FR2639542A1 - Radiopharmaceutical product having cardiac tropism, containing a nitrido complex of a transition metal, and method for preparing it - Google Patents

Abstract

The invention relates to a radiopharmaceutical product having cardiac tropism, containing a nitrido complex of a transition metal, and to a method for preparing it. This complex corresponds to the formula: (M/N)L<1>L<2)<I> in which M is a transition metal, for example <99m>Tc, <186>Re or <188>Re, and L<1> and L<2>, which may be identical or different, correspond to the formula: in which R<1> and R<2> can be alkyl radicals.t

Description

RADIOPHARMACEUTICAL PRODUCT WITH TROPISM OF THE HEART
INCLUDING A NITRIDO COMPLEX OF A TRANSI METAL
TION. AND ITS PREPARATION PROCESS.

The present invention relates to a
radiopharmaceutical with cardiac tropism
comprising a transition metal nitrido complex
comprising a part M - N, in which M represents
smells like a transition metal.

It is specified that the term “transition metal” is understood to mean a metal in which the layer d is partial
the ment fulfills in the usual degree of oxidation of this metal. These are the elements filling
periods III to XII of the periodic table of elements å a. eighteen columns.

As an example of such metals, we
can cite Tc, Ru, Co, Pt, Fe, Os, Ir, W, Re, Cr,
Mo, Mn, Ni, Rh, Pd, Nb and Ta.

Technetium nitrido complexes have
been described by J. Baldas and Col. in documents
following: international patent application W0-85 / 03
063, J. Chem. Soc. Dalton Trans., 1981, pages
1798-1801, and the book "Technetium in Chemistry
and Nuclear Medicine ", Ed. M. Nicolini, G. Bandoli,
U. Mazzi, Cortine Vint. Verone, 1986, pages 103-108.

In these documents, we describe the preparation
tion of technetium nitrido complexes by reaction
substitution on 99mTcNCl4 and it is indicated
that these complexes can be used as
radiopharmaceuticals, except these documents
do not give any convincing results on the fixation
of these complexes in the body, and do not provide
not that they can present a cardiac tropism.

Among the radiopharma ceuticals having a cardiac tropism, there are known technetium complexes containing as ligand isonitriles substituted with an ether, as described in European patent application EP-A-0233368, and technetium complexes based on dioxime as described in European patent EP-A-0268801.

These complexes are formed from ligands that are difficult to synthesize.

Also, research has been developed to find other cardiac-tropic radiopharmaceuticals exhibiting satisfactory properties for use as diagnostic or therapeutic products, in particular for scintigraphy of the myocardium.

The present invention specifically relates to a radiopharmaceutical product with a cardiac tropism, which comprises a complex of a transition metal corresponding to the formula
(M, N) L1L2 (I) in which M is a transition metal and L1 and L2, which may be the same or different, have the formula

where R1 and R2, which may be the same
or different, represent a linear alkyl radical
re or branched from 1 to 10 carbon atoms, no
substituted or substituted by groups -0-R3, -ooC-R3, -oCNR4R5 or -NR4R5 in which R3 is a linear or branched alkyl radical of 1 to 5 carbon atoms and R4 and R5, which may be identical or different, are hydrogen atoms or linear or branched alkyl radicals of 1 to 5 carbon atoms, or in which R1 and R2 together form a hydrocarbon ring optionally containing one or more heteroatoms.

According to a preferred embodiment of the invention R1 and R2 represent alkyl radicals. Preferably, R1 and R2 are identical,
L1 and L2 are preferably also the same.

By way of example, L1 and L2 can correspond to the following formulas:

In these complexes, the transition metal used depends in particular on the application of the radiopharmaceutical.

Thus, when we want to use the product for the diagnosis, we use a transition metal
radioactive, having a relatively short half-life, for example technetium 99m.

In the case where it is desired to use the radiopharmaceutical for therapy, a transition metal emitting radiation effective for therapy, and having a long lifespan, such as rhenium, for example, is used.
Re-186 or Re-188.

