WO1992005154A1 - Novel nitrogen-sulfur ligands useful in radiographic imaging agents - Google Patents

Novel nitrogen-sulfur ligands useful in radiographic imaging agents Download PDF

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Publication number
WO1992005154A1
WO1992005154A1 PCT/US1991/006479 US9106479W WO9205154A1 WO 1992005154 A1 WO1992005154 A1 WO 1992005154A1 US 9106479 W US9106479 W US 9106479W WO 9205154 A1 WO9205154 A1 WO 9205154A1
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hydrogen
group
mono
poly
radionuclide
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PCT/US1991/006479
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French (fr)
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Raghavan Rajagopalan
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Mallinckrodt Medical, Inc.
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    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • C07K14/81—Protease inhibitors
    • C07K14/815—Protease inhibitors from leeches, e.g. hirudin, eglin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K51/00—Preparations containing radioactive substances for use in therapy or testing in vivo
    • A61K51/02—Preparations containing radioactive substances for use in therapy or testing in vivo characterised by the carrier, i.e. characterised by the agent or material covalently linked or complexing the radioactive nucleus
    • A61K51/04—Organic compounds
    • A61K51/0474—Organic compounds complexes or complex-forming compounds, i.e. wherein a radioactive metal (e.g. 111In3+) is complexed or chelated by, e.g. a N2S2, N3S, NS3, N4 chelating group
    • A61K51/0478—Organic compounds complexes or complex-forming compounds, i.e. wherein a radioactive metal (e.g. 111In3+) is complexed or chelated by, e.g. a N2S2, N3S, NS3, N4 chelating group complexes from non-cyclic ligands, e.g. EDTA, MAG3
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
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    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
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    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/62—Oxygen or sulfur atoms
    • C07D213/63—One oxygen atom
    • C07D213/68—One oxygen atom attached in position 4
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    • C07F13/00—Compounds containing elements of Groups 7 or 17 of the Periodic Table
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    • C07K—PEPTIDES
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    • C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • C07K14/575—Hormones
    • C07K14/655—Somatostatins
    • C07K14/6555—Somatostatins at least 1 amino acid in D-form
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K2121/00—Preparations for use in therapy
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K2123/00—Preparations for testing in vivo

Definitions

  • the present invention relates to novel ligands for forming radionuclide complexes, new complexes incorporating such ligands, processes for preparing such complexes, imaging agents incorporating such complexes, and methods of imaging using such imaging agents.
  • radiographic imaging agents for visualizing skeletal structures, organs, or tissues, is well known in the area of biological and medical research and diagnostic procedures.
  • T e procedure whereby such imaging is accomplished generally involves the preparation of radioactive ag-ents, which, when introduced to the biological subject, are localized in the specific skeletal structures, organs cr tissues to be studied.
  • the localized radioactive agents may then be traced, plotted or scintiphotographe by radiation detectors, such as, traversing scanners or scintillation cameras.
  • the distribution and relative intensity of the detected radioactive agents indicates the position of the tissue in which the agent is localized, and also shows the presence of aberrations, pathtological conditions or the like.
  • the radiographic imaging agents comprise radionuclide-labelled compounds; such as complexes of technetium 99m, rhenium 186 or rhenium 188, or other applicable radionuclides; with appropriate carriers, and auxiliary agents, such as del-ivery vehicles suitable for injection into, or aspiration by, the patient, physiological buffers and salts, and the like.
  • radionuclide-labelled compounds such as complexes of technetium 99m, rhenium 186 or rhenium 188, or other applicable radionuclides
  • auxiliary agents such as del-ivery vehicles suitable for injection into, or aspiration by, the patient, physiological buffers and salts, and the like.
  • the present invention relates particularly to novel aminothiol ligands that are suitable for complexing with a radionuclide, and are useful as general imaging agents for diagnostic purposes.
  • novel ligands having the general formula:
  • R 1 and R 2 may the same or different and are selected from the group consisting of hydrogen, alkyl, aryl, hydroxyl, alkoxyl, mono- or poly- hydroxyalkyl, mono- or poly- alkoxyalkyl, acyl, alkoxycarbonyl, or carbamoyl;
  • A is selected from the group consisting of
  • n 1 to 3
  • R 3 , R 4 and R 5 are defined in the same manner as R 1 and R 2 above, and wherein 7 is
  • R 6 and R 7 are defined in the same manner as R 1 and R 2 above, and wherein J is hydrogen or another suitable protecting group such as ethylaminocarbonyl; and B is selected from the group consisting of
  • ligands according to the present invention have the general formula (I) above, wherein R 1 is hydrogen; R 2 is selected from the group consisting of butoxycarbonyl, acetyl, ethyl, or hydrogen; A is -(CH 2 ) n - wherein n
  • the present invention also relates to novel ligands having the general formula:
  • R 10 is selected from the group consisting of hydrogen, alkyl, aryl, hydroxyl, alkoxyl, mono- or poly- hydroxyalkyl, mono- or poly- alkoxyalkyl, acyl, alkoxycarbonyl, or carbamoyl;
  • R n is a suitable sulfur protecting group selected from the group defined in the same manner as R 10 above;
  • D is selected from the group consisting of
  • g 1 to 3
  • Q is selected from the group consisting of
  • R 15 and R 16 are defined in the same manner as R 10 above, and wherein L is hydrogen or another suitable protecting group such as ethylaminocarbonyl; and E is selected from the group consisting of
  • ligands according to the present invention have the general formula (II) above, wherein R 10 is hydrogen; R 11 is 0
  • the novel ligands described above may be incorporated into radionuclide complexes used as radiographic imaging agents.
  • the complexes of the present invention are prepared by reacting one of the aforementioned ligands with a radionuclide containing solution under radionuclide complex forming reaction conditions.
