respective radiopharmaceuticals in diagnosing diseases and kits (accessories) useful for the preparation of the respective radiopharmaceuticals.

[1] One form of this invention is a radiopharmaceutical containing a first ancillary ligand, a second ancillary ligand capable of stabilizing a radiopharmaceutical, a transition metal radionuclide, a transition metal chelator, a biologically active group attached to said chelator, which may have a binding group between said chelator and said biologically active groups.

[2] Preferred radiopharmaceuticals of this invention are those that have a binding group between the mentioned chelator and the mentioned biologically active group.

[3] Even more preferred radiopharmaceuticals of this invention are those that have the formula:

[(Q)d.Ln-Ch.]x-Mt(AL1)y(AL2)z

and their pharmaceutically acceptable salts characterized in that,

Q is a biologically active group;

d' is 1 to 20;

Ln is the linking group of the formula:

M1-[Y1-(CR55R56)f(Z1)F'Y2]f'-M2

indicated by that

M1 is - [(CH2)gZ1]g - (CR55R56)g''-;

M2 is - (CR55R56)g„- [Z1(CH2)g,]g'-;

g is independently 0-10;

g' is independently 0-1;

g'' is independently 0-10;

f is independently 0-10;

f' is independently 0-10;

f'' is independently 0-1;

Y1 and Y2, at each occurrence, are independently selected from:

bonds, O, NR56, C=O, C(=O)O, OC (=O)O, C (=O)NH-C=NR56, S, SO, SO2, SO3, NHC(=O), ( NH)2C (=O), (NH)2C=S;

Z 1 is independently selected at each occurrence from a C 6 -C 14 saturated, partially saturated or aromatic carbocyclic ring system, substituted with 0-4 R 57 ; and heterocyclic ring system, preferably substituted with 0-4 R57;

R55 and R56 are independently selected at each occurrence from:

hydrogen, C1-C10 alkyl substituted with 0-5 R57, alkaryl wherein the aryl is substituted with 0-5 R57;

R57 is independently selected at each occurrence from the group: hydrogen, OH, NHR58, C (=O)R58, OC (=O)R58, OC(=O)OR58, C (=O)OR58, C (=O)NR58 , C=N, SR58, SOR58, SO2R58, NHC (=O)R58, NHC (=O)NHR58, NHC(=S)NHR58, or, likewise, when linked to an additional molecule Q, R57 is independently selected at to each occurrence from the group: O, NR58, C=O, C (=O)O, OC (=O)O, C (=O)N, C=NR58, S, SO, SO2, SO3, NHC (=O ), (NH)2C (=O), (NH)2C=S; and

R 58 is independently selected at each occurrence from the group: hydrogen, C 1 -C 6 alkyl, benzyl, and phenyl;

x, y and z are independently 1 or 2;

Mt is a transition metal radionuclide selected from the group: 99mTc, 186Re and 188Re;

Ch. is a radionuclide metal chelator aligned with the transition metal radionuclide Mt, and is independently selected at each occurrence from the group: R40N = N+ = , R40R41N-N = , and R40N = N(H)-; indicated by that

R40 is independently selected at each occurrence from the group: bond with Ln, C1-C10 alkyl substituted with 0-3 R52, aryl substituted with 0-3 R52, cycloalkyl substituted with 0-3 R52, heterocyclic compound substituted with 0-3 R52, heterocycloalkyl substituted with 0-3 R 52 , aralkyl substituted with 0-3 R 52 , and alkaryl substituted with 0-3 R 52 ;

R 41 is independently selected from the group: hydrogen, aryl substituted with 0-3 R 52 -C 1 -C 10 alkyl substituted with 0-3 R 52 , and heterocyclic compound substituted with 0-3 R 52 ;

R52 is independently selected at each occurrence from the group: bond with LN, =O, F, Cl, Br, I, -CF3, -CN, -CO2R53, -C(=O)R53,

-C(=O)N(R53)2, -CHO, -CH2OR53, -OC(=O)R53, -OC(=O)OR53a, -OR53, -OC(=O)N(R53)2, - NR53C(=O)R53, -N(R53)3+,

-NR54C(=O)OR53a, NR53C(=O)N(R53)2, -NR54SO2N(R53)2, -NR54SO2 R53a, -SO3H, -SO2R53a, -SR53, -S(=O)R53a,

-SO2N(R53)2, -N(R53)2, -NHC(=NH)NHR53, -C(=NH)NHR53, =N O R53, NO2, -C(=O)NHOR53, -C(=O) NHNR53R53a,

-OCH2CO2H, 2-(1-morpholino)ethoxy;

R53, R53a, and R54 are each independently selected at each occurrence from the group: hydrogen, C1-C6 alkyl, and a bond with Ln

AL1 is the first ancillary ligand selected from the group: dioxygen ligand and functionalized aminocarboxylate;

Al2 is an alkylami ligand capable of stabilizing a radiopharmaceutical selected from the group:

[image]

indicated by that

n is 0 or 1;

X1 is independently selected at each occurrence from the group: CR64 and N;

X2 is independently selected at each occurrence from the group: CR64, CR64R64, N, NR64, O and S;

X3 is independently selected at each occurrence from the group: C, CR64, and N;

provided that the total number of heteroatoms in each ring of the AL2 ligand is from 1 to 4;

Y is selected from the group: BR64- CR64, (P=O), (P=S); and a, b, c, d, e and f indicate the location of possible double bonds, provided that e or f is a double bond;

R64 is independently selected at each occurrence from the group:

H, C1-C10 alkyl substituted with 0-3 R65, C2-C10 alkenyl substituted with 0-3 R65, C2-C10 alkynyl substituted with 0-3 R65, aryl substituted with 0-3 R65, carbocyclic compound substituted with 0-3 R65, R65; or, likewise, two R 64 may be taken together with the atom or atoms to which they are linked and with which they form a fused aromatic, carbocyclic or heterocyclic ring substituted by 0-3 R 65 ;

R65 is independently selected at each occurrence from the group: =O, F, Cl, Br, I, -CF3, -CN, -NO2, -CO2R66, -C(=O)R66, -C(=O)N(R66 )2,-N(R66)3+, -CH2OR66, -OC(=O)R66, -OC(=O)0R66a, -OR66, -OC(=O)N(R66)2, -NR66C(=O )R66, -NR67C(=O)OR66a, -NR66C(=O)N(R66)2, -NR67SO2N(R66)2, -NR67SO2 R66a, -SO3H, - SO2R66a, -SO2N(R66)2, - N( R66)2, -OCH2CO2H; and

R66, R66a and R67 are each independently selected at each occurrence from the group: hydrogen and C1-C6 alkyl.

[4] Also preferred are the radiopharmaceuticals of this invention indicated by, that

Q is a biologically active molecule selected from the group: IIb/IIIa receptor antagonists, IIb/IIIa receptor ligands, fibrin-binding peptides, leukocyte-binding peptides, chemotactic peptides, somatostatin analogs, and selectin-binding peptides;

d1 is 1 to 3;

Ln is:- (CR55R56)g'' - [Y1(CR55R56)fY2]f' - (CR55R56)g'' - indicated that

g" is 0-5;

f is 0-5;

f' is 1-5;

Y1 and Y2, at each occurrence, are independently selected from: O, NR56, C=O, C(=O)O, OC (=O)O, C (=O)NH, C = NR56, S, SO, SO2, SO3, NHC(=O), (NH)2C (=O), (NH)2C=S;

R 55 and R 56 are independently selected at each occurrence from: hydrogen, C 1 -C 10 alkyl and alkaryl;

x and y are 1;

Mt is 99mTc;

Ch. is selected from the group: R40N = N+= and R40R41N-N = ; indicated by that

R40 is independently selected at each occurrence from the group: aryl substituted with 0-3 R52, heterocyclic compound substituted with

0-3R52;

R 41 is independently selected from the group: hydrogen, aryl substituted with 0-1 R 52 -C 1 -C 3 alkyl substituted with 0-1 R 52 , and heterocyclic compound substituted with 0-1 R 52 ;

R52 is independently selected at each occurrence from the group: bond with Lp, -CO2R53, -CH2OR53, -SO3H, -SO2R53a, -N(R53)2, -N(R53)3+, -NHC(=NH)NHR53, - OCH2CO2H;

R 53 and R 53a are each independently selected at each occurrence from the group: hydrogen, C 1 -C 3 alkyl;

AL1 is a functionalized aminocarboxylate;

n is 0;

Y is BR64-;

R64 is independently selected at each occurrence from the group:

H, C1-C3 alkyl substituted with 0-3 R65, aryl substituted with 0-3 R65, and R65;

or, likewise, two R 65 may be taken together with the atom or atoms to which they are linked and with which they form a fused aromatic, carbocyclic or heterocyclic ring replaced by 0-3 R 65 ;

R65 is independently selected at each occurrence from the group: -NO2, -CO2R66, -OR66, -SO3H, and -OCH2CO2H; and

R66 is hydrogen.

[5] The most preferred radiopharmaceuticals of this invention are indicated by, that

Q is a biologically active molecule selected from the group: IIb/IIIa receptor antagonists and chemotactic peptides;

d' is 1;

Y1 and Y2 at each occurrence are independently selected from: O, NR56, C=O, C(=O)O, OC (=O)O, C (=O)NH, C=NR56, NHC(-O), (NH) 2 C(=O);

R55 and R56 are hydrogen;

z is 1;

R40 is a heterocyclic compound substituted with R52;

R41 is hydrogen;

R52 is a bond with Ln;

AL1 is tricine;

X2 is independently selected at each occurrence from the group: CR64, CR64R64, N, NR64 and O;

X 3 is N;

provided that the total number of heteroatoms in each ring of the AL2 ligand is 2 to 3;

R64 is independently selected at each occurrence from the group:

H, C1-C3 alkyl substituted with 0-1 R65, aryl substituted with 0-1 R65; and R65;

R65 is independently selected at each occurrence from the group: -NO2f -CO2R66, -OR66, and -SO3H.

[6] Specifically preferred radiopharmaceuticals are those indicated by, yes

Q is

[image]

d' is 1;

Ln is bound to Q in the carbon atom marked with * and has the formula:

- (C=O)NH(CH2)5C(=O)NH-;

[image]

it is attached to Ln in the carbon atom marked with *; Mt is 99mTc; AL1 is tricine; x, y and z are 1; and AL2 is selected from the group:

[image]

[image]

[7] Another form of this invention is a procedure for radiodiagnosing the condition of a mammal, which includes (i) applying an effective amount of radiopharmaceuticals from Claims 1-6 to said mammal, and (ii) displaying the condition of the mammal using a radiodiagnostic apparatus.

[8] Another form of this invention is a procedure for showing the location of platelet deposition in a mammal using radiodiagnostics, which includes (i) applying an effective amount of radiopharmaceuticals from Claims 1-6 to said mammal, and (ii) showing the condition of the mammal using a radiodiagnostic apparatus.

[9] Another form of this invention is a procedure for determining the deposition of platelets in a mammal, which includes the application of radiopharmaceuticals from Claims 1-6 to said mammal and diagnosing the condition of the mammal in question.

[10] Another form of this invention is a method of diagnosing a disorder associated with the deposition of platelets in a mammal comprising administering the radiopharmaceutical from Claims 1-6 to said mammal, and diagnosing the condition of said mammal.