The technetium nitrido complexes used in the ins'ntion can be prepared by the method of Baldas. However, it is generally preferred to prepare them by a simpler process, easy to carry out in a hospital department and leading to high yields.

dans laquelle R1 et R2 ont la signification donnée ci-dessus, R6 est un ion de métal alcalin, H+ ou
NH4+, et n est égal à O ou est un nombre entier allant de 1 à 3.This process comprises the following successive steps: 10) reacting an oxygen-containing compound of a transition metal M with
a) a first ligand selected from the group of aliphatic and aromatic phosphines and polyphosphines, and
b) a second reagent chosen from alkali metal and ammonium azides, and
Nitrogenous ligands comprising a unit # in which the N are linked to hydrogen atoms and / or to monovalent organic groups via a carbon atom, or in which one of the N is linked to the carbon atom of a divalent organic group through a double bond and the other N is bonded to hydrogen atoms and / or monovalent organic groups through a carbon atom, and 20) reacting the intermediate product obtained in the first step with dithiocarbamic acid or a salt of this acid corresponding to the formula

in which R1 and R2 have the meaning given above, R6 is an alkali metal ion, H + or
NH4 +, and n is 0 or is an integer ranging from 1 to 3.

When this process is carried out using technetium as the transition metal, the oxygen-containing compound of the transition metal may be alkali metal or ammonium pertechnetate.

In the case where the transition metal is rhenium, an alkali metal or ammonium perrhenate can be used.

In the first step of the process, a first technetium nitrido complex is thus prepared, which is then reacted with dithiocarbamic acid or a salt of this acid to exchange the first and second ligands with this dithiocarbamic acid or its salt.

To carry out the reaction, the first ligand and either the alkali metal or ammonium azide or the nitrogenous ligand can be aseptically introduced into a vessel, followed by the addition of the required amount of transition metal oxygenate, for example. Technetium 99m pertechnetate, after adjusting the pH to an appropriate value by adding acid or base. The reaction can then be carried out at room temperature or at a higher temperature ranging from 50 to 1000C. The temperature and the pH used depend in particular on the second nitrogenous ligand. Generally, the operation is between pH 2 and 7.

In the first step, the first and second ligands can be used in the form of aqueous, alcoholic or hydroalcoholic solutions and simply add these solutions to the oxygenated compound of the transition metal.

In the second step, the product obtained in the first step is reacted with dithiocarbamic acid or a salt of this acid in aqueous solution, generally at a pH greater than 7, for example in a sodium carbonate-bicarbonate buffer.

In this second step, it is also possible to use an alcoholic or hydroalcoholic solution of dithiocarbamic acid or of the salt of this acid.

The first ligand which makes it possible to obtain the formation of a nitrido complex is an organic ligand with an electron donor phosphorus atom chosen from phosphines and aliphatic and aromatic polyphosphines.

dans laquelle R7, R8 et R9 qui peuvent être identiques ou différents, représentent un atome d'hydrogène, un radical alkyle, un radical aryle, un radical alcoxy ou un radical alkyle ou aryle substitué par un groupement choisi parmi les radicaux amino, amido ou nitrile.The phosphines which can be used can correspond to the formula:

in which R7, R8 and R9, which may be identical or different, represent a hydrogen atom, an alkyl radical, an aryl radical, an alkoxy radical or an alkyl or aryl radical substituted with a group chosen from amino, amido or nitrile.

By way of example of phosphines of this type, mention may be made of triphenylphosphine, diethylphenylphosphine, triethylphosphine, and trimethylphosphine and tris (cyanoethyl-2) phosphine.
P (CH2-CH2CN) 3.

In the first step, it is possible to use as the second reagent either an alkali metal or ammonium azide, for example sodium azide, or a nitrogenous ligand comprising the unit
# as in Hydrazine and its derivatives. Many such nitrogen ligands can be used. Generally, it is preferred to use as the nitrogenous ligand, dithiocarbazic acid or a derivative thereof.

dans laquelle R10 représente un atome d'hydrogène, un radical alkyle ou un radical aryle, et R14 représente un atome d'hydrogène, un radical alkyle, un radical aryle, un radical alcoxy, un radical alkyle substitué par au moins un groupement choisi parmi les radicaux hydroxy, carboxy, amino, amido et mercapto, ou un radical aryle substitue par au moins un groupement choisi parmi les atomes d'halogène et les radicaux alcoxy, hydroxy, amino, mercapto et amino substitué par au moins un radical alkyle.Thus, the second nitrogenous ligand can be dithiocarbazic acid or a derivative thereof corresponding to the formula

in which R10 represents a hydrogen atom, an alkyl radical or an aryl radical, and R14 represents a hydrogen atom, an alkyl radical, an aryl radical, an alkoxy radical, an alkyl radical substituted by at least one group chosen from among hydroxy, carboxy, amino, amido and mercapto radicals, or an aryl radical substituted with at least one group chosen from halogen atoms and alkoxy, hydroxy, amino, mercapto and amino radicals substituted with at least one alkyl radical.