  • a technetium agent is desired, the reaction i ⁇ carried out with a pertechnetate solution under technetium 99m complex forming reaction conditions.
  • the solvent may then be removed by any appropriate means, such as evaporation.
  • the complexes are then prepared for administration to the patient by dissolution or suspension in a pharmaceutically acceptable vehicle.
  • the ligands of the present invention may be prepared from commercially available starting materials such as 2- (2-aminoethyl)pyridine, 2-aminomethyl pyridine, homocysteinethiola ⁇ tone, etc. by standard synthetic methods as described in the following Examples 1 - 7.
  • Radionuclide complexes according to the present invention may have the general formula:
  • radionuclide complexes according to the present invention may have the general formula:
  • a technetium radionuclide complex having the general formula (IV) may be formed from a pertechnetate solution and a ligand having the general formula (II) above, wherein R 10 is hydrogen; R ⁇ is 0
  • the radionuclide containing solution may be obtained from radionuclide generators in a known manner.
  • the pertechnetate solution may be obtained from a technetium generator in a known manner.
  • the radionuclide complex forming reaction is then carried out under appropriate reaction conditions.
  • the technetium 99m complex forming reaction is carried out under technetium complex forming temperatures, e.g. 20 * C to 100 * C for 10 minutes to several hours. A large excess of the appropriate ligands over the radionuclide complex forming amounts is preferably used.
  • the pertechnetate is used in technetium complex forming amounts, e.g. about 10 6 to 10 12 molar amounts.
  • radionuclide complexes of the present invention incorporating the ligands of the present invention have particular functional use as brain imaging agents.
  • these agents will act as opium alkaloid (e.g. morphine) mimics which may be selectively localized in the brain receptors, and may therefore exhibit optimal properties to function as diagnostic agents for the detection of brain disorders such as Alzheimer's disease, Parkinson's disease, narcotic addiction, etc.
  • opium alkaloid e.g. morphine
  • a preferred complex for use in a brain imaging agent according to the present invention has the following formula:
  • R 1 is as defined above in formula (I), and wherein
  • Z is a primary, secondary or tertiary amino functionality.
  • This complex may be formed by reaction of a pertechnetate solution with a ligand according to the present invention having the general formula (I) above, wherein R 1 is, in particular, hydrogen, hydroxyl, or methoxyl; R 2 is CH 3 ; A is R 4 R 5
  • R 6 is hydrogen or CH 3 and R 7 is hydrogen or CH 3 , and J is a suitable protecting group; and B is
  • a further preferred complex for use in a brain agent according to the present invention has the following formula:
  • R 10 is as defined above in formula (II), and wherein Q is a primary, secondary or tertiary amino functionality.
  • This complex may be formed by reaction of a pertechnetate solution with a ligand having the general formula (II) above, wherein R 10 is, in particular, hydrogen, hydroxyl, or methoxyl; R u is hydrogen or another suitable protecting group; D is
  • R 15 is hydrogen or CH 3 and F 16 is hydrogen or CH 3 , and L is a suitable protecting group; and E is
  • R 18 R 19 wherein R 18 and R 19 are hydrogen .
  • the present invention also relates to imaging agents containing a radionuclide complex as described above , in an amount sufficient for imaging , together with a pharmaceutically acceptable radiological vehicle .
  • the radiological vehicle should be suitable for injection or aspiration, such as human serum albumin; aqueous buffer solutions, e.g tris(hydromethyl) aminomettane (and its salts), phosphate, citrate, bicarbonate, etc; sterile water; physiological saline; and balanced ionic solutions containing chloride and or dicarbonate salts or normal blood plasma cations such as Ca +2 , Na + , K + , and Mg +Z .
  • the concentration of the imaging agent according to the present invention in the radiological vehicle should be sufficient to provide satisfactory imaging, for example, when using an aqueous solution, the dosage is about 1.0 to 50 millicuries.
  • the imaging agent should be administered so as to remain in the patient for about 1 to 3 hours, although both longer and shorter time periods are acceptable. Therefore, convenient ampules containing 1 to 10 ml of aqueous solution may be prepared.
  • Imaging may be carried out in the normal manner, for example by injecting a sufficient amount of the imaging composition to provide adequate imaging a d then scanning with a suitable machine, such as a gamma camera.
  • the complexes according to the present invention may be prepared in accordance with the examples set forth below.
  • Example 2 A mixture of the ligand produced in Example 1 (10 mg) in ethanol (0.9 ml) was treated with 0.01 N NaOH (0.1 ml) and technetium tartarate solution (0.1 ml). The entire mixture was heated at 100 * C for 30 minutes. After cooling, the neutral complex was purified by reverse phase HPLC.
  • Example 8 Preparation of 5-aza-3-(N-t-butoxvcarbonvl)amino-l- S-f fN-ethyllcarbamovllmercapto-4-oxo-7-f2-p ⁇ ridyl - heptane

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Abstract

The present invention relates particularly to novel aminothiol ligands that are suitable for complexing with a radionuclide, and are useful as general imaging agents for diagnostic purposes.

Description

NOVEL NITROGEN-SULFUR LIGANDS USEFUL IN RADIOGRAPHIC IMAGING AGENTS
Background of the Invention
The present invention relates to novel ligands for forming radionuclide complexes, new complexes incorporating such ligands, processes for preparing such complexes, imaging agents incorporating such complexes, and methods of imaging using such imaging agents.
The use of radiographic imaging agents for visualizing skeletal structures, organs, or tissues, is well known in the area of biological and medical research and diagnostic procedures. T e procedure whereby such imaging is accomplished, generally involves the preparation of radioactive ag-ents, which, when introduced to the biological subject, are localized in the specific skeletal structures, organs cr tissues to be studied. The localized radioactive agents may then be traced, plotted or scintiphotographe by radiation detectors, such as, traversing scanners or scintillation cameras. The distribution and relative intensity of the detected radioactive agents indicates the position of the tissue in which the agent is localized, and also shows the presence of aberrations, pathtological conditions or the like.
