JPH0339515B2 - - Google Patents

Description

Claim 1 Formula: CNR (wherein R is an aliphatic or aromatic group containing up to 20 carbon atoms, which may be substituted, and the substituents include halogen, hydroxy,
selected from the group consisting of nitro, alkyl and alkoxy. ) and isonitrile ligands with Tc, Ru, Co,
Pt, Fe, Os, Ir, W, Re, Cr, Mo, Mn, Ni,
Coordination complexes with radioactive metals selected from the group consisting of radioactive isotopes of Rh, Pd, Nb and Ta.

2 Claim 1 in which the metal is Tc
Complexes described in Section.

3 Claim 1 in which the metal is Re
Complexes described in Section.

4. The complex according to claim 1, 2 or 3, wherein the R group of the isonitrile ligand is an aliphatic group.

5. The complex according to claim 1, 2 or 3, wherein the isonitrile ligand is a hydrocarbon isonitrile.

6. The complex according to claim 1, 2 or 3, wherein the isonitrile ligand is a saturated hydrocarbon isonitrile.

7. The complex according to claim 1, wherein each coordination position of the radioactive metal is filled with an isonitrile ligand.

8. The complex according to claim 1, wherein the isonitrile ligand is a monodentate ligand.

9. The complex according to claim 1, wherein the isonitrile ligand is a bidentate ligand.

10. The complex according to claim 1, wherein the isonitrile ligand is a tridentate ligand.

11. The complex according to claim 1, wherein the complex is a cationic lipophilic complex.

12 The radioactive metal is Tc, Ru, Co, Pt,
The complex according to claim 1, which is a radioisotope of Fe, Os or Ir.

13 The radioactive metal is W, Re, Fe or Os
The complex according to claim 1, which is a radioactive isotope of.

14 The radioactive metal is Cr, Mo, Co, Tc,
Fe, Mn, W, Ru, Ni, Rh, Ir, Pd, Nb or
The complex according to claim 1, which is a radioactive isotope of Ta.

15 An isonitrile complex having the formula [A((CN)xR)yBzB′z′]n.

(In the formula, A is Tc, Ru, Co, Pt, Fe, Os, Ir,
W, Re, Cr, Mo, Mn, Ni, Rh, Pd, Nb and
is a radionuclide selected from radioisotopes of Ta; (CN)xR is a monodentate or polydentate isonitrile ligand that binds to the radionuclide through the carbon atom of the CN group; R is a 20 carbon atom B and B′ are aliphatic or aromatic groups containing up to , 1 capable of forming a coordinate bond with a halogen group and the above-mentioned radionuclide
other ligands independently selected from the class of ligands consisting of one or more species of neutral donor atoms; x and y;
are each independently an integer from 1 to 8; z and
z' is each independently 0 or an integer from 1 to 7; provided that (xy)+z+z' is 8 or less; n indicates the charge of the complex and is 0 (neutral) or a positive or negative integer. ) 16 [A(CNR) ₆ ] ⁺ isonitrile complex having the formula.

(wherein A is a radionuclide selected from technetium and ¹⁸⁸ Re, and R is an aliphatic or aromatic group containing up to 20 carbon atoms, which may be substituted and The substituents are selected from the group consisting of halogen, hydroxy, nitro, alkyl and alkoxy.) 17 Cationic lipophilic hexakis-t-butylisonitrile complex of technetium.