dans laquelle R10 représente un atome d'hydrogène, un radical alkyle ou un radical aryle ;R14 représente un atome d'hydrogène, un radical alkyle, un radical aryle, un radical alcoxy, un radical alkyte substitué par au moins un groupement choisi parmi les radicaux hydroxy, carboxy, amino, amido et mercapto, ou un radical aryle substitué par au moins un groupement choisi parmi Les atomes d'halogène et les radicaux alcoxy, hydroxy, amino, mercapto et amino substitué par au moins un radical alkyle ; et R15 et R16 qui peuvent être identiques ou différents représentent un atome d'hydrogène, un radical alkyle ou un radical alkyle substitué par au moins un groupement choisi parmi les radicaux hydroxy, carboxy, amino, amido et mercapto.It can also be a condensation product obtained by reacting dithiocarbazic acid with a ketone or an aliphatic aldehyde of formula R15-Co-R16. In this case, it responds to the formula

in which R10 represents a hydrogen atom, an alkyl radical or an aryl radical; R14 represents a hydrogen atom, an alkyl radical, an aryl radical, an alkoxy radical, an alkyl radical substituted by at least one group chosen from among hydroxy, carboxy, amino, amido and mercapto radicals, or an aryl radical substituted with at least one group chosen from halogen atoms and alkoxy, hydroxy, amino, mercapto and amino radicals substituted with at least one alkyl radical; and R15 and R16 which may be identical or different represent a hydrogen atom, an alkyl radical or an alkyl radical substituted by at least one group chosen from hydroxy, carboxy, amino, amido and mercapto radicals.

dans laquelle R10 représente un atome d'hydrogène, un radical alkyle ou un radical aryle ;R14 représente un atome d'hydrogène, un radical alkyle, un radical aryle, un radical alcoxy, un radical alkyle substitué par au moins un groupement choisi parmi les radicaux hydroxy, carboxy, amino, amido et mercapto ou un radical aryle substitué par au moins un groupement choisi parmi les atomes d'halogène et les radicaux alcoxy, hydroxy, amino, mercapto et amino substitué par au moins un radical alkyle ;;
R17 représente un atome d'hydrogène, un radical alkyle, un radical alkyle substitué par au moins un groupement choisi parmi les radicaux hydroxy, carboxy, amino, amido et mercapto, R18 représente un atome d'hydrogène, un atome d'halogène, un radical alcoxy, un radical amino, ou un radical amino substitué par au moins un groupement alkyle, R19 représente
Un atome d'hydrogène, un radical hydroxy ou un radical mercapto, E représente un atome de carbone ou un atome d'azote, et n est un nombre entier allant de 1 à 4, ou dans laquelle n est égal à 2 et les deux R18 sont voisins et forment ensemble un cycle aromatique.The dithiocarbazic acid derivative used as the second ligand can also be the condensation product of dithiocarbazic acid with a ketone or an aromatic aldehyde. In this case, the derivative responds to the formula:

in which R10 represents a hydrogen atom, an alkyl radical or an aryl radical; R14 represents a hydrogen atom, an alkyl radical, an aryl radical, an alkoxy radical, an alkyl radical substituted by at least one group chosen from among hydroxy, carboxy, amino, amido and mercapto radicals or an aryl radical substituted with at least one group chosen from halogen atoms and alkoxy, hydroxy, amino, mercapto and amino radicals substituted with at least one alkyl radical;
R17 represents a hydrogen atom, an alkyl radical, an alkyl radical substituted by at least one group chosen from hydroxy, carboxy, amino, amido and mercapto radicals, R18 represents a hydrogen atom, a halogen atom, a alkoxy radical, an amino radical, or an amino radical substituted by at least one alkyl group, R19 represents
A hydrogen atom, a hydroxy radical or a mercapto radical, E represents a carbon atom or a nitrogen atom, and n is an integer ranging from 1 to 4, or in which n is equal to 2 and both R18 are neighbors and together form an aromatic ring.