[11] Another form of this invention is a kit for preparing radiopharmaceuticals, which includes:

(a) a previously determined amount of a sterile, pharmaceutically acceptable reagent of the formula:

(Q)d,Ln-Ch;

(b) a predetermined amount of a sterile, pharmaceutically acceptable first ancylamog ligand, AL1, selected from the group:

dioxygen ligand and functionalized aminocarboxylate;

(c) a predetermined amount of a sterile, pharmaceutically acceptable ligand, AL2, selected from the group:

[image]

(d) a predetermined amount of a sterile, pharmaceutically acceptable reducing agent; and

(e) preferably, a predetermined amount of one or more sterile, pharmaceutically acceptable ingredients selected from the group: transfer ligands, buffers, lyophilizing agents, stabilizing agents, solubilizing agents and bacteriostats;

indicated by that

Q is a biologically active molecule;

d' is 1 to 20;

Ln is the linking group of the formula:

M1-[Y1 (CR55R56)f(Z1)f''Y2]f-M2,

indicated by that

M1 is - [(CH2)Z1]g' - (CR55R56)g'' -;

M2 is - (CR55R56)g'' - [Z1(CH2)g]g' -;

g is independently 0-10;

g' is independently 0-1;

g'' is independently 0-10;

f is independently 0-10;

f' is independently 0-10;

f'' is independently 0-1;

Y1 and Y2, at each occurrence, are independently selected from: bond, O, NR56, C=O, C(=O)O, OC (=O)O, C (=O)NH-C=NR56, S, SO, SO2, SO3, NHC(=O), (NH)2C (=O), (NH)2C=S;

Z 1 is independently selected at each occurrence from a C 6 -C 14 saturated, partially saturated or aromatic carbocyclic ring system, substituted with 0-4 R 57 ; and a heterocyclic ring system, optionally substituted with 0-4 R57;

R55 and R56 are independently selected at each occurrence from: hydrogen; C1-C10 alkyl substituted with 0-5 R57, alkaryl wherein the aryl is substituted with 0-5 R57;

R57 is independently selected at each occurrence from the group: hydrogen, OH, NHR58, C (=O)R58, OC (=O)R58, OC(=O)OR58, C (=O)OR58, C (=O)NR58 , C=H, SR58, SOR58, SO2R58, NHC (=O)R58, NHC (=O)NHR58, NHC(=S)NHR58, or, likewise, when linked to an additional molecule Q, R57 is independently selected at to each occurrence from the group: O, NR58, C=O, C(=O)O, OC (=O)O, C (=O)N, C=NR58, S, SO, SO2, SO3, NHC (=O ), (NH)2C (=O), (NH)2C=S; and

R 58 is independently selected at each occurrence from the group: hydrogen, C 1 -C 6 alkyl, benzyl, and phenyl;

Ch. is a radionuclide metal chelator selected from the group: R40R41N-N=C(C1-C3 alkyl)2 and =R40NNH2-, and R40R41N-N=CR80R81, indicated that

R40 is independently selected at each occurrence from the group: a bond with Ln, C1-C10) alkyl substituted with 0-3 R52, aryl substituted with 0-3 R52, cycloalkyl substituted with 0-3 R52, heterocyclic compound substituted with 0-3 R52 , heterocycloalkyl substituted with 0-3 R 52 , aralkyl substituted with 0-3 R 52 , and alkaryl substituted with 0-3 R 52 ;

R41 is independently selected from the group: hydrogen, alkyl substituted with 0-3 R52 , C1-C10 alkyl substituted with 0-3 R52 , and heterocyclic compound substituted with 0-3 R52 ;

R52 is independently selected at each occurrence from the group: bond with Ln =O,'F, Cl, Br, I, -CF3, -CN, -CO2R53, -C(=O)R53,

-C(=O)N(R53)2, -CHO, -CH2OR53, -OC(=O)R53, -OC(=O)OR53a, -OR53, -OC(=O)N(R53)2, - NR53C(=O)R53, -N(R53)3+, -NR54C(=O)OR53a, -NR53C(=O)N(R53)2, -NR54SO2N(R53)2, -NR54SO2 R53a, -SO3H, - SO2R53a, -SR53, -S(=O)R53a, -SO2N(R53)2, -N(R53)2 -NHC( = NH)NHR53, -C( = NH)NHR53, = N O R53, NO2, -C (=O)NHOR53, -C( = O)NHNR53R53a, -OCH2CO2H, 2-(1-morpholino)ethoxy;

R 53 , R 53a , and R 54 are each independently selected at each occurrence from the group consisting of: alkyl, C 1 -C 6 alkyl, and a bond with Ln;

R80 and R81 are independently selected from the group:

H, C1-C10 alkyl, -CN, -CO2R85, -C(=O)R85, -C(=O)N(R85)2, C2-C10 1-alkene substituted with 0-3 R84, C2-C10 1 -alkyne substituted with 0-3R84, aryl substituted with 0-3 R84, unsaturated heterocyclic compound substituted with 0-3 R84, and unsaturated carbocyclic compound substituted with 0-3 R84, provided that when one of R80 and R81 is H or alkyl , then the other is not H or alkyl;

or, likewise, R80 and R81 may be taken together with the divalent carbon radical shown to form:

[image]

indicated by that

R82 and R83 may be independently selected from the group:

H, R84, C1-C10 alkyl substituted with 0-3 R84, C2-C10 alkenyl substituted with 0-3R84, C2-C10 alkynyl substituted with 0-3 R84, aryl substituted with 0-3 R84, heterocyclic compound substituted with 0- 3 R84 and carbocyclic compound replaced by 0-3 R84;

or, likewise, R82 and R83 may be taken together to form a fused aromatic or heterocyclic ring;

R84 is independently selected at each occurrence from the group: =O, F, Cl, Br, I, -CF3, -CN, -CO2R85, -C(=O)R85, -C(=O)N(R85)2, -N(R85)3+-CH2OR85, -OC(=O)R85, -OC(=O)OR85a, -OR85, -OC(=O)N(R85)2, NR85C(=O)R85, NR86C( =O) OR85a, -NR85C(=O)N(R85)2, -NR86SO2N(R85)2, -NR86SO2 R85a, -SO3H, -SO2R85a, -SR85, -S(=O) R85a, -SO2N(R85) 2, -N (R85)2, -NHC(=NH)NHR85, -C(=NH)NHR85, = NOR85, -C(=O)NHOR85, -OCH2CO2H, 2-(1-morpholino)ethoxy; and

R85, R85a, and R86 are each independently selected at each occurrence from the group: hydrogen and C1-C6 alkyl.

X1 is independently selected at each occurrence from the group: CR64 and N;

X2 is independently selected at each occurrence from the group: CR64, CR64R64, N, NR64, O and S;

X3 is independently selected at each occurrence from the group: C, CR64 and N;

Y is selected from the group: BR64- CR64, (P=O), (P=S);

provided that the total number of heteroatoms in each ring of the heterocyclic compound is 1 to 4;

R64 is independently selected at each occurrence from the group: H, C1-C10 alkyl substituted with 0-3 R65, C2-C10 alkenyl substituted with 0-3 R65, C2-C10 alkynyl substituted with 0-3 R65, aryl substituted with 0- 3 R65, carbocyclic compound substituted with 0-3 R65 and R65;

or, likewise, two R64 may be taken together with the atom or atoms to which they are linked and with which they form a fused aromatic, carbocyclic or heterocyclic ring, replaced by 0-3 R65;

R65 is independently selected at each occurrence from the group: =O, F, Cl, Br, I, -CF3, -CN, -NO2, -CO2R66, -C(=O)R66, -C(=O)N(R66 )2, -N(R66)3+, -CH2OR66, -OC(=O)R66, -OC(=O)OR66a, -OR66, -OC(=O)N(R66)2, -NR66C(=O )R66, -NR67C(=O)OR66a,-NR66C(=O)N(R66)2, -NR67SO2N(R66)2, -NR67SO2 R66a, -SO3H, -SO2R66a, -SO2N(R66)2, -N( R66)2, -OCH2CO2H; and

R 66 , R 66a and R 67 are each independently selected at each occurrence from the group: hydrogen and C 1 -C 10 alkyl.

n is 0 or 1;

and a, b, c, d, e and f denote the sites of possible double bonds, provided that one of them is e or f.

[12] Preferred accessories of the present invention are those indicated by, yes

AL1 is a functionalized aminocarboxylate;

Q is a biologically active molecule selected from the group: IIb/IIIa receptor antagonists, IIb/IIIa receptor ligands, fibrin-binding peptides, leukocyte-binding peptides, chemotactic peptides, somatostatin analogs, and selectin-binding peptides;

d1 is 1 to 3;

Ln is: - (CR55R56)g„ - [Y1(CR55R56)fY2]f,. -(CR55R56)g,.-,

indicated by that

g" is 0-5;

f is 0-5;

f' is 1-5;

Y1 and Y2, at each occurrence, are independently selected from:

O, NR56, C=O C(=O)O, OC (=O)O, C (=O)NH, C=NR56, S, SO, SO2, SO3, NHC(=O), (NH)2C ( =O), (NH)2C=S;

R 55 and R 56 are independently selected at each occurrence from: hydrogen, C 1 -C 10 alkyl and alkaryl;

R40 is independently selected at each occurrence from the group: aryl substituted with 0-3R52, and heterocyclic compound substituted with

0-3 R52;

R 41 is independently selected from the group: hydrogen, aryl substituted with 0-1 R 52 , C 1 -C 3 alkyl substituted with 0-1 R 52 , and heterocyclic compound substituted with 0-1 R 52 ;

R52 is independently selected at each occurrence from the group: linkage to Ln, -CO2R53, -CH2OR53, -SO3H, -SO2R53a, -N(R53)2, -N(R53)3+, -NHC(=NH)NHR53, and -OCH 2 CO 2 H;

R53 and R53a are each independently selected at each occurrence from the group: hydrogen and C1-C3 alkyl;

R80 is independently selected at each occurrence from the group: -CO2R85, C2-C5 1-alkene substituted with 0-3 R84, C2-C5 1-alkyne substituted with 0-3 R84, aryl substituted with 0-3 R84, and

unsaturated heterocyclic compound substituted with 0-3 R84;

R 81 is independently selected at each occurrence from the group: H and C 1 -C 5 alkyl;

or, likewise, R80 and R81 can be used together with the shown divalent carbon radical with which they form:

[image]

indicated by that

R82 and R83 may be independently selected from the group: H and R84;

or, likewise, R82, R83 may be taken together to form a fused aromatic or heterocyclic ring;

R84 is independently selected at each occurrence from the group: -CO2R85, -C(=O)N(R85)2, -CH2OR85, -OC(=O)R85, -OR85, -SO3H, -N(R85)2, and -OCH 2 CO 2 H;

R 85 is independently selected at each occurrence from the group: hydrogen and (C 1 -C 3 ) alkyl.

Y is BR64-;

R64 is independently selected at each occurrence from the group:

H, C1-C3 alkyl substituted with 0-3 R65, aryl substituted with 0-3 R65 and R65;

or, likewise, two R 64 may be taken together with the atom or atoms to which they are linked and with which they form a fused aromatic, carbocyclic or heterocyclic ring substituted by 0-3 R 65 ;

R65 is independently selected at each occurrence from the group: -NO2, -CO2R66, -OR66, -SO3H, and -OCH2CO2H;

R66 is hydrogen; and

n is 0.

[13] Also desirable are those accessories that are indicated by, yes

AL1 is tricine;

Q is a biologically active molecule selected from the group: IIb/IIa receptor antagonists, and chemotactic peptides;

d' is 1;

Y 1 and Y 2 , at each occurrence, are independently selected from: O, NR 56 , C=O, C(=O)O, OC (=O)O, C (=O)NH, C=NR 56 , NHC(=O ), (NH)2C (=O);

R55 and R56 are hydrogen;

R40 is a heterocyclic compound substituted with R52;

R41 is hydrogen;

R52 is a bond with Ln;

R 80 is independently selected at each occurrence from the group: -CO 2 R 85 , C 2 -C 3 1-alkene substituted with 0-1 R 84 , aryl substituted with 0-1 R 84 , and unsaturated heterocyclic compound substituted with 0-1 R ;

R81 is H;

R 84 is independently selected at each occurrence from the group: -CO 2 R 85 , -OR 85 , -SO 3 H, and -N(R 85 ) 2 ;

R85 is independently selected at each occurrence from the group: hydrogen and methyl;

X1 is independently selected at each occurrence from the group: CR64 and N;

X2 is independently selected at each occurrence from the group: CR64, CR64R64, N, NR64, O and S;

X 3 is N;

Y is BR64-;

provided that the total number of heteroatoms in each ring of the AL1 ligand is 2 to 3;

R 64 is independently selected at each occurrence from the group: H, C 1 -C 3 alkyl substituted with 0-1 R 65 , aryl substituted with 0-1 R 65 , and R 65 ;

R 65 is independently selected at each occurrence from the group: NO 2 , -CO 2 R 66 , -OR 66 , and SO 3 H;

R66 is hydrogen; n is 0;

and a, b, c, d, e and f indicate the site of a possible double bond, provided that one of e and f is a double bond.

[14] Also preferred are those accessories which are indicated by the fact that AL2 is selected from the group:

[image]

Q is

[image]

d' is 1;

Ln is attached to Q by means of a carbon atom marked with * and has the formula:

-(C=O)NH(CH2)5C(=O)NH-;

Ch is selected from R40NNH2- and R40R41N-N=CR80R81 indicated that

R 40 is independently selected at each occurrence from the group: heterocyclic compound substituted with R 52 ;

R41 is hydrogen;

R52 is a bond with Ln;

R 80 is independently selected at each occurrence from the group: -CO 2 R 85 , C 2 -C 3 1-alkene substituted with 0-1 R 84 , aryl substituted with 0-1 R 84 , and unsaturated heterocyclic compound substituted with 0-1 R 84 ;

R81 is H;

R 84 is independently selected at each occurrence from the group: -CO 2 R 85 , -OR 85 SO 3 H, and -N(R 85 ) 2 ;

R85 is independently selected at each occurrence from the group: hydrogen and methyl.

When a variable appears more than once in a compound or formula, its definition at each individual occurrence is independent of the definition of the same at each subsequent occurrence. For example, if a group is specified to be substituted by 0-2 R52, then the group in question can be replaced by one of up to two R52s, which at each occurrence are independently selected from a well-defined list of possible R52s. Thus, according to the previous example, for the group -N(R 53 ) 2 , both substituents R 53 on N are independently selected from a well-defined list of possible R 53 . Combinations of substituents and/or variables are allowed only if such combinations result in stable compounds.

The term "stable compound" or "stable structure" herein refers to a compound that is sufficiently resistant to withstand isolation from a reaction mixture to a usable degree of purity and formulation into an effective diagnostic agent.

The term "capable of stabilizing", as used herein to describe the second auxiliary ligand AL2, means that the ligand is capable of coordinating to a transition metal radionuclide in the presence of the first auxiliary ligand and a transition metal chelator, under the conditions set forth herein, resulting in Formula 1 radiopharmaceuticals with minimal no. of isomeric forms, the relative ratio of which does not change significantly with time, and remains basically unchanged even during dissolution.

