WO1992005154A1

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

Info

Publication number: WO1992005154A1
Application number: PCT/US1991/006479
Authority: WO
Inventors: Raghavan Rajagopalan
Original assignee: Mallinckrodt Medical, Inc.
Priority date: 1990-09-14
Filing date: 1991-09-09
Publication date: 1992-04-02
Also published as: IL99485A; IL99485A0; AU8721591A

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:

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

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

-(CH_j) -

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

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:

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

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:

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:

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; R^π 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:

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:

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; R^u is hydrogen or another suitable protecting group; D is

wherein R¹³ and R¹⁴ are hydrogen and X is Q

-CH-(CH₂)_g-S-L wherein g = 1, Q is

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

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

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

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

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

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

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

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

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:

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

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;

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:

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; R^u 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; R^π 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:

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:

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 :

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:

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 :

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:

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-

-CH-tCH^-S-J or -H wherein m is 1 to 3, wherein Z is selected from the group consisting of

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- , -

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;

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:

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:

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

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:

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:

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 ,

wherein i is 1 to 3 , wherein R¹² , R¹³ and R¹⁴ are defined in the same manner as R¹⁰ above, and wherein X is

wherein g is 1 to 3, wherein Q is selected from the group consisting of

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:

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:

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

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

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 R^u 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

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

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:

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:

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:

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:

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:

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:

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:

wherein R¹⁰ is hydrogen, hydroxyl, or methoxyl, and wherein Q is a primary, secondary, or tertiary amino functionality; and a pharmaceutically acceptable vehicle.