18 (a) Formula CNR (wherein R is an aliphatic or aromatic group containing up to 20 carbon atoms, which may be substituted, and the substituents include halogen, hydroxy, nitro, an isonitrile ligand consisting of (b) Tc, Ru, Co,
Pt, Fe, Os, Ir, W, Re, Cr, Mo, Mn, Ni,
reacting a radionuclide selected from the class consisting of radioisotopes of Rh, Pd, Nb and Ta in the presence of a reducing agent in an amount sufficient to prepare the coordination complexes of (a) and (b); A method for preparing the coordination complex, comprising:

19. The method of claim 18, wherein the radionuclide is an isotope of Tc.

20. The method of claim 18, wherein the radionuclide is an isotope of Re.

21. The method of claim 18, wherein the radionuclide is an isotope of Ru, Co, Pt, Fe, Os or Ir.

22. The method of claim 18, wherein the radionuclide is a W isotope.

23 The radionuclide is Cr, Mo, Mn, Ni,
19. The method according to claim 18, which is an isotope of Rh, Pd, Nb or Ta.

24 Formula: CNR (wherein R is an aliphatic or aromatic group containing up to 20 carbon atoms, which may be substituted, and the substituents include halogen, bidroxy, nitro, alkyl and alkoxy ⁾ and ^99m Tc-pertechnetate in the presence of a reducing agent capable of reducing technetium. Method for preparing coordination complexes with Tc.

25. The method of claim 24, wherein the reducing agent is selected from the class consisting of dithionite and stannous salts.

26 Formula: CNR (wherein R is an aliphatic or aromatic group containing up to 20 carbon atoms, which may be substituted, and the substituents include halogen, hydroxy, nitro, alkyl and A radiopharmaceutical composition for contrast imaging, comprising a coordination complex of an isonitrile ligand (selected from the group consisting of alkoxy) and ^99m Tc.

27. The composition of claim 26, wherein the complex is ^99m Tc-hexakis-t-butylisonitrile.

28 Claim 26, wherein the complex is ^99m Tc-hexakis-iso-propylisonitrile
The composition described in Section.

29 Formula: CNR (wherein R is an aliphatic or aromatic group containing up to 20 carbon atoms, which may be substituted, and the substituents include halogen, hydroxy, nitro, alkyl and A radiopharmaceutical composition for detecting vascular embolism, comprising a coordination complex of an isonitrile ligand consisting of (selected from the group consisting of alkoxy) and ^99m Tc.

30. The composition of claim 29, wherein the complex is ^99m Tc-hexakis-t-butylisonitrile.

31 Claim 29, wherein the complex is ^99m Tc-hexakis-iso-propylisonitrile
The composition described in Section.

32 Formula: CNR (wherein R is an aliphatic or aromatic group containing up to 20 carbon atoms, which may be substituted, and the substituents include halogen, hydroxy, nitro, alkyl and A coordination complex of an isonitrile ligand selected from the group consisting of alkoxy and ^99m Tc is added to the cell or liposome, a radiopharmaceutical composition for detecting the position of the cell or liposome.

Description This invention was made with support from the United States Government, which has certain rights in the invention.

The present invention uses radionuclides such as ^99m Tc, ⁹⁹ Tc,
This invention relates to novel isonitrile complexes of radioactive isotopes such as ⁹⁷ Ru, ⁵¹ Cr, ⁵⁷ Co, ¹⁸⁸ Re, and ¹⁹¹ Os. However, the radionuclides are not limited to the above examples.
This complex can be easily prepared and isolated with a wide range of suitable counterions at both macro and tracer concentrations in aqueous media. They exhibit extremely effective labeling properties for various biological cells with liposomes or vesicles and lipid membranes, and are also effective contrast agents for detecting abnormalities in the tissues of various organs and the presence of blood clots. be. The complex of ^99m Tc is
This radioisotope is particularly preferred due to its desirable nuclear properties, ie, half-life and gamma ray energy.

Various contrast agents and labeling agents using radioactive isotopes have been developed in the past. However, the complexes available to date generally suffer from high cost, complexity of preparation methods, or insufficient lipophilic properties that do not provide high-quality imaging or effective labeling. Ta.