The term "substituted", as used herein, means that one or more hydrogens on a particular atom or group have been replaced with one selected from the indicated group, provided that the normal valency of that particular atom or group is not exceeded and that the substitution results in a stable compound. When the substituent is a keto group (eg =O), then two hydrogens on the atom are replaced.

The term "bond", as used herein, means a single or double bond.

The term "salt" as used herein is taken as defined in the CRC Handbook of Chemistry and Physics, 65th Edition. CRC Press, Boca Raton, Ra, 1984, as any substance that donates ions, except hydrogen or hydroxyl ions.

As used herein, the term "alkyl" includes branched and straight chain saturated aliphatic hydrocarbons having a certain number of carbon atoms; "cycloalkyl", or "carbocyclic" includes saturated and partially unsaturated ring groups, including mono-, bi-, or polycyclic systems, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl and adamantyl; "bicycloalkyl" includes saturated bicyclic groups such as [3.3.0]bicyclooctane, [4.3.0]bicyclononane, [4.4.0]bicyclodecane (decalin), [2.2.2]bicyclooctane, and so on.

As used herein, the term "alkene" or "alkenyl" includes branched and straight chain groups of the formula CnH2n -1 having a specified number of carbon atoms.

As used herein, the term "alkyne" or "alkynyl" includes branched and straight chain groups of the formula CnH2n -3 having a certain number of carbon atoms.

As used herein, the term "aryl" or "aromatic residue" means phenyl or naphthyl which, in case of substitution, may be substituted at any position.

The term "heterocyclic" or "heterocyclic ring system" as used herein means a stable five- to seven-membered monocyclic or bicyclic ring, or a seven- to ten-membered bicyclic heterocyclic ring that may be saturated, partially unsaturated or aromatic, and consists of carbon atoms and 1 to 4 heteroatoms independently selected from the group consisting of N, O and S, where the nitrogen and sulfur heteroatoms may be oxidized, and the nitrogen may be quaternized, including any bicyclic group in which one of the aforementioned heterocyclic rings is attached to a benzene ring.

A heterocyclic ring can be attached to its attached group on any heteroatom or carbon atom resulting in a stable structure. The heterocyclic rings described herein may be substituted at the carbon or nitrogen atom if the resulting compound is stable. Examples of such heterocycles include, but are not limited to, benzopyranyl, thiadiazine, tetrazolyl, benzofuranyl, benzothiophenyl, indolene, quinoline, isoquinolinyl or benzimidazolyl, piperidinyl, 4-piperidone, 2-pyrrolidone, tetrahydrofuran, tetrahydroquinoline, octahydroisoquinoline, azocine, triazine (including 1,2,3-, 1,2,4-, and 1,3,5-triazine), 6H-1,2,5-thiadiazine, 2H, 6H-1,5,2-dithiazine, thiophene, tetrahydrothiophene, thiantrene, furan, pyran, isobenzofurah, chromene, xanthene, phenoxanthine, 2H-pyrrole, pyrrole, imidazole, pyrazole, thiazole, isothiazole, oxazole (including 1,2,4- and 1,3,4-oxazole), isoxazole, triazole , pyridine, pyrazine, pyrimidine, pyridazine, indolizine, isoindole, 3H-indole, indole, 1H-indazole, purine, 4H-quinolysine, isoquinoline, quinoline, phthalazine, naphthyridine, quinoxaline, quinazoline, cinnoline, pteridine, 4aH-carbazole, carbazole , b-carboline, phenanthridine, acridine, perimidine, phenanthroline, phenazine, phenarsazine, phenothiazine, furazan, phenoxazine, isochroman, chroman, pyrrolidine, pyrroline, imidazolidin, imi dazoline, pyrazolidine, pyrazoline, piperazine, indoline, isoindoline, quinuclidine, or morpholine. Also included are fused ring and helical compounds containing, for example, the above-mentioned heterocycles.

As used herein, the term "alkaryl" means an aryl group bearing an alkyl group of 1-10 carbon atoms; the term "aralkyl" means an alkyl group of 1-10 carbon atoms bearing an aryl group; the term "arylalkyl" means an aryl group bearing an alkyl group of 1-10 carbon atoms bearing an aryl group; and the term "heterocycloalkyl" means an alkyl group of 1-10 carbon atoms bearing a heterocycle.

A "reducing agent" is a compound that reacts with a radionuclide, which is usually obtained as a relatively unreactive compound in a highly oxidized state, to reduce its oxidation state by donating electrons to the radionuclide, thereby making it more reactive. Reducing agents useful in the preparation of radiopharmaceuticals and in diagnostic kits (accessories) useful in the preparation of said radiopharmaceuticals include, but are not limited to, stannous chloride, stannous fluoride, formamidine sulfinic acid, ascorbic acid, cysteine, phosphines, and copper or iron salts. Other reducing agents are described in Brodack et. al., PCT Application 94/22496, which is incorporated herein by reference.

"Transfer ligand" is a ligand that forms an intermediate complex with a radionuclide that is stable enough to prevent unwanted side reactions, but at the same time labile enough to become a radiopharmaceutical. The formation of intermediate complexes is kinetically favorable, while the formation of radiopharmaceuticals is thermodynamically favorable. Transportable ligands useful in the preparation of radiopharmaceuticals and diagnostic kits useful in the preparation of said radiopharmaceuticals include, but are not limited to, gluconate, glucoheptonate, mannitol, glucorate, N,N,N',N'-ethylenediaminetetraacetic acid, pyrophosphate, and methylenediphosphonate. Generally, transfer ligands consist of oxygen or nitrogen donor atoms.

The term "donor atom" refers to an atom that is directly bonded to a metal by a chemical bond.

"Auxiliaries" or "co-ligands" are ligands that are incorporated into the radiopharmaceutical during its synthesis. They serve to complete the coordination sphere of the radionuclide together with the chelator or the radionuclide binding unit of the reagent. For radiopharmaceuticals consisting of binary ligand systems, the radionuclide coordination sphere is composed of one or more chelators or binding units of one or more reagents, and of one or more auxiliary or co-ligands, provided that the two types of ligands, chelators or binding units. For example, a radiopharmaceutical consisting of one chelator or binding unit of one reagent and two equal auxiliary or co-ligands and a radiopharmaceutical consisting of two chelator or binding units of one or two reagents and one auxiliary or co-ligand are considered to be consist of binary ligand systems. For radiopharmaceuticals consisting of triple ligand systems, the radionuclide coordination sphere consists of one or more chelators or binding units of one or more reagents and one or more of two different types of auxiliary or co-ligands, provided that there are a total of three types of ligands , chelators or binding units. For example, a radiopharmaceutical consisting of one chelator or binding unit of one reagent and two different auxiliary or co-ligands is considered to consist of a triple ligand system.

Auxiliary (ancillary) or co-ligands useful in the preparation of radiopharmaceuticals and in diagnostic kits useful for the preparation of said radiopharmaceuticals consist of one or more oxygen, nitrogen, carbon, sulfur, phosphorus, arsenic, tin, and tellurium donor atoms. The ligand can be a transition ligand in the synthesis of radiopharmaceuticals, and can also be used as an auxiliary (ancillary) or co-ligand in another radiopharmaceutical. Whether the ligand will be called transition or auxiliary or co-ligand depends on whether the ligand remains in the coordination sphere of the radionuclide in the radiopharmaceutical, which is determined by the coordination chemistry of the radionuclide and the chelator or binding unit of one or more reagents.

A "chelator" or "binding unit" is a moiety or group on a reagent that binds to a metal radionuclide by forming chemical bonds with one or more donor atoms.

The term "binding site" means the site in vivo or in vitro where the biological agents of the molecule bind.

A "diagnostic kit" consists of a group of components, called formulations, in one or more containers that are used by the end user in a clinical or pharmacological setting to synthesize a radiopharmaceutical. The kit contains all components necessary for the synthesis and use of radiopharmaceuticals except those that are easily accessible to every user, for example water or salt solution for injections, radionuclide solution, equipment for heating the kit during radiopharmaceutical synthesis as needed, equipment necessary for administering radiopharmaceuticals to the patient such as injections and protective equipment, and display equipment (image acquisition).

"Buffer" is a compound used to control the pH of the kit during its manufacture and during the synthesis of the radiopharmaceutical.

"Lyophilising agent" is a component with suitable physical properties for lyophilization, such as glass transition temperature, and is added to the diagnostic kit (accessory) to improve the physical properties of the combination of all components in the kit (accessory) for lyophilization.

"Stabilizing agent" is a component that we add to a radiopharmaceutical or diagnostic kit in order to stabilize the radiopharmaceutical after its synthesis or to extend the durability of the kit itself (accessories) until its use. Stabilizers can be antioxidants, reducing agents or radical scavengers and ensure better stability by reacting with substances that degrade other components or radiopharmaceuticals.

"Solubilizing agent" is a component that improves the solubility of one or more other components in the medium required for radiopharmaceutical synthesis.

"Bacteriostatic" is a component that stops the growth of bacteria in the diagnostic kit (accessory) during its storage before use or after the kit has been used for the synthesis of radiopharmaceuticals.

The radiopharmaceuticals of this invention have the formula [(Q)d'Ln-Ch']x-Mt(AL1)y(AL2)z, where Q denotes a biologically active group, d1 denotes whole numbers from 1-20, Ln is an optional coupling group , Ch is a radionuclide metal chelator or binding unit bound transition metal radionuclide, Mt, has the formula R40N=N+ = , R40R41N-N=, or R40N=N(H)-, AL1 is the first auxiliary (ancillary) or co-ligand, AL2 is the second ancillary or co-ligand, x, y, z are independently 1 or 2.

Biologically active molecule Q can be a protein, antibody, antibody particle, peptide or polypeptide, or a peptidomimetic containing a sequence or unit to recognize a receptor or binding site expressed at the site of disease, or for a receptor or binding site expressed on blood platelets or leukocytes. The exact chemical composition of Q is chosen based on the stage of the disease to be diagnosed, the localization mechanism to be applied, to ensure an optimal combination of localization ratio, clearance and radionuclide decay.

-For the purposes of this invention, the term thromboembolic disease is taken to include venous and arterial disorders and pulmonary embolism, which are the result of the formation of blood clots (thrombus).

For the diagnosis of thromboembolic disorders or atherosclerosis, Q is selected from the group consisting of cyclic IIb/IIIa receptor antagonist compounds described in pending U.S. Pat. patent application Ser. No. 08/218,861 (equivalent to WO 94/22494); RGD containing peptides described in U.S. Patents 4,578,079, 4,792,525, applications PCT US88/04403, PCT US89/01742, PCT US90/03788, PCT US91/02356 and by Ojima et. al., 204th Meeting of the Amer. Chem. Soc, 1992, Abstract 44; peptides that are antagonists of the fibrinogen receptor described in European patent applications 90202015.5, 90202030.4, 90202032.2, 90202032.0, 90311148.2, 90311151.6, 90311537.6, specific binding peptides and polypeptides described as IIb/IIIa ligands for laminin polymerization site, ligands for fibrin, fibrinogen, or thrombin ligands in PCT WO 93/23085 (excluding technetium binding groups); Oligopeptides corresponding to the lla protein described in PCT WO 90/00178; hirudin-based peptides described in PCT WO90/03391; llb/llla receptor ligands described in PCT WO 90/15818; thrombus, platelet binding peptides or atherosclerotic plaques described in PCT WO 92/13572 (excluding the technetium binding group) or GB9313965.7; fibrin binding peptides described in U.S. Patents 4,427,646 and 5,270,030; Peptides based on hirudin described in U.S. Patent 5,279,812; or fibrin binding proteins described in U.S. Patent 5,217,705; guanine derivatives k which bind to IIb/IIIa receptors described in U.S. Pat. Patent 5,086,069; or tyrosine derivatives described in European patent application 0478328A1 and in Hartman et. al., J. Med. Chem., 1992, 35, 4640; or oxidized low-density lipoproteins (LDL).

For the diagnosis of infection, inflammation or transplant rejection, Q is selected from the group consisting of leukocyte binding peptides described in PCT WO 93/17719 (excluding the technetium binding group), PCT WO 92/13572 (excluding the technetium binding group) or U.S. Sir. No. 08/140000; chemotactic peptides described in European patent application 90108734.6 or in A. Fischman et. al., Semin. Nuc. Med., 1994, 24, 154; or Leukostimulating agents described in U.S. Pat. Patent 5,277,892.

For the diagnosis of cancer, Q is selected from the group of somatostatin analogues described in the UK. Patent application 8927255.3 or PCT WO 94/00489, selectin binding peptides in PCT WO 94/05269, domains of biological function described in PCT WO 93/12819, platelet factor 4 or growth factors (PDGF, EGF, FGF, TNF, MCSF or 11-8).

Q may also represent proteins, antibodies, antibody particles, peptides, polypeptides, or peptidomimetics that bind to receptors or binding sites on other tissues, organs, enzymes, or fluids. Examples include B-amyloid proteins that have been shown to accumulate in patients with Alzheimer's disease, peptides derived from atrial naturing factor that bind to myocardial and renal receptors, antimyosin antibodies that bind to infarcted tissue areas, or nitroimidazole derivatives that accumulate in hypoxic areas in vivo.