dans laquelle R10 représente un atome d'hydrogène, un radical alkyle ou un radical aryle ;R14 représen- te un atome d'hydrogène, un radical alkyle, un radical aryle, un radical alcoxy, un radical alkyle substitué par 4 moins un groupement choisi parmi les radicaux hydroxy, carboxy, amino, amido et mercapto, ou un radical aryle substitué par au moins un groupement choisi parmi les atomes d'halogène et les radicaux alcoxy, hydroxy, amino, mercapto et amino substitué par au moins un radical alkyle ;
R17 représente un atome d'hydrogène, un radical alkyle, un radical alkyle substitué par au moins un groupement choisi parmi les radicaux hydroxy, carboxy, amino, amido et mercapto, R18 représente un atome d'hydrogène, un atome d'halogène, un radical alcoxy, un radical amino, ou un radical amino substitué par au moins un groupement atkyle, G est S ou 0, et p est 1, 2 ou 3.The product obtained by condensation of dithiocarbazic acid with a ketone comprising a 5-link heterocycle can also be used as a second ligand. In this case, the second ligand corresponds to the formula:

in which R10 represents a hydrogen atom, an alkyl radical or an aryl radical; R14 represents a hydrogen atom, an alkyl radical, an aryl radical, an alkoxy radical, an alkyl radical substituted with 4 minus one selected group from hydroxy, carboxy, amino, amido and mercapto radicals, or an aryl radical substituted with at least one group chosen from halogen atoms and alkoxy, hydroxy, amino, mercapto and amino radicals substituted with at least one alkyl radical;
R17 represents a hydrogen atom, an alkyl radical, an alkyl radical substituted by at least one group chosen from hydroxy, carboxy, amino, amido and mercapto radicals, R18 represents a hydrogen atom, a halogen atom, a alkoxy radical, an amino radical, or an amino radical substituted by at least one alkyl group, G is S or 0, and p is 1, 2 or 3.

By way of example of second nitrogenous ligands which may be used, mention may be made of S-methyl-beta-N (2-hydroxyphenyl) methylene dithiocarbazate, S-methyidithiocarbazate, S-methyl -N-methyl-dithiocarbazate , alpha-N-methyl-S-methyt- -beta-N-pyridylmethylene di thi ocarbazate,
and alpha-N-methyl-S-methyl-beta-N (2-hydroxyphenyl) methylene dithiocarbazate.

When the radiopharmaceutical of the invention is intended for diagnosis, it is generally necessary to prepare it at the time of use.

dans laquelle R1, R2 et R6 ont la signification donnée ci-dessus.Also, a subject of the invention is also a kit for the preparation of a radiopharmaceutical product with a cardiac tropism, which comprises: a first vial containing a phosphine; - a second vial containing either sodium azide or dithiocarbazic acid or a derivative thereof, and - a third vial containing dithiocarbamic acid or a salt of this acid corresponding to the formula

in which R1, R2 and R6 have the meaning given above.

With this kit, the desired radiophcmaceutical can be prepared directly in a nuclear medicine hospital unit by mixing the contents of the first two vials with a solution of the oxygenated transition metal compound, for example an alkali metal pertechnetate solution or ammonium, then add to the product thus obtained the contents of the third vial.

The products present respectively in the first, second and third vials can be in liquid form or in lyophilized form.

In some cases, the contents of the first two vials can also be mixed before use. In this case, the kit will only include a first vial containing a phosphine and the second reagent consisting of either sodium azide or dithiocarbazic acid or a derivative thereof, and a second vial containing dithiocarbamic acid. or a salt of this acid corresponding to the formula VI given above.

Since the products are intended for intravenous injection into living beings, appropriate manufacturing and processing conditions must be used to obtain suitably sterile and pyrogen-free solutions.

To prepare the solutions, sterile and pyrogen-free water or alcoholic or hydroalcoholic, sterile and pyrogen-free solutions can be used, and the solutions can be stored under nitrogen.

In order to prepare lyophilized compositions, solutions obtained under the same conditions as above are subjected to lyophilization in conventional equipment.

The radiopharmaceuticals of the invention can be used in particular for scintigraphy of the myocardium.

In this case, after preparation of the technetium nitrido complex, the latter is injected into the patient to be examined, and the heart is then examined by scintigraphy.

For the injection of the product, the amounts of the various ligands are such that they correspond substantially to the stoichiometry of the complexes to be obtained. The final amount injected depends in particular on the ligands used and their toxicity.