Although there have been reports on isonitrile complexes of various non-radioactive metals, there has been no suggestion that isonitrile complexes of radionuclides have useful and desirable properties as contrast agents or labeling agents. Oxine complexes of ^99m Tc have been reported for platelet labeling. Wistow et al., J. Nucl.
Med., Vol. 19, pp. 483-487 (1978). Direct labeling of red blood cells with ^99m Tc by a reductive process and use of the labeled cells for imaging has also been reported. Smith et al., J.
Nucl.Med., Vol. 17, pp. 126-132 (1976). ^99m
Various complexes of Tc and arsenic- and phosphorus-containing organic compounds have also been proposed for use as contrast agents and labeling agents. Deutsch etc.
Science, Vol. 214, pp. 85-86 (1981); J.
Nucl.Med., Vol. 22, pp. 897-907 (1981);
European Patent Application No. 81400618.5 (October 1981)
Public notice number 0038756 on the 28th).

^99m Tc is commonly supplied to clinical laboratories in the form of pertechnetate, and since this radionuclide has a desirable half-life and gamma energy,
Preferably, the complex of the invention contains ^99m Tc. However, as mentioned above, complexes with other radionuclides are also encompassed within the broad scope of the invention.
Furthermore, since pertechnetate is generally easily available, it is convenient to use it as a kit for preparing various ^99m Tc complexes.

Therefore, the present invention provides Tc, Ru, Co, Pt, Fe, Os,
Ir, W, Re, Cr, Mo, Mn, Ni, Rh, Pd, Nb
and a radioisotope of Ta and a radioactive metal (radionuclide) selected from the group consisting of the substituents are selected from the group consisting of halogen, hydroxy, nitro, alkyl and alkoxy. .
Preferably, the isonitrile complexes of the invention consist of one of the above-mentioned radiometals in which each coordination site is filled with an isonitrile ligand. The isonitrile ligand may be monodentate or polydentate, for example bidentate or tridentate. The invention further includes a kit for converting a radionuclide, such as ^99m Tc pertechnetate, to the above-described complex. The kit then contains a reducing agent capable of reducing the isonitrile ligand and the radiometal to form a coordination complex.

For purposes of the present invention, useful radionuclides are radioactive metals that have decay properties that lend themselves to use as tracers.

The complex of one embodiment of the present invention is represented by the following formula.

[A((CN)xR)yBzB′z′]n In the formula, A is Tc, Ru, Co, Pt, Fe, Os, Ir,
Radioactive isotopes of W, Re, Cr, Mo, Mn, Ni, Rh, Pd, Nb, and Ta, such as ^99m Tc, ⁹⁹ Tc,
is a radionuclide selected from ⁹⁷ Ru, ⁵¹ Cr, ⁵⁷ Co, ¹⁸⁸ Re and ¹⁹¹ Os; (CN)xR is a monodentate or polydentate isonitrile ligand bonded to the radionuclide through the carbon atom of the CN group; and R are as defined above; B and B' are independently selected from other ligands known to those skilled in the art that result in isonitrile complexes, solvents such as water, chlorine and bromine. a group, and a ligand consisting of one or more neutral donor atoms capable of binding to said radionuclide;
and y are each independently an integer from 1 to 8; z
and z′ are each independently 0 or an integer from 1 to 7; provided that (xy)+z+z′ is 8 or less; and
n indicates the charge of the complex, and in relation to the valence state of A and the charges of R, B and B', it can be 0 (neutral),
or a positive or negative integer. Desired counterions may be present, depending on the complex charging requirements, provided that the complex is pharmaceutically acceptable for use in vivo.

In the above formula, R is an organic group which may have a further neutral donor atom capable of forming a coordinate bond with the radionuclide, as defined above. If such additional donor atom(s) are used, the number of such donor atom(s) is such that (xy)+z+z′ is 8
must be added to x such that z and z' are determined within the above constraints as follows.

A neutral donor atom is defined as an atom with a free pair of electrons that can accept a proton to become a charged ligand or complex with a radionuclide to form a coordination complex. Examples of neutral donor atoms suitable for use in the present invention include, for example, arsenic, phosphorous, nitrogen, sulfur, oxygen, selenium, tellurium, and the like.