Group Ch. it is called hydrazido (with the formula R4OR41N-N=), or diazenido (with the formula R40N=N+= or R40N = N(H)-) group and serves as a point of attachment of the radionuclide to the rest of the radiopharmaceutical marked with the formula (Q)d-Ln or ( Q)d'-. The diazenido group can either be terminal (only one atom of the group is attached to the radionuclide) or chelating. In order to obtain a chelating diazenido group, at least one other atom of the group, located at R40, must be attached to the radionuclide. Atoms attached to the metal are called donor atoms.

The transition metal radionuclide, Mt, is selected from the group: technetium-99m, rhenium-186 and rhenium-188. For diagnostic purposes, the isotope Tc-99m is recommended. Its half-life of 6 hours and gamma radiation energy of 140 keV are almost ideal for gamma scintigraphy using equipment and procedures well known to those skilled in the art. Rhenium isotopes also emit gamma rays of energy compatible with gamma scintigraphy, however, they also emit high-energy beta particles that are harmful to living tissue. These beta rays can be used for therapeutic purposes, for example in cancer radiotherapy.

The coordination sphere of a radionuclide includes all ligands or groups attached to the radionuclide. The transition radionuclide, Mt, in order to achieve stability, is characterized by a coordination number (number of donor atoms) consisting of an integer greater than or equal to 4 and less than or equal to 8; which means that 4 to 8 atoms are bonded to the metal and then it is said to have a complete coordination sphere. The coordination number necessary for a stable radionuclide complex is determined by the type of radionuclide, its oxidation state, and the type of donor atom. If the chelator or binding unit Ch. does not provide the atoms necessary to stabilize the metal radionuclide by completing its coordination sphere, the coordination sphere is completed with donor atoms from other ligands, which are called auxiliary (ancils) or co-ligands, and can be either terminal or chelating.

A large number of ligands can be used as auxiliary (ancylams) or co-ligands, and their selection is determined by various factors such as facilitating the synthesis of radiopharmaceuticals, chemical and physical properties of the auxiliary ligand, speed of formation, yield, and the number of isomeric forms of radiopharmaceuticals obtained, possibility administration of the auxiliary or co-ligand in question to the patient without accompanying physiological consequences for the patient, and the compatibility of the ligand with the lyophilized formulation of the kit. The charge and lipophilicity of the auxiliary ligand affects the charge and lipophilicity of the radiopharmaceutical. For example, the use of 4,5-dihydroxy-1,3 benzene elisulfonate results in radiopharmaceuticals with two additional anionic groups because the sulfonate groups become anionic under physiological conditions. The use of N-alkyl substituted 3,4-hydroxypyridinone results in radiopharmaceuticals with different degrees of lipophilicity, depending on the size of the alkyl substituents.

The radiopharmaceuticals of the present invention contain two types of auxiliary or co-ligands designated as AL1 and AL2. Auxiliary (ancillary) ligands AL1 consist of two or more solid donor atoms such as oxygen and amine nitrogen (sp3 hybridized). Donor atoms occupy at least two positions in the coordination sphere of the metal radionuclide, Mt; auxiliary (ancillary) ligand AL1 serves as one of the three ligands in the ternary ligand system. Examples of auxiliary ligand AL1 include, but are not limited to, dioxygen ligands and functionalized amino carboxylates. A large number of such ligands are available from commercial sources.

Auxiliary (ancillary) dioxygen ligands include ligands that are coordinated to the metal via at least two donor oxygen atoms. Examples include, but are not limited to: glucoheptonate, gluconate, 2-hydroxyisobutyrate, lactate, tartrate, mannitol, glucorate, maltol, kojic acid, 2,2-bis(hydroxymethyl)propionic acid, 4,5-dihydroxy-1,3 -benzene disulfonate, and substituted or unsubstituted 1,2 or 3,4 hydroxypyridinones. (The ligand names in these examples refer to the protonated or unprotonated forms of the ligand.).

Functionalized aminocarboxylates include ligands that contain a combination of amine nitrogen and oxygen donor atoms. Examples include, but are not limited to: iminodiacetic acid, 2,3-diaminopropionic acid, nitriletriacetic acid, N,N'-ethylenediaminodiacetic acid, N,N,N'-ethylenediaminotriacetic acid, hydroxyethylethylenediaminotriacetic acid, and N,N' -ethylenediamino bis-hydroxyphenylglycine.

(The ligand names in these examples refer to protonated or unprotonated forms of the ligand.).

A series of functionalized aminocarboxylates was presented by Bridger et. al. in the US Patent 5,350,837, herein incorporated by reference, resulting in an improved rate of formation of technetium-labeled and hydrazine-modified proteins. We have found that some of these aminocarboxylates enhance the utility of the radiopharmaceuticals of this invention. The most preferred auxiliary (ancillary) ligands of AL1 are functionalized aminocarboxylates which are derivatives of -glycine; and the most preferred of them is tricine (tri(hydroxymethyl)methylglycine).

Another type of auxiliary (ancylamic) ligand AL2 consists of one or more soft donor atoms selected from this group: imino nitrogen (sp2 hybridized), sulfur (sp2 hybridized) and carbon (sp hybridized); atoms that have a π-acidic label. AL2 ligands can be singly, doubly or triply serrated, where the serration is defined as the number of donor atoms in the ligand. One of the two donor atoms in a doubly and one of the three in a tridentate ligand must be a soft donor atom.

Ligands AL2 consisting of imino nitrogens are unsaturated or aromatic 5- or 6-membered nitrogen-containing heterocycles. Ligands consisting of sulfur (sp2 hybridized) donor atoms are thiocarbonyls containing half of C=S. Ligands consisting of carbon (sp hybridized) donor atoms are isonitriles, which contain half of the CNR, where R is an organic radical. A large number of such ligands are available from commercial sources. Isonitrile can be synthesized as described in European Patent 0107734 and in U.S. Pat. Patent 5,279,811, incorporated herein by reference. Preferred auxiliary (ancillary) ligands AL2 are unsaturated or aromatic 5- or 6-membered heterocycles. The most suitable auxiliary (ancillary) ligands of AL2 are unsaturated five-membered heterocycles.

Auxiliary (ancillary) ligands AL2 can be substituted by alkyl, aryl, alkoxyl, heterocycle, aralkyl, alkaryl and arylalkaryl groups, and may or may not carry functional groups containing heteroatoms such as oxygen, nitrogen, phosphorus or sulfur. Examples of such functional groups include, but are not limited to: hydroxyl, carboxyl, carboxamide, nitro, ether, ketone, amino, ammonium, sulfonate, sulfonamide, phosphonate, and phosphonamide. Functional groups can be chosen so that they change the lipophilicity and solubility in water of certain ligands, which can affect the biological properties of radiopharmaceuticals, such as changing the distribution in non-target tissues, cells and fluids, and the mechanism and rate of elimination from the body.

The radiopharmaceuticals from this invention can be easily prepared by adding the radionuclide salt, the reagent of Formula 2, the auxiliary ligand AL1, the auxiliary ligand AL2, and a reducing agent, to an aqueous solution at temperatures from room to 100°C.

(Q)d'Ln-Ch (2)

and from pharmaceutically acceptable salts wherein: Q, d', Ln are as defined earlier, Ch is a radionuclide metal chelator selected from the group: R4OR41N-N=C(C1-C3 alkyl)2 and R40NNH2-, and R40R41N-N=C(R80 )(R81), and from pharmaceutically acceptable salts. The synthesis of the reagent of formula 2 is described in the pending patent application U.S.S.N. 08/476,296.

When Ch is a hydrazone group, it must first be converted to a hydrazine of the formula R40R41NNH2, which may or may not be protonated, before combining with the metal radionuclide, Mt. The chelator or binding unit, Ch, when bound to the metal radionuclide, Mt, is labeled Ch. The conversion of the hydrazone group to hydrazine can take place either before the reaction with the radionuclide, whereby the radionuclide and the auxiliary (ancillary) or co-ligand or ligands are combined, but not with the reagent, but with a hydrolyzed form of the reagent carrying a chelator or binding unit, Ch, or is performed in the presence of a radionuclide whereby the reagent itself is mixed with the radionuclide and an auxiliary or co-ligand or ligands. In this second case, the pH of the reaction mixture must be neutral or acidic.

Alternatively, the radiopharmaceuticals of this invention can be prepared by first preparing the radionuclide salt, auxiliary (ancillary) ligand AL1, and reducing agent in an aqueous solution at a temperature from room to 100°C, whereby a transient radionuclide complex with the auxiliary ligand AL1 is formed , and then the reagent of Formula 2 and auxiliary (ancillary) ligand AL2 are added, and the reaction continues at temperatures from room to 100°C.

In the following case, the radiopharmaceuticals from this invention can be prepared by first mixing the radionuclide salt, the auxiliary (ancillary) ligand AL1, the reagent of formula 2 and the reducing agent in an aqueous solution at temperatures from room to 100°C, whereby a transient radionuclide complex is formed, and then auxiliary (ancillary) ligand AL2 is added and the reaction continues at temperatures from room to 100°C.

The complete preparation time varies depending on the type of radionuclide, the types and amounts of reactants, and the procedure used in the preparation. The preparation can be complete, resulting in a radiopharmaceutical yield > 80%, in 1 minute or it can take more time.

If higher purity radiopharmaceuticals are required or desired, the products may be purified by any of a number of techniques well known to those skilled in the art, such as liquid chromatography, solid phase extraction, solvent extraction, dialysis, or ultrafiltration.

Technetium and rhenium radionuclides are preferably in the chemical form of pertechnetate or perhenate and a pharmaceutically acceptable cation. The parthenate salt form is preferably sodium parthenate such as that obtained from commercial Tc-99 generators. The amount of pertechnetate used to prepare the radiopharmaceutical of the present invention may range from 0.1 mCi to 1 Ci, or, more preferably, from 1 to 200 mCi.

The amount of the reagent of Formula 2 used to prepare the radiopharmaceutical of the present invention may range from 0.1 μg to 10 mg or, more preferably, from 0.5 μg to 100 μg. The amount to be used will be determined by the amount of other reactants and the identity of the Formula 1 radiopharmaceutical to be prepared.

The amounts of auxiliary AL1 ligands used may range from 0.1 mg to 1 g or, more preferably, from 1 mg to 100 mg. The exact amount for a particular radiopharmaceutical is a function of the identity of the Formula 1 radiopharmaceutical to be prepared, the procedure used, and the amount and identity of other reactants. An excessive amount of AL1 will lead to the formation of side products (byproducts) consisting of technetium-labeled AL1 without a biologically active molecule or side products consisting of technetium-labeled biologically active molecules with an ancillary ligand AL1, but without an auxiliary (ancillary) ligand AL2. Too little AL1 will lead to other side products such as technetium-labeled biologically active molecules with ancillary ligand AL2, but without ancillary ligand AL1 or reduced hydrolyzed technetium, or technetium colloid.

The amounts of auxiliary ligands AL2 used can be in the range of 0.001 mg to 1 g or, more preferably, 0.01 mg to 10 mg. The exact amount of a particular radiopharmaceutical is a function of the identity of the Formula 1 radiopharmaceutical to be prepared, the procedure used, and the amount and identity of other reactants. An excessive amount of AL2 will lead to the formation of side products (by-products) consisting of technetium-labeled AL2 without a biologically active molecule or side products consisting of technetium-labeled biologically active molecules with an ancylam ligand AL2, but a bephancylam ligand AL1. If the middle (Q) d'-Ln-Ch. brings one or more substituents consisting of a soft donor atom, as defined above, at least a tenfold molar excess of the ancillary ligand AL2 relative to the reagent of Formula 2 is required to prevent the substituent from interfering with the coordination of the ancillary ligand AL2 with the metal radionuclide, Mt.

Suitable reducing agents for the synthesis of radiopharmaceuticals of the present invention include stannous salts, dithionite or bisulfite salts, borohydride salts and formamidinesulfitic acid, the salts being in any pharmaceutically acceptable form. The preferred reducing agent is a stannous salt. The amount of reducing agent used may range from 0.001 mg to 10 mg or, more preferably, from 0.005 mg to 1 mg.

The specific structure of the radiopharmaceutical of this invention will depend on the identity of the biologically active molecule Q, the number d', the identity of the linker Ln, the identity of the chelating medium Ch, the identity of the auxiliary ligand AL1, the identity of the auxiliary ligand AL2 and the identity of the radionuclide Mt. The identities of Q, Ln and Ch and the number of d' are determined by the choice of reagents of formula 2 or 3. For a specific reagent of Formula 2 or 3, the amount of reagent, the amount and identity of auxiliary (ancillary) ligands AL1 and AL2, the identity of the radionuclide Mt and the synthesis conditions used are determined will the structure of Formula 1 radiopharmaceuticals.

Radiopharmaceuticals synthesized using concentrations of reagents of Formula 2 or 3 that are <100 μg/ml will consist of a single hydrazido or diazenido group Ch; the value of x will be 1. Those synthesized using concentrations >1 mg/ml will consist of two hydrazido groups; the value of x will be 2. Two Ch. groups can be the same or different. For most applications, only a limited amount of a biologically active molecule can be injected without causing unwanted side effects, such as chemical toxicity, interference with biological processes, or changes in the biodistribution of radiopharmaceuticals. Therefore, radiopharmaceuticals where X equals 2, which require higher concentrations of Formula 2 reagents that partly consist of the biologically active molecule, will have to be diluted or purified after synthesis to avoid side effects.