In general, the radiographic imaging agents comprise radionuclide-labelled compounds; such as complexes of technetium 99m, rhenium 186 or rhenium 188, or other applicable radionuclides; with appropriate carriers, and auxiliary agents, such as del-ivery vehicles suitable for injection into, or aspiration by, the patient, physiological buffers and salts, and the like. Detailed Description of the Invention
The present invention relates particularly to novel aminothiol ligands that are suitable for complexing with a radionuclide, and are useful as general imaging agents for diagnostic purposes. In particular the present invention relates to novel ligands having the general formula:
Figure imgf000004_0001
wherein R1 and R2 may the same or different and are selected from the group consisting of hydrogen, alkyl, aryl, hydroxyl, alkoxyl, mono- or poly- hydroxyalkyl, mono- or poly- alkoxyalkyl, acyl, alkoxycarbonyl, or carbamoyl; A is selected from the group consisting of
R3 R4 R5
1
(CH2)„- , -C- or -CH -C-
wherein n is 1 to 3, wherein R3, R4 and R5 are defined in the same manner as R1 and R2 above, and wherein 7 is
\
-CH-(CH2)B-S-J or -H
wherein is 1 to 3, wherein Z is selected from the group consisting of
Figure imgf000004_0002
wherein R6 and R7 are defined in the same manner as R1 and R2 above, and wherein J is hydrogen or another suitable protecting group such as ethylaminocarbonyl; and B is selected from the group consisting of
-(CHj) -
Figure imgf000005_0003
wherein p is 1 to 3, wherein 1 is 0 or 1, wherein R8 and R9 are defined in the same manner as R1 and R2 above, and wherein 7 is as defined above.
In a preferred embodiment, ligands according to the present invention have the general formula (I) above, wherein R1 is hydrogen; R2 is selected from the group consisting of butoxycarbonyl, acetyl, ethyl, or hydrogen; A is -(CH2)n- wherein n
Figure imgf000005_0001
wherein 1 = 0, R8 is hydrogen and Y is Z
-CH-(CH2)m-S-J wherein m = 1, Z is -H, and J is a suitable protecting group.
The present invention also relates to novel ligands having the general formula:
Figure imgf000005_0002
wherein R10 is selected from the group consisting of hydrogen, alkyl, aryl, hydroxyl, alkoxyl, mono- or poly- hydroxyalkyl, mono- or poly- alkoxyalkyl, acyl, alkoxycarbonyl, or carbamoyl; Rn is a suitable sulfur protecting group selected from the group defined in the same manner as R10 above; D is selected from the group consisting of
>12 >13 >ι<
-(CH2)r -C- or -CH - C-
I
wherein i is 1 to 3, wherein R , R13 and R1 are defined in the same manner as R10 above, and wherein Σ is
Q
I -CH-(CH2)g-S-L
wherein g is 1 to 3, wherein Q is selected from the group consisting of
Figure imgf000006_0001
wherein R15 and R16 are defined in the same manner as R10 above, and wherein L is hydrogen or another suitable protecting group such as ethylaminocarbonyl; and E is selected from the group consisting of
II II M II
- (CH2 ) „- , - C-CH2-NH-C-CH2- , -C-CH- , or -C-CH - CH-
R17 R18 R19
wherein h is 1 to 3, wherein R17, R18 and R19 are defined in the same manner as R10 above.
In another preferred embodiment, ligands according to the present invention have the general formula (II) above, wherein R10 is hydrogen; R11 is 0
-C-Phenyl ; D is -(CH2)j- wherein i = 1; and E is 0 0
... CH2-NH-C-CH2-
The novel ligands described above, may be incorporated into radionuclide complexes used as radiographic imaging agents. The complexes of the present invention are prepared by reacting one of the aforementioned ligands with a radionuclide containing solution under radionuclide complex forming reaction conditions. In particular, if a technetium agent is desired, the reaction iβ carried out with a pertechnetate solution under technetium 99m complex forming reaction conditions. The solvent may then be removed by any appropriate means, such as evaporation. The complexes are then prepared for administration to the patient by dissolution or suspension in a pharmaceutically acceptable vehicle.
The ligands of the present invention may be prepared from commercially available starting materials such as 2- (2-aminoethyl)pyridine, 2-aminomethyl pyridine, homocysteinethiolaσtone, etc. by standard synthetic methods as described in the following Examples 1 - 7.
Radionuclide complexes according to the present invention may have the general formula:
Figure imgf000007_0001
wherein M is an appropriate radionuclide such as technetium or rhenium, and R1 and R2 are as defined above in formula (I) . In a preferred embodiment a technetium radionuclide complex having the general formula (III) may be formed from a pertechnetate solution and a ligand having the general formula (I) above, wherein R1 is hydrogen; R2 is butoxycarbonyl, acetyl, ethyl or hydrogen; A is -(CH2)n- wherein n = 2; and B is O R8
-C-C-(CH2),-
I
Y wherein 1 = 0, R8 is hydrogen and Y is Z
-CH-(CH2)m-S-J wherein m = 1, Z is -H, and J is a suitable protecting group.
Also, radionuclide complexes according to the present invention may have the general formula:
Figure imgf000008_0001
wherein M represents an appropriate radionuclide, such as technetium or rhenium and wherein R10 is as defined above in formula (II). In a preferred embodiment, a technetium radionuclide complex having the general formula (IV) may be formed from a pertechnetate solution and a ligand having the general formula (II) above, wherein R10 is hydrogen; Rπ is 0
-C-Phenyl ; D is -(CH2)j- wherein i = 1; and E is 0 O
-C-CH2-NH-C-CH2- . The radionuclide containing solution may be obtained from radionuclide generators in a known manner. For example, when forming a technetium complex, the pertechnetate solution may be obtained from a technetium generator in a known manner. The radionuclide complex forming reaction is then carried out under appropriate reaction conditions. For example, the technetium 99m complex forming reaction is carried out under technetium complex forming temperatures, e.g. 20* C to 100*C for 10 minutes to several hours. A large excess of the appropriate ligands over the radionuclide complex forming amounts is preferably used. For example, when forming a technetium complex, at least a ten fold excess of the ligands over the pertechnetate solution is used. The pertechnetate is used in technetium complex forming amounts, e.g. about 106 to 1012 molar amounts.