The complexes of the present invention can be neutral, positively charged or negatively charged, but lipophilic cationic complexes are preferred.

Any desired counterion may be present in the composition. For example, in the case of cationic complexes, chlorine ion, fluoride ion, bromide ion, iodide ion, hydroxide ion, sulfate ion, bisulfate ion, dihydrogen phosphate ion, fluoroborate ion, hexafluorophosphate ion, etc. It is. Depending on the individual radionuclide, valence state, and other complexation conditions, a particular radiometal may have a
It may have up to 8 isonitrile ligands. As mentioned above, each isonitrile ligand binds to the radionuclide through the carbon atom of the isonitrile. The complexes of the present invention are preferably mechanically inert and therefore preferably stable products.
However, the complex need only be sufficiently stable for the intended purpose.

The organic group R can be either aliphatic or aromatic, and may be substituted with various charged or uncharged groups. When the organic group R has a charged substituent, the charge on the resulting complex is
It is the sum of the charge of B′) and the charge of the radionuclide.
Possible aromatic R groups include phenyl, tolyl,
There are xylyl, naphthyl, diphenyl and substituted aromatic groups containing halogens such as chlorine, bromine, iodine or fluorine as substituents; hydroxy, nitro, alkyl, alkoxy, etc.; possible aliphatic R groups include alkyl groups; , preferably containing 1 to 20 carbon atoms, such as methyl, ethyl, n-propyl, isopropyl, n-butyl,
Examples include isobutyl, n-hexyl, 2-ethylhexyl, dodecyl, and stearyl. Substituents may be present in aliphatic groups, including the same substituents and others listed above for aromatic groups.

The isonitrile ligand is a polydentate ligand, e.g.
In the case of bidentate ligands with the CNRNC structure, the organic moiety of the ligand may be the same as defined as R above. In such cases the number of isonitrile ligands required for each complex is suitably reduced.

Generally, the desired lipophilic properties within the complex can be achieved without the need for substituents, so for simplicity it is preferred to use an unsubstituted hydrocarbon group as the R group. However, the lipophilic properties of the complexes may make them suitable for labeling specific substances, transporting membranes such as the blood-brain barrier, or imaging dynamic processes associated with specific organs and their mechanisms. Further changes can be made by changing .

Another embodiment of the complex of the present invention is [A
(CNR) ₆ ] It is a homoleptic six-coordinated (hexakis) cation complex with the formula ⁺ . In the formula, A is technetium or ¹⁸⁸ Re
A monovalent radionuclide selected from CNR
is a monodentate isonitrile ligand and R is an organic group as defined above. Suitable counterions also exist, such as those described above.

The complexes of the present invention can be easily prepared by mixing the radioactive metal salt and the isonitrile ligand in an aqueous medium at room temperature to reflux temperature or higher, if necessary in the presence of a suitable reducing agent. and macro (carrier addition, e.g. ⁹⁹ Tc) concentration and
Tracer (carrier-free, eg ^99m Tc) concentrations below 10 ^-6 molar can be obtained and isolated in high yields. In some cases, the isonitrile ligand itself acts as a reducing agent, in which case no additional reducing agent is required. Suitable reducing agents, where addition is necessary or desirable, are well known to those skilled in the art. The reaction is generally complete in 5 minutes to 2 hours, depending on the nature of the particular reagents used. Radiolabeled complexes are prepared in a manner similar to the corresponding non-radioactive isonitrile complexes by simply replacing the corresponding non-radioactive element in the starting material with the desired radionuclide. However, technetium is an exception because all technetium isotopes are radioactive.