The identities and amounts of the auxiliary ligands AL1 and AL1 used will determine the values of the variables y and z. The y and z values can independently be integers from 1 to 2. Combined, the y and z values will result in a technetium coordination sphere consisting of at least five and no more than seven donor atoms. For monodentate auxiliary ligands AL2, z can be an integer from 1 to 2; for doubly or triply dentate auxiliary (ancylam) ligands AL2, z is 1.

The preferred combination for monodentate ligands is y equal to 1 or 2 and z equal to 1. The preferred combination for doubly (bidentate) or triply (tridentate) dentate ligands is y equal to 1 and z equal to 1.

Another aspect of this invention are diagnostic kits (accessories) for the preparation of radiopharmaceuticals used as contrasts (imaging agents) for diagnosing cardiovascular disorders, infectious diseases, inflammatory diseases and cancer. The diagnostic kits (accessories) of this invention consist of one or more vials (tubes) containing a sterile, non-pyrogenic formulation consisting of a predetermined amount of reagents of the formula (Q)d'-Ln-Ch or (Q)d.- Ln-Hz, one or two auxiliary or co-ligands and optional other components such as reducing agents, transfer ligands, buffers, lyophilizing acids, stabilizing agents, solubilizing agents and bacteriostatics. The inclusion of one or more optional components in the formulation will often improve the ease of synthesis of the radiopharmaceutical making it more practical for the end user, the ease of manufacturing the kit (kit), the shelf life of the kit, or the stability and storage time of the radiopharmaceutical. The improvement achieved by the inclusion of an optional component in the formulation must be weighed against the increased complexity of the formulation and the increased cost of manufacturing the kit (accessory). One or more vials containing all or part of the formulation may independently be in the form of a sterile solution or lyophilized solid.

Buffers useful in the preparation of radiopharmaceuticals and in diagnostic kits useful in the preparation of said radiopharmaceuticals include, but are not limited to, phosphate, citrate, sulfosalicylate, and acetate. A more complete list can be found in the US Pharmacopeia.

Freeze-drying agents useful in the preparation of diagnostic kits (kits) useful in the preparation of radiopharmaceuticals include, but are not limited to, mannitol, lactose, sorbitol, dextran, Ficol, and polyvinylpyrrolidine (PVP). Stabilizing agents useful for the preparation of radiopharmaceuticals and for diagnostic kits (accessories) useful for the preparation of said radiopharmaceuticals include, but are not limited to, ascorbic acid, cysteine, monothioglycerol, sodium bisulfite, sodium metabisulfite, gentic acid, and inositol.

Solubilizing agents useful for the preparation of radiopharmaceuticals and for diagnostic kits (accessories) useful for the preparation of said radiopharmaceuticals include, but are not limited to, ethanol, glycerin, polyethylene glycol, propylene glycol, polyoxyethylene sorbitan monooleate, sorbitan monooleate, polysorbate, ole(oxyethylene) poly(oxypropylene)poly(oxyethylene) block copolymers (Pluronics) and lecithin. Preferred solubilizing agents are polyethylene glycol and Pluronics.

Bacteriostatics useful for the preparation of radiopharmaceuticals and for diagnostic kits useful for the preparation of said radiopharmaceuticals include, but are not limited to, benzyl alcohol, benzalkonium chloride, chlorobutanol, and methyl, propyl, or butyl paraben.

One component in a diagnostic kit can also have multiple functions. A reducing agent can also act as a stabilizing agent, while a buffer can also act as a transfer ligand, a lyophilizing agent can also serve as a transfer, ancillary or co-ligand and so on.

The predetermined amounts of each formulation ingredient are determined for a variety of reasons which in some cases are specific to a particular ingredient while in other cases depend on the amount of another ingredient or the presence and amount of an optional ingredient. In principle, the minimum amount of each component that gives the desired effect of the formulation is used. The desired effect of the formulation is that the end user can synthesize the radiopharmaceutical and have a high degree of certainty that the radiopharmaceutical can be safely injected into the patient and that it will provide diagnostic information about the location of the patient's disease.

The diagnostic kits of the present invention will also contain written instructions for synthesizing radiopharmaceuticals intended for the end user. These instructions may be attached to one or more vials (tubes) or to the container in which the vial or vials are packaged for shipment, or may be in the form of a separate paper inserted into the package.

Another aspect of the present invention relates to a method of imaging the site of thrombotic disease in a patient and includes: (1) synthesizing a radiopharmaceutical using a reagent of the present invention that can be located at sites of thrombotic disease by virtue of the interaction between the biologically active group, Q, of the radiopharmaceutical and the receptor or binding site expressed at the site of disease or a receptor or binding site on an endogenous blood component that accumulates at that site; (2) administration of said radiopharmaceutical to the patient via injection or infusion; (3) Imaging the patient using either planar or SPECT gamma scintigraphy.

Another aspect of this invention deals with a method of showing the site of infection or infectious disease in a patient and includes: (1) synthesizing a radiopharmaceutical using a reagent of the present invention that can be located at sites of infection or infectious disease due to the interaction between the biologically active group, Q, the radiopharmaceutical and the receptor or binding sites expressed at the site of disease or receptors or binding sites on an endogenous blood component that accumulates at that site; (2) administration of said radiopharmaceutical to the patient via injection or infusion; (3) Imaging the patient using either planar or SPECT gamma scintigraphy.

Another aspect of the present invention relates to a method of imaging sites of inflammation in a patient and includes: (1) synthesizing a radiopharmaceutical using a reagent of the present invention that can be located at sites of inflammation by virtue of the interaction between the biologically active group, Q, of the radiopharmaceutical and a receptor or binding site expressed on to a site of inflammation or a receptor or binding site on an endogenous blood component that accumulates at that site; (2) administration of said radiopharmaceutical to the patient via injection or infusion; (3) Imaging the patient using either planar or SPECT gamma scintigraphy.

Another aspect of the present invention relates to a method of imaging cancer sites in a patient and includes: (1) synthesizing a radiopharmaceutical using a reagent of the present invention that can be located at cancer sites by virtue of the interaction between the biologically active group, Q, of the radiopharmaceutical and a receptor or binding site expressed on at a cancer site or a receptor or binding site on an endogenous blood component that accumulates at that site; (2) administration of said radiopharmaceutical to the patient via injection or infusion; (3) Imaging the patient using either planar or SPECT gamma scintigraphy.

Radiopharmaceuticals are given by intravenous injection, usually in saline, at a dose of 1 to 100 mCi per 70 kg of body weight or, preferably, at a dose of 5 to 50 mCi. Display is performed using known procedures.

Examples

The materials used to synthesize the radiopharmaceuticals of the present invention described in the following examples were obtained as follows. The reagent of Formula 2, Cyclo(D-Val-NMeArg-Gli-Asp-Mamb(hydrazino-nicotinyl-5-Aca)) was synthesized as described in a pending U.S. patent application. Sir. No. 08/218,861 (equivalent to WO 94/22494). Auxiliary (ancillary) ligands tricine, tris(1-pyrazolyl)borohydride, imidazole, 2-methyl-5-nitroimidazole, ornidazole, metronidazole, 1,2,4-triazole, 3-nitro-1,2,4-triazole, acetyl Histamine, urocanic acid, 2-methylimidazoline, 4-methyl-5-thiazoleethanol, tris(3,5-dimethyl-1-pyrazolyl)borohydride, adenosine, 8-hydroxyquinoline-5-sulfonic acid, and stannous chloride were obtained from commercial sources and used in the form in which they were received. Deionized water was obtained from the Milli-Q Water System and has a quality of >18 MΩ. Technetium-99m-pertechnetate (99mTc04) was obtained from a Dupont Pharma 99Mo/99mTc generator.

Example 1

Synthesis of 99mTc (tricine) (tris(1-pyrazolyl)borohydride)-cyclo(D-Val-NMeArg-Gli-Asp-Mamb(hydrazino-nicotinyl-5-Aca))

In a 10 ml tube, add 0.4 ml of 99mTc04 (100 mCi/ml) eluent, then 0.1 ml of Cyclo(D-Val-NMeArg-Gly-Asp-Mamb(hydrazino-nicotinyl-5-Aca)) (100 μg/ml) in saline, 0.3 ml tricin (100 mg/ml, pH 7) and 10 μl SnCl2 (10 mg/ml) in 1N HCl. The reaction mixture is heated to 50 °C for 15 minutes. 0.25 ml of tris(1-pyrazolyl)borohydride (20 mg/ml) in salt solution was added to the above reaction solution. The mixture is heated to 50 °C for 30 minutes, and then analyzed by HPLC Method 1.

Example 2

Synthesis of 99mTc (tricine) (imidazole)-cyclo(D-Val-NMeArg-Gli-Asp-Mamb(hydrazino-nicotinyl-5-Aca))

In a 10 ml tube, add 0.3 ml of 99mTc04 solution (100 mCi/ml) in salt solution, 0.4 ml of tricine solution (100 mg/ml, pH-5.0) in H2O, 0.1 ml of cyclo (D-Val-NMeArg-Gli-Asp-Mamb(hydrazino-nicotinyl-5-Aca)) (100 μg/ml) in H2O and 10 μl of a solution of SnCl2-2 H2O (10 mg/ml) in 1.0 N HCl . The reaction mixture is left to stand at room temperature for 15 minutes. After adding 0.4 ml of a solution of imidazole (10 mg/ml) in H2O, the reaction mixture is heated to 70°C for 30 minutes, and then analyzed by HPLC Method 1.

Example 3

Synthesis of 99rnTc (tricine)(1,2,4-triazole)-cyclo(D-Val-NMeArg-Gli-Asp-Mamb(hydrazino-nicotinyl-5-Aca))

In a 10 ml tube, add 0.3 ml of 99mTc04 solution (100 mCi/ml) in salt solution, 0.4 ml of tricine solution (100 mg/ml, ph-5.0) in H2O, 0.2 ml of cyclo (D-Val-NMeArg-Gli-Asp-Mamb(hydrazino-nicotinyl-5-Aca)) (50 μg/ml) in H2O, 0.2 ml solution of 3-nitro-1,2,4-triazole (30 mg /ml) in H2O and 5 μl of SnCl2-2 H2 solution (10 mgTml).in 1.0 N HCl. The reaction mixture is heated to 75 °C for 25 minutes, and then analyzed by HPLC Method 1.

Example 4

Synthesis of 99mTc (tricine)(3-nitro-1,2,4-triazole)-cyclo(D-Val-NMeArg-Gli-Asp-Mamb(hydrazino-nicotinyl-5-Aca))

In a 10 ml test tube, add 0.3 ml of a solution of 99mTc04 (100 mCi/ml) in salt solution, 0.4 ml of a solution of tricin (100 mg/ml, pH-5.0) in H2O, 0.2 ml of a solution of cyclo (D-Val-NMeArg-Gli-Asp-Mamb(hydrazino-nicotinyl-5-Aca)) (50 μg/ml) in H2O, 0.2 ml solution of 3-nitro-1,2,4-triazole (30 mg /ml) in H2O and 5 μl of a solution of SnCl2-2 H2O (10 mg/ml) in 1.0 N HCl. The reaction mixture is heated to 75°C for 25 minutes, and then analyzed by HPLC Method 1.

Example 5

Synthesis of 99mTc (tricine)(acetylhistamine)-cyclo(D-Val-NMeArg-Gli-Asp-Mamb(hydrazino-nicotinyl-5-Aca))

In a 10 ml test tube, add 0.4 ml of 99mTcO4 (100 mCi/ml) eluent, then 0.2 ml of cyclo(D-Val-NMeArg-Gli-Asp-Mamb(hydrazino-nicotinyl-5-Aca)) solution ( 50 μg/ml) in saline, 0.3 ml tricine (100 mg/ml, pH 7) and 10 μl SnCl2 (10 mg/ml) in 1 N HCl. The reaction mixture is heated to 55 °C for 15 minutes. 0.5 ml of acetyl histamine (20 mg/ml) in H2O is added to the above reaction solution. The mixture is heated to 55°C for 60 minutes, and then analyzed by HPLC Method 1.

Example 6

Synthesis of 99mTc (tricine)(metronidazole)-cyclo(D-Val-NMeArg-Gli-Asp-Mamb(hydrazino-nicotinyl-5-Aca))

In a 10 ml test tube, add 0.4 ml of a solution of 99mTc04 (100 mCi/ml) in salt solution, 0.3 ml of a solution of tricin (100 mg/ml, ph-5.0) in H20, 0.2 ml of a solution of cyclo (D-Val-NMeArg-Gli-Asp-Mamb(hydrazino-nicotinyl-5-Aca)) (50 μg/ml) in H2O and 10 μl of a solution of SnCl2 2 H2O (10 mg/ml) in 1.0 N HCl. The reaction mixture is heated to 50 °C for 30 minutes. After addition of 0.5 ml metronidazole solution (20 mg/mj) in H2O, the reaction mixture is heated to 70 °C for 30 minutes and then analyzed by HPLC Method 1.