It is believed that certain radionuclide complexes of the present invention incorporating the ligands of the present invention have particular functional use as brain imaging agents. In particular, it is believed that these agents will act as opium alkaloid (e.g. morphine) mimics which may be selectively localized in the brain receptors, and may therefore exhibit optimal properties to function as diagnostic agents for the detection of brain disorders such as Alzheimer's disease, Parkinson's disease, narcotic addiction, etc.
A preferred complex for use in a brain imaging agent according to the present invention has the following formula:
Figure imgf000010_0001
wherein R1 is as defined above in formula (I), and wherein
Z is a primary, secondary or tertiary amino functionality. This complex may be formed by reaction of a pertechnetate solution with a ligand according to the present invention having the general formula (I) above, wherein R1 is, in particular, hydrogen, hydroxyl, or methoxyl; R2 is CH3; A is R4 R5
-CH -C- I Y wherein R4 and R5 are hydrogen and Y is Z
-CH-(CH2)m-S-J wherein m = 1, Z is ^ 6
-N
\.» wherein R6 is hydrogen or CH3 and R7 is hydrogen or CH3 , and J is a suitable protecting group; and B is
O R8 II I -C-C- (CH2 ) ,-
Y wherein 1 = 1, R8 is hydrogen and Y is -H.
A further preferred complex for use in a brain agent according to the present invention has the following formula:
Figure imgf000011_0001
wherein R10 is as defined above in formula (II), and wherein Q is a primary, secondary or tertiary amino functionality.
This complex may be formed by reaction of a pertechnetate solution with a ligand having the general formula (II) above, wherein R10 is, in particular, hydrogen, hydroxyl, or methoxyl; Ru is hydrogen or another suitable protecting group; D is
Figure imgf000011_0003
wherein R13 and R14 are hydrogen and X is Q
-CH-(CH2)g-S-L wherein g = 1, Q is
Figure imgf000011_0002
wherein R15 is hydrogen or CH3 and F16 is hydrogen or CH3 , and L is a suitable protecting group; and E is
O
II -C-CH - CH-
R18 R19 wherein R18 and R19 are hydrogen .
The present invention also relates to imaging agents containing a radionuclide complex as described above , in an amount sufficient for imaging , together with a pharmaceutically acceptable radiological vehicle . The radiological vehicle should be suitable for injection or aspiration, such as human serum albumin; aqueous buffer solutions, e.g tris(hydromethyl) aminomettane (and its salts), phosphate, citrate, bicarbonate, etc; sterile water; physiological saline; and balanced ionic solutions containing chloride and or dicarbonate salts or normal blood plasma cations such as Ca+2, Na+, K+, and Mg+Z.
The concentration of the imaging agent according to the present invention in the radiological vehicle should be sufficient to provide satisfactory imaging, for example, when using an aqueous solution, the dosage is about 1.0 to 50 millicuries. The imaging agent should be administered so as to remain in the patient for about 1 to 3 hours, although both longer and shorter time periods are acceptable. Therefore, convenient ampules containing 1 to 10 ml of aqueous solution may be prepared.
Imaging may be carried out in the normal manner, for example by injecting a sufficient amount of the imaging composition to provide adequate imaging a d then scanning with a suitable machine, such as a gamma camera.
The complexes according to the present invention may be prepared in accordance with the examples set forth below.
Example ι
Preparation of 5-aza-3- f N-t-butoxycarbonvl amino- 1- mercapto-4-oxo-7- ( 2-pyridyl ) -heptane
Figure imgf000013_0001
A mixture of 2-(2-aminoethyl)pyridine (2.44 g, 0.02 mol) and N-t butoxycarbonyl-homocysteinethiolactone (4.22 g, 0.02 mol) in acetonitrile (50 ml) was heated under reflux for 12 hours. Thereafter, the reaction mixture was kept at room temperature for 6 hours by which time colorless crystals had separated. The solid was collected by filtration, washed with cold acetonitrile, and dried. 13C-NMR (CDC13) 6 171.2, 159.3, 155.4, 149.2, 136.4, 123.3, 121.5, 79.9, 53.7, 38.8, 36.9, 34.8, 32.6, 28.3.
Example 2 Preparation of 3-acetamido-5-aza-l-mercapto-4-oxo-7- (2-pvriavl) heptane
Figure imgf000013_0002
A mixture of N-acetylhomocysteinethiolactone (4.77 g, 0.03 mol) and 2-(2-aminoethyl) pyridine (3.66 g, 0.03 mol) in acetonitrile (50 ml) was heated under reflux for 12 hours. The solvent was removed under reduced pressure and the residue was treated with ethyl acetate (50 ml). The precipitate was collected, dried and recrystallized from acetonitrile to give colorless solid. 13C-NMR (CDC13) 6 171.4, 170.6, 159.4, 149.3, 136.6, 123.4, 121.8, 51.7, 38.5, 36.8, 34.9, 32.7, 22.8.
Example 3 Preparation of 3-amino-5-aza-l-mercapt:o-4-oxo-7- (2- pyridvll heptane
Figure imgf000014_0001
A solution of the butoxycarbonyl derivative from Example 1, (4 g) and trifluoroacetic acid (20 ml) was kept at room temperature for 1 hour. The reaction mixture was poured onto ether (500 ml). the precipitate was collected, washed with ether and dried. The compound was pure enough for the next step.