In the case of technetium, for example ⁹⁹ Tc or ^99m Tc, the complex according to the invention is prepared by mixing pertechnetate (Tc ⁺⁷ ) with the desired isonitrile in an aqueous medium;
Preferably, it is produced by subsequently adding to the reaction mixture a suitable reducing agent for reducing technetium. Suitable reducing agents include alkali metal dithionites, stannous salts, sodium borohydride, and others well known.

In the isonitrile technetium complex of the present invention, the oxidation state of technetium is, for example, +3, +4 or +
It can also be prepared from the preformed technetium complex of 5 by treating it with an excess of isonitrile ligand under appropriate conditions. For example, a technetium-isonitrile complex can contain the desired isonitrile ligand,
It can also be prepared by reacting with a hexas-thiourea complex or a technetium-glucoheptonate complex of Tc ^{+3 or} analogs.

To maximize the yield of technetium in the complexation reaction, an excess of isonitrile ligand of up to 50 mol % to 100 mol % or more can be used. After the reaction, the desired complex can be separated from the reaction mixture if necessary by crystallization or precipitation or by conventional chromatography or ion exchange chromatography.

The following specific examples are intended to more fully illustrate the nature of the invention and are not intended to limit the scope of the invention.

Example 1 Preparation of hexakis-(t-butylisonitrile)technetium()hexafluorophosphate from [Tc()(tu) ₆ ] ³⁺ (tu=thiourea) In a 500 ml round bottom flask with a stir bar, [ ^99Tc (thiourea) ₆ ]Cl ₃ 0.84g (0.13mol), methanol (25ml)
and 0.1 g (1.3 mmol) of t-butylisonitrile were added. 1.5 while stirring the reaction mixture.
After refluxing for an hour, the resulting pale yellow solution was transferred to a 100 ml beaker and water (40 ml) was added. The volume was reduced by half by stirring and heating on a hot plate, followed by the addition of 30 ml of water to reduce the volume by half as before.

Cool the almost colorless solution to room temperature and add water (10ml)
Upon addition of 0.5 g [NH ₄ ][PF ₆ ], a white solid precipitated and was collected by suction. This was washed with water (10ml) and ether (10ml) and dried in vacuo.

Yield of [t-C ₄ H ₉ NC) ₆ ⁹⁹ Tc] [PF ₆ ] 0.06g
(0.08 mmol) Equivalent to 62% on Tc basis. Melting point = 222°C. The complex is soluble in polar solvents and recrystallized by slow evaporation from an acetone/water solution (4:1 vol/vol) to give white crystals.

C ₃₀ H ₅₄ F ₆ N ₆ Analytical value as PTc C H N Calculated value (%) 48.50 7.34 11.32 Actual value 48.60 7.25 11.32 Optical spectrum (in CH ₃ CN) 260 nm (shoulder) 235 nm = 8 × 10 ⁴ cm ^-1 Mol ^-1 infrared (KBr) ν (CN) = 2080 cm ^-1 (strong) Electrical conductivity (CH ₃ CN; 10 ^-3 M) Λ = 140 ohm ^-1 cm ² mole ^-1 field desorption mass spectrometry (positive ion mode) m/Z = 597 (cation, C ⁺ ) Example 2-6 Added carrier [(RNC) ₆ Tc] Standard preparation method for ⁺ cation R is -CH ₃ (-methyl), -n -C ₃ H ₇ (-n-propyl), -i-C ₃ H ₇ (-isopropyl) -C
(CH ₃ ) ₃ (-tertiary butyl), -cyclohexyl.

In a 50 ml round bottom flask, add ethanol (10 ml), water (10 ml, pH adjusted to 12 with NaOH), RNC 2.5 ml,
0.438M Ammonium Pertechnetate ( _NH4 )
0.7 ml of [ ⁹⁹ TcO ₄ ] and a stirrer were added. For analytical convenience, ^99m Tc isotope was often used as a tracer. A second solution containing 0.21 g of sodium dithionite (Na ₂ S ₂ O ₄ ) in water (5 ml, PH 12) was prepared and added dropwise to the first reaction mixture. The solution was brought to reflux using a heating mantle and held there for 15 minutes. A further 50 mg Na ₂ S ₂ O ₄ solution was added dropwise and the solution was refluxed for a further 30 minutes.