Example 7

Synthesis of 99mTc (tricine)(2-methylimidazoline)-cyclo(D-Val-NMeArg-Gli-Asp-Mamb(hydrazino-nicotinyl-5-Aca))

In a 10 ml tube, add 0.4 ml of 99mTcO4 (100 mCi/ml) eluent, then 0.2 ml of cyclo(D-Val-NMeArg-Gli-Asp-Mamb(hydrazino-nicotinyl-5-Aca)) solution ( 50 μg/ml) in saline, 0.3 ml of tricine (100 mg/ml, pH 7) and 10 μl of SnCl2 solution (10 mg/ml) in 1 N HCl. The reaction mixture is heated to 50 °C for 15 minutes. 0.5 ml of 2-methylimidazoline (20 mg/ml) in salt solution is added to the above reaction solution. The mixture is heated to 55 °C for 60 minutes, and then analyzed by HPLC Method 1.

Example 8

Synthesis of 99mTc (tricine)(3-pyridinesulfonic acid) (cyclo(D-Val-NMeArg-Gli-Asp-Mamb(hydrazino-nicotinyl-5-Aca))

In a 10 ml test tube, add 0.4 ml of tricine solution (100 m/ml, pH 5.0) in H2O, 0.4 ml of Cyclo(D-Val-NMeArg-Gli-Asp-Mamb(hydrazino-nicotinyl- 5-Aca)) (50 μg/ml) in H20, 0.2 ml of a solution of 3-pyridinesulfonic acid in H20, 0.3 ml of a solution of 99mTcO4 in saline and 25 μl of a solution of SnCl2-2 H2O (10 mg/ml) in 0.1 N HCl. The mixture is heated to 80 °C for 20 minutes, and then analyzed by HPLC Method 1.

Example 9

Synthesis of 99mTc (tricine)(4-methyl-5-thiazolethanol)-cyclo(D-Val-NMeArg-Gli-Asp-Mamb(hydrazino-nicotinyl-5-Aca))

0.4 ml of 99mTc04 eluent (100 mCi/ml) is added to a 10 ml test tube, then 0.2 ml of cyclo(D-Val-NMeArg-Gli-Asp-Mamb(hydrazino-nicotinyl-5-Aca))( 50 μg/ml) in saline, 0.3 ml tricine (100 mg/ml, pH 7) and 10 μl SnCl2 (10 mg/ml) in 1 N HCl. The reaction mixture is heated to 50 °C for 30 minutes. 0.5 ml of 4-methylthiazoleethanol (10 mg/ml) in salt solution is added to the above reaction solution. The mixture is heated to 75 °C for 30 minutes and then analyzed by HPLC Method 1.

Example 10

Synthesis of 99mTc (tricine)(tris(3,5-dimethylpyrazolyl)borohydride)-cyclo(D-Val-NMeArg-Gli-Asp-Mamb(hydrazino-nicotinyl-5-Aca))

Add 0.2 ml of 99mTc04 eluent (100 mCi/ml), then 0.2 ml of cyclo(D-Val-NMeArg-Gli-Asp-Mamb(hydrazino-nicotinyl-5-Aca))(50) to a 10 ml tube. μg/ml) in salt solution, 0.4 ml of tricine (100 mg/ml, pH 7), 0.2 ml of tris(3,5-dimethylpyraxolyl)borohydride (20 mg/ml) in salt solution and 10 p, 1 SnCl2 (10 mg/ml) in 1N HCl. The mixture is heated to 75 °C for 30 minutes and then analyzed by HPLC Method 1.

Example 11

Synthesis of 99rT>Tc (tricine)(4-pyridineethanesulfonic acid)-cyclo(D-Val-NMeArg-Gli-Asp-Mamb(hydrazino-nicotinyl-5-Aca))

In a 10 ml test tube, add 0.4 ml of a solution of tricine (100 mg/ml, pH 5.0) in H2O, 0.4 ml of cyclo(D-Val-NMeArg-Gly-Asp-Mamb(hydrazino-nicotinyl-5 -Aca))(50 μg/ml) in H2O, 0.4 ml of a solution of 4-pyridineethanesulfonic acid (35 mg/ml) in H2O, 0.2 ml of a solution of 99mTc (250 mCi/ml) in saline and 25 μl of a solution SnCl 2 -2H 2 O (10 mg'ml) in 0.1 N HCl. The reaction mixture is heated to 80 °C for 20 minutes and then analyzed by HPLC using Method 1.

Example 12

Synthesis of 99mTc (tricine)(oronidazole)-cyclo(D-Val-NMeArg-Gli-Asp-Mamb(hydrazino-nicotinyl-5-Aca))

In a 10 ml test tube, add 0.4 ml of a solution of 99mTc04 (100 mCi/ml) in saline, 0.2 ml of a solution of tricin (100 mg/ml, pH5.0) in H2O, 0.2 ml of a solution of (D- Val-NMeArg-Gli-Asp-Mamb(hydrazino-nicotinyl-5-Aca))(50 μg/ml) in H2O and 10 μl SnCl2-2H2O (10 mg/ml) in 1.0 N HCl. The reaction mixture is allowed to stand at room temperature for 20 minutes. After adding 0.5 ml of a solution of amidazole (20 mg/ml) in H2O, the reaction mixture is heated to 70 °C for 30 minutes and then analyzed by HPLC using Method 1.

Example 13

Synthesis of 99nYc (tricine)(4-(3H)pyrimidone)-cyclo(D-Val-NMeArg-Gli-Asp-Mamb(hydrazino-nicotinyl-5-Aca))

In a 10 ml test tube, add 0.4 ml of a solution of tricine (100 mg/ml, pH 5.0) in H2O, 0.4 ml of cyclo(D-Val-NMeArg-Gli-Asp-Mamb(hydrazino-nicotinyl-5 -Aca))(50 μg/ml) in H2O, 0.2 ml of a solution of 4-(3H)pyrimidone (10 mg/ml) in H2O, 0.3 ml of a solution of 99mTc (100 mCi/ml) in saline and 25 μl of a solution of SnCl2-2H2O (10 mg/ml) in 0.1 N HCl. The reaction mixture is heated to 80 °C for 20 minutes and then analyzed by HPLC using Method 1.

Example 14

Synthesis of 99mTc (tricine)(2-methyl-5-nitroimidazole)-cyclo(D-Val-NMeArg-Gli-Asp-Mamb(hydrazino-nicotinyl-5-Aca))

In a 10 ml test tube, add 0.4 ml of a solution of 99mTc04 (100 mCi/ml) in saline, 0.2 ml of a solution of tricin (100 mg/ml, pH5.0) in H2O, 0.2 ml of a solution of (D- Val-NMeArg-Gli-Asp-Mamb(hydrazino-nicotinyl-5-Aca))(50 μg/ml) in H 2 O and 10 μl of a solution of SnCF 2 -2H 2 O (10 mg/ml) in 1.0 N HCl. The reaction mixture is allowed to stand at room temperature for 15 minutes. After adding 0.2 ml of a solution of 2-methyl-5-nitroimidazole (10 m/ml) in H2O, the reaction mixture was heated to 70 °C for 30 min and then analyzed by HPLC using Method 1.

[image]

The values listed in Table 1 were obtained using HPLC procedures 1 or 2. One retention time is shown for most of these examples. The two isomers that these radiopharmaceuticals contain are usually not completely resolved by these HPLC procedures. It is characteristic that at the main peak there is a shoulder.

Analytical procedures (methods)

HPLC Procedure (method) 1

Column: Vydac C18 (4.6 mm x 25 cm)

Flow rate: 1 ml/min

Solvent A = 0.01 M pH 6 phosphate buffer

Solvent B = acetonitrile

Gradient: t = 0 100% A

t= 15 min 70% A 30% B

t= 25 min 25% A 75% B

Detection by sodium iodide test

HPLC. Procedure 2

Column: Zorbax Rx C18 (4.6 mm x 25 cm)

Flow rate: 1 ml/min

Solvent A = 90:10 0.025 M pH 8 phosphate buffered acetonitrile

Solvent B = 50:50 0.025 M ph 8 phosphate buffer: acetonitrile

Gradient:

t= 0 min 100% A

t = 25 min 100% B

Detection by sodium iodide test

Application

The radiopharmaceuticals described herein are useful as contrast agents (imaging agents) for the diagnosis of cardiovascular disorders, such as thromboembolic disease or atherosclerosis, infectious disease or cancer. Radiopharmaceuticals consist of technetium-99m-labeled hydracino or dazenido modified biologically active molecules that are selectively localized at the sites of the disease and in this way enable obtaining images of these areas using gamma scintigraphy.

Canine Deep Vein Thrombosis Model: This model encompasses the triad of events (hypercoagulable state, stasis period, low shear environment) key to the formation of an actively growing venous, fibrin-rich clot (thrombus). The procedure is as follows: Adult mixed-breed dogs both of both sexes (9-13 kg) were anesthetized with pentobarbital sodium (35 mg/kg, i.v.) and ventilated with room air via an endotracheal tube (12 pressures/min, 25 ml/kg). In order to determine arterial pressure, a polyethylene catheter was introduced into the right femoral artery tubing (catheter) (PE-240) filled with saline solution and connected to a Statham pressure transducer (P23ID; Oxnard, CA). Anterior arterial blood pressure was determined by silencing the pulsatile pressure signal. Heart rate was monitored using a cardiotachometer (BiotacrT/Grass Quincy, MA) triggered by an electrode (lead) II electrocardiogram obtained using limb electrodes. A probe (PE-240) was inserted into the right femoral vein for drug administration. From ob of the jugular vein is an isolated 5 cm section, freed from the fascia and covered with silk sutures. A microthermistor probe ("probe") is placed on the blood vessel serving as an indirect measure of venous flow. An embolectomy balloon catheter was used to induce a 15-minute stasis period, during which time a hypercoagulable state was induced using 5 U of thrombin (American Diagnosticia, Greenwich CT) injected into the occluded segment. Fifteen minutes later, flow was re-established by deflating the balloon. The radiopharmaceutical was introduced during the first 5 minutes of re-establishment of flow, and the rate of incorporation (absorption) was monitored by gamma scintigraphy.

Dog arteriovenous shunt model: Adult mixed-breed dogs of both sexes (9-13 kg) were anesthetized with pentobarbital sodium (35 mg/kg, i.v.) and ventilated with room air via an endotracheal tube (12 pressures/min, 25 ml/kg ). To determine arterial pressure, a polyethylene tube (catheter) (PE-240) filled with saline and water was inserted into the right femoral artery and connected to a Statham pressure transducer (P23ID; Oxnard, CA). Mean arterial blood pressure determination by silencing the pulsatile pressure signal. Heart rate was monitored using a cardiotachometer (Biotach, Grass Quincy, MA) driven by an electrode (lead) II electrocardiogram obtained using limb electrodes. A probe (PE-"24g) was inserted into the jugular vein for drug administration. Polyethylene tubes treated with silicone (Sigmacote, Sigma Chemical Co. St. Louis, MO) and filled with a saline solution connected to the femoral vein were inserted into both femoral arteries and femoral veins. 5 cm long section of silicone-coated tubing (PE-240) to create extracorporeal arterio-venous (A-V) "shunts" (junctions). The patency of the "shunt" was monitored using a Doppler flow system (model VF-1, Crystal Biotech Inc. , Hopkinton, MA) and flow testing (2-2.3 mm, Titronics Med. Inst., Oowa City, IA) was performed proximal to the "shunt" site, junction. All parameters were continuously monitored with a polygraph recorder (model 7D Grass ) with a paper speed of 1GTmm/min or 25 mm/sec.

After completion of the 15-minute post-surgical stabilization period, the introduction of a thrombogenic surface (4-0 silk, braided fiber, 5 cm long, Ethicon, Inc., Somerville, NJ) to form an occlusive clot (thrombus) in the "shunt" (junction), while one "shunt" served as a control for the other.

Two consecutive 1-hour "shunt" periods were used with the test agent in the form of a 5-minute infusion starting 5 minutes before the introduction of the thrombogenic surface. At the end of each one-hour "shunt" period, the silk was carefully removed and weighed, and the percentage of incorporation was determined by "well counting". The weight of the thrombus was calculated by subtracting the weight of the silk before insertion from the total weight of the silk removed from the "shunt". Arterial blood was drawn before the first "shunt" and every 30 minutes thereafter to determine blood clearance, blood collagen-induced total platelet aggregation, thrombin-induced platelet degranulation (Platelet ATP release), prothrombin time, and platelet count. Likewise, standardized bleeding time measurements were performed at 30-minute intervals.

Complexes in which the biologically active molecules, Q, are chemotactic peptides, can be evaluated for their clinical utility as radiopharmaceuticals for diagnosing infections by performing imaging studies in an experimental guinea pig model of focal infection.

Focal infection model in guinea pig: Hartlev guinea pigs; unspecified gender; weighing between 200 - 250 grams, they were without food and water overnight, before the procedure. Each guinea pig was anesthetized with a mixture of ketamine 25-55 mg/kg/IM and xylazine 2-5 mg/kg/IM. A #10 trochar needle is used to introduce a 5 cm long piece of umbilical cord that is immersed in a 6% solution of sodium caseinate (it is a chemoattractant) into the right loin and place it on the left side of the peritoneal cavity. This chemoattractant investment serves as a focal point for the recruitment of white blood cells. The puncture site is closed with Nexabain, skin glue (if needed). The animals were allowed to recover for 18 hours.