Example 4 Preparation of 5-aza-3-ethγlamino-l-n.ercapto-4-oxo- 7-f2-pyridyH heptane
Figure imgf000014_0002
A solution of diborane in tetrahydrofuran (1 M, Aldrich) (60 ml) was added dropwise to an ice-cold solution of the diamide of Example 2 (4 g) in tetrahydrofuran (20 ml). After the addition, the reaction mixture was heated under reflux for 2 hours. The reaction mixture was then cooled in an ice bath and excess diborane was decomposed by dropwise addition of ice-cold water. The solution was taken to dryness under reduced pressure and the residue was rediεsolved in methylene chloride (100 ml) washed with water (2 x 100 ml), dried (Na2S0 ), filtered and the filtrate was taken to dryness under reduced pressure. The residue was chromatographed over silica gel (200 g) using CH2C12/CH30H (9:1) as eluent to furnish the desired compound as colorless gum (1 g). l3C-NMR (CDC13) 6 174.7, 159.0, 148.9, 137.2, 123.7, 121.9, 61.2, 49.8, 42.3, 38.3, 37.4, 36.8, 20.8, 14.7.
Example 5 Preparation of 7-(S-frengoyl) ercaptP-2,5-diaza-3,6- dioxo- l- ( 2-pyridvl) heptane
H!NT
Figure imgf000015_0001
A mixture of S-(benzoyl)merσaptoacetoxy succinimide (1.4 g) and l-amino-3-aza-2-oxo-4-(2-pyridyl) butane (0.8 g) in acetonitrile (20 ml) was stirred at room temperature for 1 hour. The white precipitate was collected, washed with water, dried, and recrystallized from acetonitrile to give 700 mg of colorless solid. 13C- NMR (CDC1,) 6 191.9, 168.9, 156.5, 149.2, 137.0, 136.1, 134.3, 128.9, 127.7, 122.5, 122.0, 44.3, 43.3, 32.5.
Example 6 "Tc labelling of the liσand of Example 1
Figure imgf000016_0001
A mixture of the ligand produced in Example 1 (10 mg) in ethanol (0.9 ml) was treated with 0.01 N NaOH (0.1 ml) and technetium tartarate solution (0.1 ml). The entire mixture was heated at 100*C for 30 minutes. After cooling, the neutral complex was purified by reverse phase HPLC.
Exa le 7 99mTc labelling of the liσand of Example 5
Figure imgf000016_0002
A mixture of the ligand produced in Example 5 (10 mg) in ethanol (0.1 ml) and 0.0001 N NaOH (0.9 ml) and. technetium tartarate solution (0.1 ml) was heated at 100*C for 45 minutes to yield neutral complex in high yield and purity. No HPLC purification was required. Example 8 Preparation of 5-aza-3-(N-t-butoxvcarbonvl)amino-l- S-f fN-ethyllcarbamovllmercapto-4-oxo-7-f2-pγridyl - heptane
Figure imgf000017_0001
O γJC L 'NHEt
A mixture of 2-aminomethyl pyridine (2.44 g, 0.02 mol) and N-t butoxycarbonyl-homocysteinethiolactone (4.22 g, 0.02 mol) in acetonitrile (50 ml) was heated under reflux for 16 hours. Thereafter, the reaction mixture was cooled to room temperature and was treated with ethyl isocyanate (2 ml). The solution was stirred at room temperature for 16 hours. The solvent was removed under reduced pressure and the residue was treated with CH2C12 (50 ml) and water (50ml). The organic layer was separated, washed with water, dried (MgS04), filtered, and the filtrate taken to dryness under reduced pressure to give the desired compound as a pale yellow gum. Purification by silica gel chromatography (ethyl acetate acetone, 4:1) yeilded pure ligand (1.2g) as an off white solid. 13C-NMR (CDC13) 6 171.6, 156.6, 155.6, 149.0, 136.7, 122.3, 121.7, 80.0, 53.7, 44.6, 36.4, 33.9, 28.3, 26.1, 14.9.
The foregoing has been a discussion of the preferred embodiments of the present invention, but is not intended to limit the invention in any way. Rather, many modifications, variations and changes in detail may be made within the scope of the present invention.

Claims

What is claimed is:
1. A ligand useful in forming radionuclide complexes, said ligand having the general formula:
Figure imgf000018_0001
wherein R1 and R2 may the same or different and are selected from the group consisting of hydrogen, alkyl, aryl, hydroxyl , alkoxyl, mono- or poly- hydroxyalkyl, mono- or poly- alkoxyalkyl, acyl, alkoxycarbonyl, or carbamoyl; A is selected from the group consisting of
R3 R4 R5
I I I
-(CH2)n- , -C- , or -CH -C-
Y Y wherein n is 1 to 3, wherein R3, R4 and R5 are defined in the same manner as R1 and R2 above, and wherein Y is
is selected from the
Figure imgf000018_0002
wherein R6 and R7 are defined in the same manner as
R1 and R2 above, and wherein J is a suitable protecting group.; and B is selected from the group consisting of
O R8 0 R9 O
II I II I II
-(CH2)p- , -C-C-(CH2)r , or -C-C -C-
Y Y wherein p is 1 to 3, wherein 1 is 0 or 1, wherein R8 and R9 are defined in the same manner as R1 and R2 above, and wherein Y is as defined above.
A ligand according to claim 1, wherein R1 is hydrogen; R2 is butoxycarbonyl; A is -(CH2)n- wherein n = 2; and B is O R8
II I -C-C-(CH2),-
Y wherein 1 = 0, R8 is hydrogen and Y is z
-CH-(CH2)m-S-J wherein m = 1, Z is -H, and J is a suitable protecting group.