Generally, satisfactory results are obtained using total amounts of ligands ranging from 0.05 to 0.40 mg / kg of body weight.

The total dose of transition metal, for example technetium, is generally in the range of 185 to 740Mbq (5 to 20millicuries).

After administration of the transition metal nitrido complex, a satisfactory examination can be performed within 0.5 to 3 hours with good contrast, sharp images and good lesion detection.

Other characteristics and advantages of the invention will emerge more clearly on reading the following examples, given of course by way of illustration and not limiting.

Example I: Preparation of the nitruro-bis (diethyldithiocarbamate) complex 99mTc (V) (TcNDEDC).

a) Preparation of the intermediate product.

In a penicillin-type bottle, 0.4 ml of a solution containing 2.10-2 mol / L (2.5 mg / ml) of S-methyldithiocarb cate in ethyl alcohol is introduced, then 0.2 ml of a solution at 2.10 ~ 2mol / l (Smg / ml) of triphenylphosphine in ethyl alcohol and 0.1ml of 1N hydrochloric acid. 0.5 to 1 ml of a sodium pertechnetate solution (Tc99m) is then added and the reaction is carried out at 800C for 30 minutes or at 1000C for 15 minutes.

b) Preparation of the final complex.

To the contents of the flask obtained in step a), 0.1ml of 1N NaOH solution and 0.5ml of a solution containing 0.18mol / l of trihydrated sodium diethyldithiocarbamate (40mg / ml) in a buffer are added. 0.5 mol / l-1 sodium carbonate-bicarbonate
at pH 9.0.

The reaction is carried out for 15 minutes at 100 C, for 30 minutes at 800 C, or for 60 minutes at room temperature.

The radio-chemical purity of the complex obtained is tested by carrying out thin-layer chromatography using silica gel and toluene as a solvent.

The complex obtained has an Rf of 0.3 to 0.4.

The radio chemical purity is greater than or equal to 93X.

Example 2 Preparation of the nitruro-bis (Cdi-ethyidithiocarbamate) 99mTc (V) (TcNDEDC) complex.

a) Preparation of the intermediate product.

In a penicillin-type flask, 0.2ml of a solution containing 7.7.10-2mol / l (5.0mg / ml) of sodium azide in water is introduced, then 0.2ml of a solution containing 2.10-2 mol / l (5mg / ml) of triphenylphosphine in ethyl alcohol and 0.1ml of 1N hydrochloric acid. 0.5 to 1 ml of a sodium pertechnetate solution (Tc-99m) is then added and the reaction is carried out at 800C for 30 minutes or at 100 C for 15 minutes.

b) Preparation of the final product.

To the contents of the flask obtained in step a), as in Example 1, 0.1 ml of a 1N NaOH solution and 0.5 ml of a solution containing 0.18 mol / l (40 mg / ml) are added. of sodium diethyldithiocarbamate trihydrate in a carbonate / sodium bicarbonate buffer at 0.5 mol / l and at pH 9. The reaction is carried out as in Example 1.

The radiochemical purity of the product is also tested by thin layer chromatography and the results are identical to those of Example 1.

Example 3: Preparation of the nitruro-bis (diethyldithiocarbamate) 99mTc (V> (TcNDEDC) complex.

a) preparation of the intermediate product.

In a penicillin-type bottle, 0.2ml of a solution containing 7.7.10-2mol / l (5mg / ml) of sodium azide in water is introduced, then 0.4ml of a solution containing 1.10-2mol / l (2mg / ml) of tris (cyanoethyl-2) phosphine in water and 0.1ml of IN hydrochloric acid.

0.5 to 5 ml of a solution of sodium pertechnetate (99mTc) is then added and the reaction is carried out at 800C for 30 minutes or at 1000C for 15 minutes. (Preparation without alcohol)
b) Preparation of the final complex
The same procedure is followed as in Example 1, paragraph b) to prepare the complex
TcNDEDC from the intermediate product obtained above.

Example 4 Preparation of the nitruro-bis (diethyldithiocarbamate) complex 99mTc (V) (TcNDEDC).

a) Preparation of the intermediate product.

In a pe-ciLLine-type flask, 0.2 ml of a solution containing 7.7.10-2mol / l (5 mg / ml) of sodium azide in water is introduced, then 0.4 ml of a solution containing 1.10 -2mol / l of tris (cyanoethyl-2) phosphine.