Eighteen hours later, guinea pigs were anesthetized with ketamine 25-55 mg/kg/IM and xylazine 2-5 mg/kg/IM to achieve Phase III/Degree III anesthesia and ensure adequate injection of the test agent into the lateral saphenous vein. Once the guinea pigs have received the test agent, they are placed behind a lead barrier and observed for 1-4 hours. At the appropriate time after receiving the injection, the animals are killed with pentobarbital sodium 65 mg/kg, i.v. and biodistribution is performed. During the course of this research, blood samples were obtained by cardiac puncture.

the results

The results obtained by evaluating the radiopharmaceuticals from Example 1 on the canine arteriovenous "shunt" (junction) model are shown in Figure 1. The results of the positive control, In-111-labeled autologous platelets, and the negative controls, Tc-99m-albumin and I-125- fibrinogen. All values refer to the first one-hour "shunt" period. The obtained data show that the radiopharmaceutical from Example 1 was introduced, absorbed into the thrombi under both mixed arterial and mixed venous conditions, equivalent to the positive control and to a significantly greater extent than the negative control. Thrombus to blood ratios (target to background ratios) of 114 (mixed arterial) and 3.1 (venous) indicate that thrombi can be readily distinguished from surrounding tissue and fluid by standard imaging techniques known to those skilled in the art. An important advantage of the radiopharmaceutical from Example 1 compared to the positive control, In-111 platelets, is that the cumbersome in vitro labeling procedure used to label autologous platelets with In-111 is not necessary. In this way, the time needed to obtain diagnostic information is shortened and the potential danger of exposing the nuclear medical technician to pathogens of blood origin, such as HIV, is avoided.

Claims (14)