A ligand according to claim 1, wherein R1 is hydrogen; R2 is acetyl; A is -(CH2)n- wherein n = 2; and B is O R8 1/ . -C-C-(CH2),-
Y wherein 1 = 0 , R8 is hydrogen and Y is
Z
-CH- (CH2 )m-S-J wherein m = 1, Z is -H, and J is a suitable protecting group.
A ligand according to claim 1, wherein R1 is hydrogen; R2 is ethyl; A is -(CH2)n- wherein n = 2;
Figure imgf000019_0001
wherein 1 = 0 , R8 is hydrogen and Y is Z / -CH-fCH^-S-J wherein m = 1, Z is -H, and J is a suitable protecting group.
5. A ligand according to claim 1, wherein R1 is hydrogen; R2 is hydrogen; A is -(CH2)n- wherein n
2; and B is 0 R8 II I -C-C-(CH2),-
Y wherein 1 = 0, R8 is hydrogen and Y is
Z -CH-(CH2)ffl-S-J wherein m = 1 , Z is -H, and J is a suitable protecting group.
6. A ligand useful in forming radionuclide complexes, said ligand having the general formula:
Figure imgf000021_0001
wherein R10 is selected from the group consisting of hydrogen, alkyl, aryl, hydroxyl, alkoxyl, mono- or poly- hydroxyalkyl, mono- or poly- alkoxyalkyl, acyl, alkoxycarbonyl, or carbamoyl; Ru is a suitable sulfur protecting group selected from the group defined in the same manner as R10 above; D is selected from the group consisting of
R12 RI3 R14
I I I
- {CH,) ~ , -C- , or -CH - C- z ' I I
X X wherein i is 1 to 3 , wherein R12 , R13 and R14 are defined in the same manner as R10 above , and wherein
X is
Q -CH- (CH2 ) g-S-L
wherein g is 1 to 3 , wherein Q is selected from the group consisting of
-H , -NH2 , or -N
\ R16 wherein R15 and R16 are defined in the same manner as R10 above, and wherein L is a suitable protecting group; and E is selected from the group consisting of 0
II
-(CH2)h- -C-CH2-NH-C-CH2- -C-CH-
.17
or -C-CH - CH-
R18 R19 wherein h is 1 to 3, and wherein R17, R18 and R19 are defined in the same manner as R10 above.
A ligand according to claim 6, wherein R10 is hydrogen; Rπ is 0
-C-Phenyl ; D is -(CH2)j- wherein i = 1; and E is
O 0
II II
-C-CH2-NH-C-CH2- .
8. A radionuclide complex having the general formula:
Figure imgf000023_0001
where M is a radionuclide, and wherein R1 and R2 may be the same or different and are selected from the group consisting of hydrogen, alkyl, aryl, hydroxyl, alkoxyl, mono- or poly- hydroxyalkyl, mono- or poly- alkoxyalkyl, acyl, alkoxycarbonyl, or carbamoyl.
9. A complex according to claim 8, wherein M is technetium or rhenium.
10. A complex according to claim 9, wherein R2 is selected from the group consisting of butoxycarbonyl, acetyl, ethyl and hydrogen.
11. A complex according to claim 10, wherein R2 is butoxycarbonyl .
12. A radionuclide complex having the general formula:
Figure imgf000024_0001
wherein M is a radionuclide, and wherein R10 is selected from the group consisting of hydrogen, alkyl, aryl, hydroxyl, alkoxyl, mono- or poly- hydroxyalkyl, mono- or poly- alkoxyalkyl, acyl, alkoxycarbonyl, or carbamoyl.
13. A complex according to claim 12, wherein M is technetium or rhenium.
14 . A radionuclide complex having the general formula :
Figure imgf000025_0001
wherein R1 is hydrogen, hydroxyl, or methoxyl, and wherein Z is a primary, secondary, or tertiary amino functionality.
15. A radionuclide complex having the general formula:
Figure imgf000025_0002
wherein R10 is hydrogen, hydroxyl, or methoxyl, and wherein Q is a primary, secondary, or tertiary amino functionalit . 24
16. A method of making a radionuclide complex having the general formula :
Figure imgf000026_0001
wherein M is a radionuclide, and wherein R1 and R2 may be the same or different and are selected from the group consisting of hydrogen, alkyl, aryl, hydroxyl, alkoxyl, mono- or poly- hydroxyalkyl, mono- or poly- alkoxyalkyl, acyl, alkoxycarbonyl, or carbamoyl; said method comprising reacting a radionuclide containing solution and a ligand having the general formula:
Figure imgf000026_0002
wherein R1 and R2 may be the same or different and are selected from the group consisting of hydrogen, alkyl, aryl , hydroxyl, alkoxyl, mono- or poly- hydroxyalkyl , mono- or poly- alkoxyalkyl, acyl, alkoxycarbonyl, or carbamoyl; A is selected from the group consisting of
R3 R4 R5
I I I
- (CH2) n- , -C- , or -CH -C-
Y Y wherein n is 1 to 3, wherein R3, R4 and R5 are defined in the same manner as R1 and R2 above, and wherein Y is
-CH-tCH^-S-J or -H wherein m is 1 to 3, wherein Z is selected from the group consisting of
Figure imgf000027_0001
wherein R6 and R7 are defined in the same manner as R1 and R2 above , and J is a suitable protecting group; and B is selected from the group consisting of
- (CH2) p- , -
Figure imgf000027_0002
wherein p is 1 to 3, wherein 1 is 0 or 1, wherein R8 and R9 are defined in the same manner as R1 and R2 above, and wherein Y is as defined above.
17. A method according to claim 16, wherein R1 is hydrogen; R2 is butoxycarbonyl, acetyl, ethyl or hydrogen; A is -(CH2)ft- wherein n = 2;
Figure imgf000027_0003
Y wherein 1 = 0, R8 is hydrogen and Y is
Z
-CH-(CH2)m-S-J wherein m = 1 , Z is -H, and J is a suitable protecting group.