0.5 to 5 ml of a sodium pertechnetate solution (99mTc) is then added and the reaction is carried out at 80 ° C. for 30 minutes or at 10 ° C. for 15 minutes.

This operation takes place at a ph close to 7.

b) Preparation of the final product.

To the contents of the flask obtained in step a), 0.5ml of a solution containing 0.18mol / l (40mg / ml) of trihydrated sodium diethyldithiocarbamate in a 0.5mol sodium carbonate / bicarbonate buffer is added. / l and at pH9. The reaction is carried out as in Example 1.

Example 5 Preparation of the nitruro-bis (dimethyldithiocarbamate) complex 99mTc (V) (TcNDMDC).

The same procedure is followed as in Example .1, replacing in the last step the diethyldithiocarbamate with 0.5ml of a solution containing 0.18mol / l of sodium dimethyldithiocarbamate (30mg / ml) in the same buffer. .

The technetium complex TcNDMDC is thus obtained with a radiochemical purity equivalent to that of Example 1.

Example 6 Preparation of the nitruro-bis (di-n-propyldithiocarbamate) complex 99mTc (V) (TcNDPDC).

The same procedure is followed as in Example 1, replacing the diethyldithiocarbamate with 0.5 ml of a solution containing 0.18 mol / l (40.7 mg / ml) of sodium di-n-propyldithiocarbamate sesquihydrate in a mixture of sodium carbonate-bicarbonate buffer at 0.5 mol / l and at pH 9 and ethyl alcohol in a 7: 3 volume ratio.

This gives the technetium complex
TcNDPDC exhibiting a radiochemical purity equivalent to that of Example 1.

Examples 7 to 9
In these examples, the properties of the complexes obtained in Examples 1, 5 and 6 are tested by determining their biodistribution in male rats of the Sprague Dawley breed, weighing 200 + 20 g.

In this case, the rats, anesthetized with sodium pentobarbital, are injected with a dose corresponding to 15ymol / kg body weight of myotropic ligand, which corresponds to a radiation dose of 1 to 2.5 which.

5 minutes, 30 minutes, or 60 minutes after the injection of the product, the rats are sacrificed, their organs are removed and the radioactivity present in each of the organs is determined.

The results obtained are given in the table below, and expressed as a percentage of the injected radioactivity found in the organ, after sampling and counting.

The values given in each cell of the table represent the mean value and the two extreme values.

In view of this table, it can be seen that these complexes have a good cardiac tropism.