1. A radiopharmaceutical, characterized in that it contains a first ancillary ligand, a second ancillary ligand capable of stabilizing the radiopharmaceutical, a transition metal radionuclide, a transition metal chelator, a biologically active group connected to said chelator, which preferably has a binding group between said chelator and said biologically active groups. 2. The radiopharmaceutical from Claim 1 characterized in that it has a binding group between the specified chelator and the specified biologically active group. 3. Radiopharmaceutical from Requirement 2 formula: [(Q)d'-Ln-Ch]x-Mt(AL1)y(AL2)z and its pharmaceutically acceptable salts, characterized in that Q is a biologically active group; d' is 1 to 20; Ln is the linking group of the formula: M1-[Y1(CR55R56)f(Z1)f''Y2]f-M2, whereby M1 is - [(CH2)gZ1]g,-(CR55R56)g„ -; M2 is - (CR55R56)g''-[Z1(CH2)g]g, -; g is independently 0-10; g' is independently 0-1; g" is independently 0-10; f is independently 0-10; f' is independently 0-10; f'' is independently 0-1; Y1 and Y2, at each occurrence, are independently selected from: bonds, O, NR56, C=O, C(=O)O, OC (=O)O, C (=O)NH-, C=NR56, S, SO, SO2, SO3, NHC(=O), (NH)2C (=O), (NH)2C=S; Z 1 is independently selected at each occurrence from a C 6 -C 14 saturated, partially saturated or aromatic carbocyclic ring system, substituted with 0-4 R 57 ; and heterocyclic ring system, preferably substituted with 0-4 R57; R55 and R56 are independently selected at each occurrence from: hydrogen, C1C10 alkyl substituted with 0-5 R57, alkaryl wherein the aryl is substituted with 0-5 R57; R57 is independently selected at each occurrence from hydrogen groups, OH, NHR58, C (=O)R58, OC (=O)R58, OC(=O)OR58, C(=O)OR58, C (=O)NR58, C =N, SR58, SOR58, SO2R58, NHC (=O)R58, NHC (=O)NHR58, NHC(=S)NHR58, or, likewise, when linked to an additional molecule Q, R57 is independently selected at each occurrence from the group: O, NR58, C=O, C (=O)O, OC (=O)O, C (=O)N, C=NR58, S, SO, SO2, SO3, NHC (=O), (NH)2C (=O), (NW)2C=S; and R 58 is independently selected at each occurrence from the group: hydrogen, C 1 -C 6 alkyl, benzyl, and phenyl; x, y and z are independently 1 or 2; Mt is a transition metal radionuclide selected from the group: 99mTc, 186Re and 188Re; Ch. is a radionuclide metal chelator aligned with the transition metal radionuclide Mt, and is independently selected at each occurrence from the group: R40N = N+ = , R40R41N-N = , and R40N = N(H)-; indicated by that R40 is independently selected at each occurrence from the group: bond with Ln, C1-C10 alkyl substituted with 0-3 R52, aryl substituted with 0-3 R52, cycloalkyl substituted with 0-3 R52, heterocyclic compound substituted with 0-3 R52, heterocycloalkyl substituted with 0-3 R 52 , aralkyl substituted with 0-3 R 52 , and alkaryl substituted with 0-3 R 52 ; R 41 is independently selected from the group: hydrogen, aryl substituted with 0-3 R 52 , C 1 -C 10 alkyl substituted with 0-3 R 52 , and heterocyclic compound substituted with 0-3 R 52 ; R52 is independently selected at each occurrence from the group: bond with Ln =O, F, Cl, Br, I, -CF3, -CN, -CO2R53, -C(=O)R53, -C(=O)N(R53)2, -CHO, -CH2OR53, -OC(=O)R53, -OC(=O)OR53a, -OR53, -OC(=O)N(R53)2, - NR53C(=O)R53, -N(R53)3+, -NR54C(=O)OR53a, -NR53C(=O)N(R53)2, -NR54SO2N(R53)2, -NR54SO2 R53a, -SO3H, -SO2R53a, -SR53, -S(=O)R53a, -SO2N(R53)2, -N(R53)2, -NHC(=NH)NHR53, -C(=NH)NHR53, =N O R53, NO2, -C(=O)NHOR53, -C(=O) NHNR53R53a, -OCH2CO2H, 2-(1-morpholino)ethoxy; R53, R53a, and R54 are each independently selected at each occurrence from the group: hydrogen, C1-C6 alkyl, and a bond with Ln; AL1 is the first ancillary ligand selected from the group: dioxygen ligand and functionalized aminocarboxylate; AL2 is an ancillary ligand capable of stabilizing a radiopharmaceutical selected from the group: [image] indicated by that n is 0 or 1; X1 is independently selected at each occurrence from the group: CR64 and N; X2 is independently selected at each occurrence from the group: CR64, CR64R64, N, NR64, O and S; X3 is independently selected at each occurrence from the group: C, CR64, and N; provided that the total number of heteroatoms in each ring of the AL2 ligand is from 1 to 4; Y is selected from the group: BR64-, CR64, (P=O), (P=S); and a, b, c, d, e and f indicate the location of possible double bonds, provided that e or f is a double bond; R64 is independently selected at each occurrence from the group: H, (C1-C10 alkyl substituted with 0-3 R65, C2-C10 alkenyl substituted with 0-3 R65, C2-C10 alkynyl substituted with 0-3 R65, aryl substituted with 0-3 R65, carbocyclic compound substituted with 0-3 R 65 , R 65 ; or, likewise, two R 64 may be taken together with the atom or atoms to which they are linked and with which they form a fused aromatic, -carbocyclic or heterocyclic ring substituted by 0-3 R 65 ; R65 is independently selected at each occurrence from the group: =O, F, Cl, Br, I, -CF3, -CN, -NO2, -CO2R66, -C(=O)R66, -C(=O)N(R66)2, -N(R66)3+ , -CH2OR66, -OC(=0)R66, -OC(=O)OR66a, -OR66, -OC(=O)N(R66)2, -NR66C(=O)R66, -NR67C(=O)OR66a , -NR66C(=O)N(R66)2, -NR67SO2N (R66)2, -NR67SO2 R66a, -SO3H, - SO2R66a, -SO2N(R66)2, - N(R66)2, -OCH2CO2H; and R 66 , R 66a and R 67 are each independently selected at each occurrence from the group: hydrogen and C 1 -C 6 alkyl. 4. The radiopharmaceutical from Claim 3 indicated that Q is a biologically active molecule selected from the group: IIb/IIIa receptor antagonists, IIb/IIIa receptor ligands, fibrin-binding peptides, leukocyte-binding peptides, chemotactic peptides, somatostatin analogs, and selectin-binding peptides; d' is 1 to 3; Ln is - (CR55R56)g''-[Y1(CR55R56)f'Y2]f'-(CR55R56)g'' indicated by that g" is 0-5; f is 0-5; f' is 1-5; Y1 and Y2, at each occurrence, are independently selected from: O, NR56, C=O, C(=O)O, OC (=O)O, C(=O)NH, C=NR56, S, SO, SO2, SO3, NHC(=O), (NH) 2C (=O), (NH)2C=S; R 55 and R 56 are independently selected at each occurrence from: hydrogen, C 1 -C 10 alkyl and alkaryl; x and y are 1; Mt is 99mTc; Ch is selected from the group: R40N = N+= and R40R41N-N = ; indicated by that R 40 is independently selected at each occurrence from the group: aryl substituted with 0-3 R 52 , heterocyclic compound substituted with 0-3 R 52 ; R 41 is independently selected from the group: hydrogen, aryl substituted with 0-1 R 52 , C 1 -C 3 alkyl substituted with 0-1 R 52 , and heterocyclic compound substituted with 0-1 R 52 ; R52 is independently selected at each occurrence from the group: bond with Ln, -CO2R53, -CH2OR53, -SO3H, -SO2R53a, -N(R53)2, -N(R53)3+, -NHC(=NH)NHR53, - OCH2CO2H; R 53 and R 53a are each independently selected at each occurrence from the group: hydrogen, C 1 -C 3 alkyl; AL1 is a functionalized aminocarboxylate; n is 0; Y is BR64-; R64 is independently selected at each occurrence from the group: H, C1-C3 alkyl substituted with 0-3 R65, aryl substituted with 0-3 R65, and R65; or, likewise, two R 65 may be taken together with the atom or atoms to which they are linked and with which they form a fused aromatic, carbocyclic or heterocyclic ring replaced by 0-3 R 65 ; R65 is independently selected at each occurrence from the group: -NO2, -CO2R66, -OR66, -SO3H, and -OCH2CO2H; and R66 is hydrogen. 5. The radiopharmaceutical from Claim 4, characterized in that Q is a biologically active molecule selected from the group: IIb/IIIa receptor antagonists and chemotactic peptides; d' is 1; Y1 and Y2 are independently selected at each occurrence from: O, NR56, C=O, C(=O)O, OC (=O)O, C (=O)NH, C=NR56, NHC(=O), (NH)2C(=O); R55 and R56 are hydrogen; z is 1; R40 is a heterocyclic compound substituted with R52; R41 is hydrogen; R52 is a connection with Ln AL1 is tricine; X2 is independently selected at each occurrence from the group: CR64, CR64R64, N, NR64 and O; X 3 is N; provided that the total number of heteroatoms in each ring of the ligand is AL2 to 3; R64 is independently selected at each occurrence from the pool: H, C1-C3 alkyl substituted with 0-1 R65, aryl substituted with 0-1 R65; and R65; R65 is independently selected at each occurrence from the group: -NO2, -CO2R66, -OR66, and -SO3H. 6. The radiopharmaceutical from Claim 3, characterized in that Q is [image] d' is 1; Ln is bound to Q in the carbon atom marked with * and has the formula: -(C=O)NH(CH2)5C(=O)NH-; [image] it is attached to Ln in the carbon atom marked with *; Mt is 99mTc; AL1 is tricine; x, y and z are 1; and AL2 is selected from the group: [image] [image] 7. The procedure for radiodiagnosing the condition of a mammal, which includes (i) applying an effective amount of radiopharmaceuticals from Claims 1-6 to said mammalT and (ii) showing the condition of the mammal using a radiodiagnostic device. 8. Procedure for showing the place of platelet deposition in a mammal using radiodiagnostics, which includes (i) applying an effective amount of radiopharmaceuticals from Claims 1-6 to said mammal, and (ii) showing the state of the mammal using a radiodiagnostic apparatus. 9. The procedure for determining the deposition of platelets in a mammal, which includes the application of radiopharmaceuticals from Claims 1-6 to the mentioned mammal and diagnosing the condition of the mammal in question. 10. A method of diagnosing a disorder associated with platelet deposition in a mammal comprising administering a radiopharmaceutical from Claims 1-6 to said mammal, and diagnosing the condition of said mammal. 11. Accessories for preparing radiopharmaceuticals include: (a) a previously determined amount of a sterile, pharmaceutically acceptable reagent of the formula: (Q)d'Ln-Ch; (b) a predetermined amount of a sterile, pharmaceutically acceptable first ancillary ligand, AL1, selected from the group: dioxygen ligand and functionalized gaminocarboxylate; (c) a predetermined amount of a sterile, pharmaceutically acceptable ligand, AL2, selected from the group: [image] (d) a predetermined amount of a sterile, pharmaceutically acceptable reducing agent; and (e) preferably, a predetermined amount of one or more sterile, pharmaceutically acceptable ingredients selected from the group: transfer ligands, buffers, lyophilizing agents, stabilizing agents, solubilizing agents and bacteriostats; indicated by that Q is a biologically active molecule; d' is 1 to 20; Ln is the linking group of the formula: M1-[Y1 (CR55R56)f(Z1)f''-Y2]f'M2, indicated by that M1 is - [(CH2)gZ1]g'-(CR55R56)g''-; M2 is -(CR55R56)g''-[Z1(CH2)g]g'-; g is independently 0-10; g' is independently 0-1; g'' is independently 0-10; f is independently 0-10; f' is independently 0-10; f'' is independently 0-1; Y1 and Y2, at each occurrence, are independently selected from: bonds, O, NR56, C=O, C(=O)O, OC (=O)O, C (=O)NH-C=NR56, S, SO, SO2, SO3, NHC(=O), ( NH)2C (=O), (NH)2C=S; Z 1 is independently selected at each occurrence from a C 6 -C 14 saturated, partially saturated or aromatic carbocyclic ring system, substituted with 0-4 R 57 ; and a heterocyclic ring system, optionally substituted with 0-4 R57; R55 and R56 are independently selected at each occurrence from: hydrogen; C1-C10 alkyl substituted with 0-5 R57, alkaryl wherein the aryl is substituted with 0-5 R57; R57 was independently selected at each occurrence from the group: hydrogen, OH, NHR58, C (=O)R58, OC (=O)R58, OC(=O)OR58, C (=O)OR58, C (=O)NR58, C=N, SR58, SOR58, SO2R58 , NHC (=O)R58, NHC (=O)NHR58, NHC(=S)NHR58, or, likewise, when linked to an additional molecule Q, R57 is independently selected at each occurrence from the group: O, NR58, C=O, C (=O)O, OC (=O)O, C (=O)N, C=NR58, S, SO, SO2, SO3 , NHC (=O), (NH)2C (=O), (NH)2C=S; and R 58 is independently selected at each occurrence from the group: hydrogen, C 1 -C 6 alkyl, benzyl, and phenyl; Ch. is a radionuclide metal chelator selected from the group: R40R41N-N=C(C1-C3 alkyl)2 and R40NNH2- and R40R41N-N=CR80R81 indicated that R40 is independently selected at each occurrence from the group: bond with Ln, C1-C10 alkyl substituted with 0-3 R52, aryl substituted with 0-3 R52, cycloalkyl substituted with 0-3 R52, heterocyclic compound substituted with 0-3 R52, heterocycloalkyl substituted with 0-3 R 52 , aralkyl substituted with 0-3 R 52 , and alkaryl substituted with 0-3 R 52 ; R 41 is independently selected from the group: hydrogen, alkyl substituted with 0-3 R 52 , C 1 -C 10 alkyl substituted with 0-3 R 52 , and heterocyclic compound substituted with 0-3 R 52 ; R52 is independently selected at each occurrence from the group: bond with Ln, =O, F, Cl, Br, I, -CF3, -CN, -CO2R53, -C(=O)R53, -C(=O)N( R53)2, -CHO, -CH2OR53, -OC(=O)R53, -OC(=O)OR53a, -OR53, -OC(=O)N(R53)2, -NR53C(=O)R53, - N(R53)3+, -NR54C(=O)OR53a, -NR53C(=O)N(R53)2, -NR54SO2N(R53)2, -NR54SO2 R53a, -SO3H, -SO2R53a, -SR53, -S( =O)R53a, -SO2N(R53)2, -N(R53)2, -NHC(=NH)NHR53, -C(=NH)NHR53, = N O R53, NO2, -C(=O)NHOR53, - C(=O)NHNR53R53a, -OCH2CO2H, 2-(1-morpholino)ethoxy; R 53 , R 53a , and R 54 are each independently selected at each occurrence from the group consisting of: alkyl, C 1 -C 6 alkyl, and a bond with Ln; R80 and R81 are independently selected from the group: H, C1-C10 alkyl, -CN, -CO2R85, -C(=O)R85, -C(=O)N(R85)2, C2-C10 1-alkene substituted with 0-3 R84, C2-C10 1 -alkyne substituted with 0-3R84, aryl substituted with 0-3 R84, unsaturated heterocyclic compound substituted with 0-3 R84, and unsaturated carbocyclic compound substituted with 0-3 R84, provided that when one of R80 and R81 is H or alkyl , then the other is not H or alkyl; or, likewise, R80 and R81 may be taken together with the divalent carbon radical shown to form: [image] indicated by that R82 and R83 may be independently selected from the group: H, R84, C1-C10 alkyl substituted with 0-3 R84, C2-C10 alkenyl substituted with 0-3R84, C2-C10 alkynyl substituted with 0-3 R84, aryl substituted with 0-3 R84, heterocyclic compound substituted with 0- 3 R84 and carbocyclic compound replaced by 0-3 R84; or, likewise, R82 and R83 may be taken together to form a fused aromatic or heterocyclic ring; R84 is independently selected at each occurrence from the group: =O, F, Cl, Br, I, -CF3, -CN, -CO2R85, -C(=O)R85, -C(=O)N(R85)2, -N(R85)3+-CH2OR85, -OC(=O)R85, -OC(=O)OR85a, -OR85, -OC(=O)N(R85)2, -NR85C(=O)R85, - NR86C(=O)OR85a, -NR85C(=O)N(R85)2, -NR86SO2N(R85)2, -NR86SO2 R85a, -SO3H, -SO2R85a, -SR85, -S(=O) R85a, -SO2N( R85)2, -N(R85)2, -NHC( = NH)NHR85, -C(=NH)NHR85, = NOR85, -C(=O)NHOR85, -OCH2CO2H, 2-(1-morpholino)ethoxy; and R85, R85a, and R86 are each independently selected at each occurrence from the group: hydrogen and C1-C6 alkyl. X1 is independently selected at each occurrence from the group: CR64 and N; X2 is independently selected at each occurrence from the group: CR64, CR64R64, N, NR64, O and S; X3 is independently selected at each occurrence from the group: C, CR64 and N; Y is selected from the group: BR64- CR64, (P=O), (P=S); provided that the total number of heteroatoms in each ring of the heterocyclic compound 1 to 4; R64 is independently selected at each occurrence from the group: H, C1-C10 alkyl substituted with 0-3 R65, C2-C10 alkenyl substituted with 0-3 R65, C2-C10 alkynyl substituted with 0-3 R65 aryl substituted with 0-3 R65, carbocyclic compound substituted with 0-3 R65 and R65; or, likewise, two R64 may be taken together with the atom or atoms to which they are linked and with which they form a fused aromatic, carbocyclic or heterocyclic ring, replaced by 0-3 R65; R65 is independently selected at each occurrence from the group: =O, F, Cl, Br, I, -CF3, -CN, -NO2, -CO2R66, -C(=O)R66, -C(=O)N(R66 )2, -N(R66)3+, -CH2OR66, -OC(=O)R66, -OC(=O)OR66a, -OR66, -OC(=O)N(R66)2, -NR66C(=O )R66, -NR67C(=O)OR66a, -NR66C(-O)N(R66)2, -NR67SO2N(R66)2, -NR67SO2 R66a, -SO3H, -SO2R66a, -SO2N(R66)2, -N( R66)2, -OCH2CO2H; and R66, R66a and R67 are each independently selected at each occurrence from the group: hydrogen and C1-C6 alkyl. n is 0 or 1; and a, b, c, d, e and f denote the sites of possible double bonds, provided that one of them is e or f. 12. Accessory from Claim 11, indicated that AL1 is a functionalized aminocarboxylate; Q is a biologically active molecule selected from the group: IIb/IIIa receptor antagonists, IIb/IIIa receptor ligands, fibrin-binding peptides, leukocyte-binding peptides, chemotactic peptides, somatostatin analogs, and selectin-binding peptides; d1 is 1 to 3; Ln is: -(CR55R56)g„ -[Y1(CR55R56)fY2]f'-(CR55R56)g'' - indicated that g" is 0-5; f is 0-5; f' is 1-5; Y1 and Y2, at each occurrence, are independently selected from: O, NR56, C=O, C(=O)O, OC (=O)O, C (=O)NH, C=NR56, S, SO, SO2, SO3, NHC(=O), (NH) 2C (=O), (NH)2C=S; R 55 and R 56 are independently selected at each occurrence from: hydrogen, C 1 -C 10 alkyl and alkaryl; R40 is independently selected at each occurrence from the group: aryl substituted with 0-3R52, and heterocyclic compound substituted with 0-3R52; R 41 is independently selected from the group: hydrogen, aryl substituted with 0-1 R 52 , C 1 -C 3 alkyl substituted with 0-1 R 52 , and heterocyclic compound substituted with 0-1 R 52 ; R52 is independently selected at each occurrence from the group: bond with Ln, -CO2R53, -CH2OR53, -SO3H, -SO2R53a, -N(R53)2, -N(R53)3+, -NHC(=NH)NHR53, and -OCH2CO2H; R53 and R53a are each independently selected at each occurrence from the group: hydrogen and C1-C3 alkyl; R80 is independently selected at each occurrence from the group: -CO2R85, C2-C5 1-alkene substituted with 0-3 R84, C2-C5 1-alkyne substituted with 0-3 R84, aryl substituted with 0-3 R84, and unsaturated heterocyclic joint replaced with 0-3 R84 R 81 is independently selected at each occurrence from the group: H and C 1 -C 5 alkyl; or, likewise, R80 and R81 can be used together with the shown divalent carbon radical with which they form: [image] indicated by that R82 and R83 may be independently selected from the group: H and R84; or, likewise, R82, R83 may be taken together to form a fused aromatic or heterocyclic ring; R84 is independently selected at each occurrence from the group: -CO2R85, -C(=O)N(R85)2, -CH2OR85, -OC(=O)R85, -OR85, -SO3H, -N(R85)2, and -OCH2CO2H; R85 is independently selected at each occurrence from the group: hydrogen and C1-C3 alkyl. Y is BR64-; R 64 is independently selected at each occurrence from the group: H, C 1 -C 3 alkyl substituted with 0-3 R 65 , aryl substituted with 0-3 R 65 and R 65 ; or, likewise, two R 64 may be taken together with the atom or atoms to which they are linked and with which they form a fused aromatic, carbocyclic or heterocyclic ring substituted by 0-3 R 65 ; R65 is independently selected at each occurrence from the group: -NO2, -CO2R66, -OR66, -SO3H, and -OCH2CO2H; R66 is hydrogen; and n is 0. 13. Accessories from Claim 11, indicated that AL1 is tricine; Q is a biologically active molecule selected from the group: IIb/IIIa receptor antagonists, and chemotactic peptides; d' is 1; Y1 and Y2, at each occurrence, are independently selected from: O, NR56, C=O, C(=O)O, OC (=O)O, C (=O)NH, C=NR56, NHC(=O), (NH)2C (=0); R55 and R56 are hydrogen; R40 is a heterocyclic compound substituted with R52; R41 is hydrogen; R52 is a bond with Ln; R80 is independently selected at each occurrence from the group: -CO2R85, C2-C3 1-alkene substituted with 0-1 R84, aryl substituted with 0-1 R84, and unsaturated heterocyclic compound substituted with 0-1 R84; R81 is H; R 84 is independently selected at each occurrence from the group: -CO 2 R 85 , -OR 85 , -SO 3 H, and -N(R 85 ) 2 ; R85 is independently selected at each occurrence from the group: hydrogen and methyl; X1 is independently selected at each occurrence from the group: CR64 and N; X2 is independently selected at each occurrence from the group: CR64, CR64R64, N, NR64, O and S; X 3 is N; Y is BR64-; provided that the total number of heteroatoms in each ring of the AL1 ligand is 2 to 3; R64 is independently selected at each occurrence from the group: H, C 1 -C 3 alkyl substituted with 0-1 R 65 , aryl substituted with 0-1 R 65 , and R 65 ; R 65 is independently selected at each occurrence from the group: NO 2 , -CO 2 R 66 , -OR 66 , and SO 3 H; R66 is hydrogen; n is O; and a, b, c, d, e and f indicate the site of a possible double bond, provided that one of e and f is a double bond. 14. Accessories from Claim 11, indicated that AL2 is selected from the group: [image] Q is [image] d'is 1; Ln is attached to Q by means of a carbon atom marked with * and has the formula: -(C=O)NH(CH2)5C(=O)NH-; Ch is selected from R40NNH2- and R40R41N-N=CR80R81, indicated that R 40 is independently selected at each occurrence from the group: heterocyclic compound substituted with R 52 ; R41 is hydrogen; R52 is a bond with Ln; R 80 is independently selected at each occurrence from the group: -CO 2 R 85 , C 2 -C 3 1-alkene substituted with 0-1 R 84 , aryl substituted with 0-1 R 84 , and unsaturated heterocyclic compound substituted with 0-1 R 84 ; R81 is H; R 84 is independently selected at each occurrence from the group: -CO 2 R 85 , -OR 85 , SO 3 H, and -N(R 85 ) 2 ; R85 is independently selected at each occurrence from the group: hydrogen and methyl.