18. A method according to claim 17 , wherein M is technetium or rhenium, said radionuclide containing solution is a pertechnetate or perrheneate solution respectively, and R2 is butoxycarbonyl . 19. A method of making a radionuclide complex having the general formula:
Figure imgf000028_0001
wherein R1 is hydrogen, hydroxyl, or methoxyl, and wherein Z is a primary, secondary, or tertiary amino functionality; said method comprising reacting a radionuclide containing solution and a ligand having the general formula:
Figure imgf000028_0002
wherein R1 is hydrogen, hydroxyl, or methoxyl; R2 may be the same as or different from R1 and is selected from the group consisting of hydrogen, alkyl, aryl, hydroxyl, alkoxyl, mono- or poly- hydroxyalkyl, mono- or poly- alkoxyalkyl, acyl, alkoxycarbonyl, or carbamoyl; A is selected from the group consisting of
R3 R4 R5
I / I
-(CH2)n- , -C- , or -CH -C-
Y Y wherein n is 1 to 3, wherein R3, R4 and R5 are defined in the same manner as R2 above, and wherein Y is
Z I -CH-(CH2) -S-J , or -H wherein m is 1 to 3, wherein Z is selected from the group consisting of
Figure imgf000029_0001
wherein R6 and R7 are defined in the same manner as
R2 above, and wherein J is a suitable protecting group; and B is selected from the group consisting of
O R8 O R9 O
II I H I 1/
-(CH2)p- , -C-C-(CH2)(- , or -C-C -C-
Y Y wherein p is 1 to 3, wherein 1 is 0 or 1, wherein R8 and R9 are defined in the same manner as R2 above, and wherein Y is as defined above.
20. A method according to claim 19, R2 is CH3;
A is R4 R5 I I -CH -C- I Y wherein R4 and R5 are hydrogen and
Y is Z
-CH-(CH2)m-S-J wherein m = 1, Z is -R6
-N
^ 7 wherein R6 is hydrogen or CH3 and R7 is hydrogen or
CH3, and J is a suitable protecting group; and B is
0 R8
-C-C-(CH2).-
Y wherein 1 =1, R8 is hydrogen and Y is -H.
21. A method according to claim 20, said radionuclide containing solution is a pertechnetate solution. 22. A method of making a radionuclide complex having the general formula:
Figure imgf000030_0001
wherein M is a radionuclide, and wherein R10 is selected from the group consisting of hydrogen, alkyl, aryl, hydroxyl, alkoxyl, mono- or poly- hydroxyalkyl, mono- or poly- alkoxyalkyl, acyl, alkoxycarbonyl, or carbamoyl, said method comprising reacting a radionuclide containing solution and a ligand having the general formula:
Figure imgf000030_0002
wherein R10 is selected from the group consisting of hydrogen, alkyl, aryl, hydroxyl, alkoxyl, mono- or poly- hydroxyalkyl, mono- or poly- alkoxyalkyl, acyl, alkoxycarbonyl, or carbamoyl; R11 is a suitable sulfur protecting group selected from the group defined in the same manner as R10 above; D is selected from the group consisting of
-(CH2)r ,
Figure imgf000030_0003
wherein i is 1 to 3 , wherein R12 , R13 and R14 are defined in the same manner as R10 above, and wherein X is
Figure imgf000031_0001
wherein g is 1 to 3, wherein Q is selected from the group consisting of
Figure imgf000031_0002
wherein R15 and R16 are defined in the same manner as
R10 above, and wherein L is a suitable protecting group; and E is selected from the group consisting of
0 0 0
]l II \l
- ( CH2 ) h- , - C-CH2-NH-C-CH2- , -C-CH-
R17
0
// or -C-CH - CH-
R18 R19 wherein h is 1 to 3, wherein R17, R18 and R19 are defined in the same manner as R10 above.
23. A method according to claim 22, wherein R10 is hydrogen; R11 is O
-C-Phenyl ; D is -(CH2)j- wherein i = 1; and E is
0 O
// // -C-CH2-NH-C-CH2- .
24. A method according to claim 23, wherein M is technetium or rhenium, and said radionuclide containing solution is a pertechnetate or perrheneate solution respectively. 25. A method of making a radionuclide complex having the general formula:
Figure imgf000032_0001
wherein R10 is hydrogen, hydroxyl, or methoxyl, and wherein Q is a primary, secondary, or tertiary amino functionality, said method comprising reacting a radionuclide containing solution and a ligand having the general formula:
Figure imgf000032_0002
wherein R10 is hydrogen, hydroxyl, or methoxyl; R11 is a suitable sulfur protecting group selected from the group consisting of hydrogen, alkyl, aryl, hydroxyl, alkoxyl, mono- or poly- hydroxyalkyl, mono- or poly- alkoxyalkyl, acyl, alkoxycarbonyl, or carbamoyl; D is selected from the group consisting of
R12
-(CH2)r , -C- , or
Figure imgf000032_0003
1 I l
X X wherein i is 1 to 3, wherein R12, R13 and R14 are defined in the same manner as R11 above, and wherein
X is Q / -CH-(CH2)g-S-L wherein ς is 1 to 3, wherein Q is selected from the group consisting of
Figure imgf000033_0001
wherein R15 and R16 are defined in the same manner as R11 above, and wherein L is a suitable protecting group; and E is selected from the group consisting of
0 0 0 ii u i.
- (CH2) h- , -C-CH2-NH-C-CH2- , -C-CH-
R17
0
1/ or -C-CH - CH-
R18 R19 wherein h is 1 to 3, wherein R17, R18 and R19 are defined in the same manner as Ru above.