<SEP> TcNDMDC <SEP> (CH3) 2N- # <SEP> TcNDMDC <SEP> (C2H5) 2N # <SEP> TNDPDC <SEP> (C3H7) 2-N- #
<tb><SEP> number <SEP> of animals <SEP>: <SEP> 3 <SEP> number <SEP> of animals <SEP>: <SEP> 5 <SEP> number <SEP> of animals <SEP>:<SEP> 5
<tb> Time <SEP> between
<tb> injection <SEP> IV
<tb> and <SEP> sacrifice <SEP> 5 <SEP> min <SEP> 30 <SEP> min <SEP> 60 <SEP> min <SEP> 5 <SEP> min <SEP> 30 <SEP> min <SEP > 60 <SEP> min <SEP> 5 <SEP> min <SEP> 30 <SEP> min <SEP> 60 <SEP> min
<tb> organs
<tb> integers
<tb><SEP> 17.5 <SEP> 18.2 <SEP> 27.5 <SEP> 20.2 <SEP> 24.1 <SEP> 25 <SEP> 27.2 <SEP> 33.2 <MS> 28.5
<tb> Fair
<tb><SEP> 16.6 <SEP> - <SEP> 18.1 <SEP> 16.7 <SEP> - <SEP> 20.0 <SEP> 27.6 <SEP> 28.5 <SEP> 14.9 <SEP> - <SEP> 22.1 <SEP> 23.2 <SEP> - <SEP> 26.1 <SEP> 24.3 <SEP> - <SEP> 26.1 <SEP> 23, 1 <SEP> - <SEP> 32.3 <SEP> 29.8 <SEP> - <SEP> 35.2 <SEP> 22.3 <SEP> - <SEP> 33.4
<tb><SEP> 5.2 <SEP> 1.9 <SEP> 1.8 <SEP> 4.9 <SEP> 3.5 <SEP> 3.0 <SEP> 2.9 <SEP> 2, 6 <SEP> 2.1
<tb> Kidneys
<tb><SEP> 5.1 <SEP> - <SEP> 5.3 <SEP> 1.8 <SEP> - <SEP> 2.1 <SEP> 1.7 <SEP> - <SEP> 2, 2 <SEP> 4.6 <SEP> - <SEP> 5.2 <SEP> 3.2 <SEP> - <SEP> 4.1 <SEP> 2.8 <SEP> - <SEP> 3.2 <SEP> 2.4 <SEP> - <SEP> 3.6 <SEP> 2.0 <SEP> - <SEP> 3.3 <SEP> 1.6 <SEP> - <SEP> 2.6
<tb><SEP> 4.4 <SEP> 6.0 <SEP> 6.5 <SEP> 9.2 <SEP> 1.8 <SEP> 1.2 <SEP> 2.6 <SEP> 1, 1 <SEP> 0.6
<tb> Lungs
<tb><SEP> 3.9 <SEP> - <SEP> 4.6 <SEP> 4.5 <SEP> - <SEP> 7.5 <SEP> 4.5 <SEP> - <SEP> 11, 5 <SEP> 8.5 <SEP> - <SEP> 9.5 <SEP> 1.6 <SEP> - <SEP> 1.9 <SEP> 1.3 <SEP> - <SEP> 1.4 <SEP> 2.1 <SEP> - <SEP> 3.4 <SEP> 1.0 <SEP> - <SEP> 1.3 <SEP> 0.4 <SEP> - <SEP> 0.9
<tb><SEP> 0.52 <SEP> 0.18 <SEP> 0.15 <SEP> 0.7 <SEP> 0.2 <SEP> 0.1 <SEP> 0.2 <SEP> 0, 2 <SEP> 0.2
<tb> Brain
<tb><SEP> 0.48 <SEP> - <SEP> 0.58 <SEP> 0.17 <SEP> - <SEP> 0.19 <SEP> 0.14 <SEP> - <SEP> 0, 16 <SEP> 0.7 <SEP> - <SEP> 0.7 <SEP> 0.2 <SEP> - <SEP> 0.2 <SEP> 0.1 <SEP> - <SEP> 0.1 <SEP> 0.1 <SEP> - <SEP> 0.2 <SEP> 0.2 <SEP> - <SEP> 0.2 <SEP> 0.1 <SEP> - <SEP> 0.2
<tb><SEP> 2.3 <SEP> 0.70 <SEP> 0.60 <SEP> 2.6 <SEP> 1.6 <SEP> 1.4 <SEP> 1.8 <SEP> 1, 5 <SEP> 1.3
<tb> Heart
<tb><SEP> 2.1 <SEP> - <SEP> 2.5 <SEP> 0.6 <SEP> - <SEP> 0.9 <SEP> 0.5 <SEP> - <SEP> 0, 7 <SEP> 2.4 <SEP> - <SEP> 2.7 <SEP> 1.6 <SEP> - <SEP> 1.7 <SEP> 1.3 <SEP> - <SEP> 1.5 <SEP> 1.4 <SEP> - <SEP> 1.9 <SEP> 1.4 <SEP> - <SEP> 1.7 <SEP> 1.2 <SEP> - <SEP> 1.4
<tb><SEP> 3.0 <SEP> 2.3 <SEP> 3.0 <SEP> 9.2 <SEP> 2.3 <SEP> 1.8 <SEP> 3.5 <SEP> 2, 0 <SEP> 1.5
<tb> Total <SEP> blood
<tb><SEP> 2.9 <SEP> - <SEP> 3.2 <SEP> 2.0 <SEP> - <SEP> 2.5 <SEP> 2.9 <SEP> - <SEP> 3, 2 <SEP> 7.5 <SEP> - <SEP> 10.1 <SEP> 1.8 <SEP> - <SEP> 3.0 <SEP> 1.6 <SEP> - <SEP> 2.2 <SEP> 2.6 <SEP> - <SEP> 4.6 <SEP> 1.8 <SEP> - <SEP> 2.5 <SEP> 1.0 <SEP> - <SEP> 1.9
<tb>

Claims (20)