The reaction mixture was transferred to a 100 ml beaker and boiled on a hot plate to evaporate the solvent and reduce the volume by half. Water (40ml) was added and the solution was cooled to room temperature. [NH ₄ ] in water (10ml)
Upon addition of 0.5 g of [PF ₆ ], a white solid precipitated immediately. Collect this by vacuum filtration and add water (10ml)
and ether (10ml) and subsequently dried in vacuo.

Recrystallization from acetone/water gave white crystalline [Tc(CNR) ₆ ][PF ₆ ] with a yield of about 90% with respect to technetium.

Examples 7-8 [Tc(CNC( _CH3 ) ₃ ) ₆ ]+hexakis-(t-butylisonitrile)technetium() cation tracer (without carrier addition) synthesis 1 Sodium dithionite reduction method Standard scintillation In the counting bottle, ⁹⁹ Mo/
^{Isosmotic brine} ₍ ²
ml), 2 drops of 1N NaOH solution, ethanol (2 ml)
and a small stirrer to mix. Next, 65μ of t-butylisonitrile was added. A second solution was prepared by dissolving 20 mg of sodium dithionite (Na ₂ S ₂ O ₄ ) in water (pH adjusted to 12 with NaOH), and this solution was added to the first solution.

The mixture was stirred for 15 minutes and then transferred to a 50 ml siliconized round bottom flask equipped with a vacuum adapter. The solvent was removed in vacuo using heat from an infrared lamp. Pour the residue into ethanol (100μ
) and then with isotonic saline (1 ml). This solution contained the isonitrile complex in a form suitable for administration to animals. The reaction product was analyzed by HPLC (high pressure liquid chromatograph) before use.

2 Sodium glucoheptonate reduction method A commercially available tin glucoheptonate radiopharmaceutical kit (Glucosan ^TM ) was prepared by New England New Clearer Co., Ltd.
England Nuclear Corporation) was reconstituted using isotonic saline (5 ml). The resulting solution was drawn out using a syringe and added to 2 mg SnCl ₂ .2H ₂ O in a scintillation bottle. Stir the mixture for 5 minutes, take out 1 ml, add t-butylisonitrile (20μ), ethanol (120μ).
and a siliconized Vacutainer ^™ tube containing a small stir bar.
The mixture was stirred for several minutes and passed through a 0.22 μm Millipore filter into a second siliconized tube. To the resulting clear solution was added isotonic saline (0.5 ml) containing the appropriate level of ^99m TcO ₄ ^- obtained by elution of a commercially available radionuclide generator. The solution was stirred for 5 minutes.

Product Extraction This step is used with any of the above syntheses to provide a pure sample of the isonitrile complex free of other materials during the synthesis.

The solution was transferred to another funnel (50 ml) and extracted twice with methylene chloride (3 ml). The organic layer was washed twice with isotonic brine (5 ml) and then transferred to a siliconized round bottom flask (50 ml) equipped with a vacuum adapter. The solution was removed in vacuo while heating with an infrared lamp. This flask was first washed with ethanol (100μ
) and followed by washing with brine (1 ml). The solution is ready for administration to animals after HPLC analysis, and the complex is in the form of a solution in a physiologically acceptable, non-toxic carrier.

Both methods can be used to prepare other complexes of the invention. Preparation targets include ^99m Tc methyl, n-
Included are propyl, isopropyl, n-butyl, tertiary butyl, and cyclohexylisonitrile complexes.

The kit according to the invention contains an amount of reducing agent for reducing the preselected radionuclide. Such kit preferably contains a predetermined amount of isonitrile ligand and a predetermined amount of reducing agent capable of reducing a predetermined amount of a preselected radionuclide. do. It is also preferred that the isonitrile ligand and reducing agent are lyophilized to increase storage stability. The isonitrile ligand and reducing agent are placed in a sealed, sterilized container.