26. A method according to claim 25, wherein R11 is hydrogen; D is R13 R14
-CH - C- X wherein R13 and R14 are hydrogen and X is
Q
-CH- (CH2 ) g-S-L wherein g = 1 , Q is
Figure imgf000033_0002
wherein R15 is hydrogen or CH3 and R16 is hydrogen or CH3, and L is a suitable protecting group; and E is
0
11 -C-CH - CH-
R18 R19 wherein R18 and R19 are hydrogen.
27. A method according to claim 26, wherein said radionuclide containing solution is a pertechnetate solution. 28. A radiographic imaging agent comprising a complex
Figure imgf000034_0001
where M is a radionuclide, and wherein R1 and R2 may be the same or different and are selected from the group consisting of hydrogen, alkyl, aryl, hydroxyl, alkoxyl, mono- or poly- hydroxyalkyl, mono- or poly- alkoxyalkyl, acyl, alkoxycarbonyl, or carbamoyl; and a pharmaceutically acceptable radiological vehicle.
29. An imaging agent according to claim 28, wherein M is technetium or rhenium.
30. An imaging agent according to claim 29, wherein R2 is selected from the group consisting of butoxycarbonyl, acetyl, ethyl and hydrogen.
31. An imaging agent according to claim 30, wherein R2 is butoxycarbonyl.
32. An imaging agent according to claim 28, wherein said vehicle is suitable for injection or aspiration and is selected from the group consisting of human serum albumin, aqueous buffer solutions, sterile water, physiological saline, and balanced ionic solutions containing chloride salts, dicarbonate salts or blood plasma cations.
33. An imaging agent according to claim 28, wherein the concentration of said complex in said vehicle is from about 1.0 to 50 millicuries. 34. A radiographic imaging agent comprising a complex having the general formula:
Figure imgf000035_0001
wherein M is a radionuclide, and wherein R10 is selected from the group consisting of hydrogen, alkyl, aryl, hydroxyl, alkoxyl, mono- or poly- hydroxyalkyl, .mono- or poly- alkoxyalkyl, acyl, alkoxycarbonyl, or carbamoyl; and a pharmaceutically acceptable vehicle.
35. An imaging agent according to claim 34, wherein said vehicle is suitable for injection or aspiration and is selected from the group consisting of human serum albumin, aqueous buffer solutions, sterile water, physiological saline, and balanced ionic solutions containing chloride salts, dicarbonate salts or blood plasma cations.
36. An imaging agent according to claim 34, wherein M is technetium or rhenium.
37. An imaging agent according to claim 34, wherein the concentration of said complex in said vehicle is from about 1.0 to 50 millicuries. 38. A radiographic imaging agent comprising a complex having the general formula:
Figure imgf000036_0001
wherein R1 is hydrogen, hydroxyl, or methoxyl, and wherein Z is a primary, secondary, or tertiary amino functionality; and a pharmaceutically acceptable vehicle.
39. An imaging agent according to claim 38, wherein said vehicle is suitable for injection or aspiration and is selected from the group consisting of human serum albumin, aqueous buffer solutions, sterile water, physiological saline, and balanced ionic solutions containing chloride salts, dicarbonate salts or blood plasma cations.
40. An imaging agent according to claim 38, wherein the concentration of said complex in said vehicle is from about 1.0 to 50 millicuries. 41. A radiographic imaging agent comprising a complex having the general formula:
Figure imgf000037_0001
wherein R10 is hydrogen, hydroxyl, or methoxyl, and wherein Q is a primary, secondary, or tertiary amino functionality.and a pharmaceutically acceptable vehicle.
42. An imaging agent according to claim 41, wherein said vehicle is suitable for injection or aspiration and is selected from the group consisting of human serum albumin, aqueous buffer solutions, sterile water, physiological saline, and balanced ionic solutions containing chloride salts, dicarbonate salts or blood plasma cations.
43. An imaging agent according to claim 41, wherein the concentration of said complex in said vehicle is from about 1.0 to 50 millicuries. 44. A method of radiographic imaging, comprising injecting a sufficient amount of an imaging agent to provide adequate imaging and then scanning with a suitable scanning machine; said imaging agent comprising a complex having the general formula:
Figure imgf000038_0001
where M is a radionuclide, and wherein R1 and R2 may be the same or different and are selected from the group consisting of hydrogen, alkyl, aryl, hydroxyl, alkoxyl, mono- or poly- hydroxyalkyl, mono- or poly- alkoxyalkyl, acyl, alkoxycarbonyl, or carbamoyl; and a pharmaceutically acceptable radiological vehicle.
45. A method of radiographic imaging, comprising injecting a sufficient amount of an imaging agent to provide adequate imaging and then scanning with a suitable scanning machine; said imaging agent comprising a complex having the general formula:
Figure imgf000039_0001
wherein M is a radionuclide and wherein R10 is selected from the group consisting of hydrogen, alkyl, aryl, hydroxyl, alkoxyl, mono- or poly- hydroxyalkyl, mono- or poly- alkoxyalkyl, acyl, alkoxycarbonyl, or carbamoyl;; and a pharmaceutically acceptable vehicle.
46. A method of radiographic imaging, comprising injecting a sufficient amount of an imaging agent to provide adequate imaging and then scanning with a suitable scanning machine; said imaging agent comprising a complex having the general formula:
Figure imgf000040_0001
wherein wherein R1 is hydrogen, hydroxyl, or methoxyl, and wherein Z is a primary, secondary, or tertiary amino functionality; and a pharmaceutically acceptable vehicle.
47. A method of radiographic imaging, con-prising injecting a sufficient amount of an uiaging agent to provide adequate imaging and then scanning with a suitable scanning machine; said imaging agent comprising a complex having the general formula:
Figure imgf000041_0001
wherein R10 is hydrogen, hydroxyl, or methoxyl, and wherein Q is a primary, secondary, or tertiary amino functionality; and a pharmaceutically acceptable vehicle.
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