1. Radiopharmaceutical product with cardiac tropism, characterized in that it comprises a complex of a transition metal corresponding to the formula: tM.s N) L1L2 CI) in which M is a transition metal and LI and L2 which may be identical to the different, correspond to the formula

in which R1 and R2, which may be identical or different, represent a linear or branched alkyl radical of 1 to 10 carbon atoms, unsubstituted or substituted by groups -Q-R3, ooC-R3, OCNR4R5 or -NR4R5 in which R3 is a linear or branched alkyl radical of 1 to 5 carbon atoms and R4 and R5 which may be the same or different, are hydrogen atoms or linear or branched alkyl radicals of 1 to 5 atoms carbon, or in which R1 and R2 together form a hydrocarbon ring optionally containing one or more heteroatoms. 2. Radiopharmaceutical product according to claim 1, characterized in that R1 and R2 represent alkyl radicals. 3. A radiopharmaceutical product according to any one of claims 1 and 2, characterized in that M represents an isotope of technetium or rhenium. 4. Radiopharmaceutical product according to claim 3, characterized in that the technetium isotope is Tc 99 m. 5. A radiopharmaceutical product according to claim 3, characterized in that the rhenium isotope is Re-186 or Re-188. 6. Radiopharmaceutical product according to any one of claims 1 to 5, characterized in that L1 and L2 are identical. 7. Radiopharmaceutical product according to claim 6, characterized in that L1 and L2 represent:

8. A radiopharmaceutical product according to claim 6, characterized in that L1 and L2 represent

9. A radiopharmaceutical product according to claim 6, characterized in that L1 and L2 represent:

formula : bamic or a salt of this acid corresponding to the in the first step with dithiocar acid carbon atom, and 20) reacting the intermediate product obtained organic mono go slowly through a to hydrogen atoms and / cu to g rou pements of a double bond and the other N is connected of a divalent organic group via which one of the N is connected to the carbon atom through a carbon atom, or in to mono-slow organic groups through the N are linked to hydrogen atoms and / or nitrogen containing a unit, N-N in which of alkali metal and ammonium and ligands b / a second reagent chosen from nitrogen -and aromatics, and aliphatic phosphines and polyphosphines a) a first ligand chosen i in the g rou pe of transition M with: 10.Process for preparing a radiopharmaceutical according to any one of claims 1 to 9, characterized in that it comprises the following successive steps: 10) reacting an oxygenated compound of a metal of to O or is an integer ranging from 1 to 3. of alkali metal, H + or Nu4 +, and n is equal given in claim 1, R6 is an ion where R1 and R2 have the meaning 11. The method of claim 10, characterized in that the transition metal is technetium. 12. The method of claim 11, characterized in that the oxygen compound of the transition metal is an alkali metal or ammonium pertechnetate. 13. The method of claim 11, characterized in that the transition metal is rhenium. 14. The method of claim 13, characterized in that the oxygenated compound of the transition metal is alkali metal or ammonium perrhenate. 15. Method according to any one of claims 10 to 14, characterized in that the first ligand is a phosphine corresponding to the formula:

in which R7, R8 and R9, which may be identical or different, represent a hydrogen atom, an alkyl radical, an aryl radical, an alkoxy radical or an alkyl or aryl radical substituted with a group chosen from amino, amido and nitrile. 16. Method according to any one of claims 10 to 14, characterized in that the first ligand is a phosphine chosen from triphenylphosphine, diethylphenylphosphine, triethylphosphine, trimethylphosphine and tris (cyanoethyl-2) phosphine. 17. Method according to any one of claims 10 to 16, characterized in that the second reagent is dithiocarbazic acid or a derivative thereof. 18. The method of claim 17, characterized in that the second reagent is chosen from S-methyldithiocarbazate, S-methyl-N-methyldithiocarbazate, alpha-N-methyLS- methyt beta-N-pyridylmethylene dithiocarbazate, S-methyl-beta-N- (2-hydroxyphenyl) methylene dithiocarbazate and alpha-N-methyl-S-methyl -beta-N (2-hy- droxyphenyl) methylene dithiocarbazate. 19. Method according to any one of claims 10 to 16, characterized in that the second reagent is sodium azide. 20. Kit for the preparation of a radiopharmaceutical product with cardiac tropism, characterized in that it comprises: - a first vial containing a phosphine; - a second bottle containing sodium azide, dithiocarbazic acid or a derivative of this one, and, - a third vial containing dithiocar acid bamic or a salt of this acid corresponding to the formula :

wherein R1 and R2 have the meaning given in claim 1, R6 is H +, NH4 + or an alkali metal ion, and n is 0, 1, 2 or 3.