In one embodiment of the present invention, the kit used to produce the complexes of the present invention from a source of ^99m Tc, such as pertechnetate in isotonic saline, which is available in most clinical laboratories, contains a specified amount of It contains the desired amount of a specific isonitrile ligand to react with pertechnetate and a reducing agent such as sodium dithionite sufficient to reduce the specified amount of pertechnetate to form the desired complex.

Injection of the t-isobutylisonitrile products of Examples 7 and 8 into an animal model, followed by conventional imaging techniques, has shown that it is possible to detect vascular emboli in the lungs and other vascular areas, as described below. found. A gamma-ray camera scanned the entire lung fields of apparently normal, healthy dogs and confirmed that they were indicative of blood clots. A small amount of ^99m Tc− is autologous solidified in a glass vessel.
They were labeled with a sulfur colloid and introduced it into the dog's lungs to scan and measure their location. When a large amount (several mCi) of ^99m Tc-hexakis-(tertiary butylisonitrile) technetium () was injected, several coagulates were observed. Computer analysis of the collected data concluded that localization was occurring. Furthermore, analysis of the initial perfusion phase of the lungs showed that there were areas of insufficient blood flow associated with several emboli. Other experiments gave similar results.

In other experiments, the isonitrile complex of the present invention was used to label liposomes, to label mammalian cells such as Chinese hamster V-79 lung fibroblasts, leukocytes isolated from rabbit blood, and human red blood cells. It was used for visualization of bone marrow, measurement of lung function, and imaging of myocardium. For example, both tertiary-butyl and isonitrile products have been used to visualize myocardial tissue with external contrast.

Such cells and liposomes can be easily labeled by warming the radiolabeled complex of the present invention with such cells or liposomes in a suitable medium, and can be easily labeled by heating the radiolabeled complex of the present invention with such cells or liposomes, as described in J.
Radioactivity uptake is measured according to the method described in NuCl.Med., Vol. 21, pp. 88-90 (1980).
Loading of the radioactive complex is possible up to a height of 29 pCi/cell. Research shows that radioactive labels last up to 16 hours
It was found that 90% retention could be achieved. Leukocytes isolated from fresh rabbit blood were labeled with a ^99m Tc complex and subsequently reinjected into the rabbit. The distribution of radiolabeled cells was tracked with a gamma camera. Liposomes were also labeled using a similar method, and their distribution within the mouse was tracked using a gamma camera.

Thus, the complexes of the present invention are useful not only for visualizing cardiac tissue, but also for detecting the presence of thrombin in the lungs and associated areas of underperfusion, for studies of pulmonary function, for renal excretion. It is easy to understand that it is useful for research and imaging of the bone marrow and hepatobiliary bladder system. The complexes are further useful for the radiolabeling of cells and blood forming elements, other animal cells, plant cells, and small organisms with a membranous exterior, such as unicellular organisms, microorganisms, and the like. Furthermore, they can be used to label previously prepared liposomes without the need for encapsulation as is the case with many other labeling agents. Finally, the complexes of the invention can be used therapeutically.

The choice of radionuclide is related to its use. For example, suitable radionuclides for diagnostic imaging include Tc,
Radioisotopes of Ru, Co, Pt, Fe, Os, and Ir, and radionuclides suitable for therapeutic use include W, Re,
Radioisotopes of Fe and Os, and radionuclides suitable for radiolabeling include Cr, Mo, Co, Tc,
Fe, Mn, W, Ru, Ni, Rh, Ir, Pd, Nb and
It is Ta.

The present invention has been described in detail, including its preferred embodiments. However, those skilled in the art will appreciate, upon consideration of this disclosure, that various modifications and improvements can be made within the spirit and scope of the invention.