FR2646157A1 - Ligands and complexes used especially in medical scanning - Google Patents

Abstract

The subject of the present invention is compounds corresponding to the following general formula: in which R1 and R3 represent, independently of one another, H, an alkyl, alkenyl, cycloalkyl, aryl or arylalkyl group or a heterocycle, which groups are optionally substituted, especially by one or more hydroxyl or alkoxy groups or halogens, R2, R<n>4 and R<n>5 represent, independently of one another, H or an alkyl, alkenyl, aryl, alkoxy, carboxyalkyl (or a salt or an alkyl, hydroxyalkyl or alkoxyalkyl ester), amide or carboxylic acid (or a salt or an alkyl ester) group, n represents an integer from 1 to 5, X represents a 5- or 6-membered heterocycle containing at least one nitrogen atom, one of the compounds represented by the formula II or one of their dehydro derivatives: in which: m is 0 or 1 and A is O, N-R6 or CH-R6 where R6 represents H or optionally substituted alkyl or aryl. The present invention also relates to coordination complexes between these ligands and a metal, as well as to kits containing said ligands, and to reactants which make it possible to lead to the formation of a coordination complex between the ligand and the metals. More particularly, the present invention relates to complexes between these ligands and technetium <99m>Tc which are useful as diagnostic agents for scanning the brain or heart and blood scanning.

Description

The present invention relates to new ligands capable of complexing metals. When these metals are radioactive, these complexes are useful in particular in medical imaging or in targeted radiotherapy depending on the nature of the radioisotope.

The present invention also relates to kits containing said ligands, said metals and reagents making it possible to lead to the formation of a coordination complex between the ligands and the metals.

More particularly, the present invention relates to complexes between these ligands and technetium 99mTc useful as diagnostic agents, in particular for imaging of the brain, heart and blood imaging.

The prerequisites for a brain imaging agent are, first of all, its ability to cross the blood-brain barrier, bind and accumulate in high concentrations in a relatively short time in the brain, and remain there for the required length of time. to perform the analysis. This requires that the complex undergoes chemical or biochemical modifications in vivo. For example, a pH shift mechanism has been suggested which takes into account the difference in pH between the blood and the intracellular medium. Thus, if an amine has a pKa value close to the pH of the brain, once inside the brain, the neutral amine complex will be protonated. The complex thus charged is trapped in the brain insofar as it is not able to leave it by a reverse mechanism taking into account the pKa of the amine. This complex can also undergo a chemical modification. This is the case with HM-PAO where the lipophilic complex turns over time into a more hydrophilic complex which does not enter the brain. The exact nature of this second complex and the mechanism that comes into play have not yet been elucidated. It is still possible that enzymatic hydrolysis of an active group occurs as observed with the "N, N'-1,2-ethylenediylbis-L-cysteine diethyl ester" (99mTc ECD) where the ester is hydrolyzed into the L, L stereoisomer and not its D, D isomer, from which it results that the retention time in the brain is different between the two isomers with a half-life time for the first greater than 144û minutes and less than 30 minutes for the last one.

Whatever mechanism is involved, an ideal complex for brain imaging purposes should have good stability in vitro, rapid uptake in the brain, and low stability in vivo i.e. faculty of modification or transformation in vivo.

Contrary to the established opinion with regard to the agents for imaging the heart, it appears that they do not necessarily have to consist of a cationic complex, but that, more likely, it is their lipophilic property which is determining.

The lipophilicity of the complexes gives them the ability to label blood cells such as macrophages and thus allow the detection of inflammation and infections.

The radioactive isotope of choice for medical imaging is 99mTc. Currently, in applications for imaging the brain, heart and inflammatory sites, "cold kits" labeled with 99mTc are not yet commercially available (MIBI: imaging of the heart) or have certain drawbacks (HMPAO: imaging of the brain and inflammatory sites). 99mTc is generally available as pertechnetate (TcO 4). Cold kits include a lyophilized composition of non-radioactive components which, after reconstitution with a 99mTcO4 pertechnetate solution, yields the desired complex. Ideally, the stability of the complex after reconstitution should be good enough so that the kit can be used. used for several hours. A frequent problem encountered with current complexes is that the 99mec complex does not guarantee sufficient stability over time.

In addition, the ligands proposed so far generally have complicated chemical structures leading to expensive preparation methods.
With the aim of providing optionally versatile diagnostic agents allowing imaging in particular of the brain, heart and blood cells such as macrophages, a search was made according to the present invention for new lipophilic and neutral ligands having the best specifications required for this purpose. effect and which overcome the aforementioned drawbacks.

A subject of the present invention is therefore compounds corresponding to the following general formula

<tb><SEP> t <SEP> R7
<tb><SEP> r <SEP> R3 <SEP> (I)
<tb> o <SEP>
<tb><SEP> R1
<tb> in which
R l and R3 represent, independently of one another, H, a group
aikyle, aikenyl, cycloalkyl, aryl, arylaikyl, a heterocycle,
groups optionally substituted, in particular by one or more
hydroxy, alkoxy or halogen groups.

R2, R4n and R5n represent, independently of one another, H, a group
aikyl, alkenyl, aryl, alkoxy, carboxyalkyl (or a salt or
an alkyl ester), hydroxyalkyl, alkoxyalkyl, am'de or
carboxylic acid (or a salt or an alkyl ester).

n represents an integer from I to 5.

X represents a 5 or 6 membered heterocycle containing at least one
nitrogen atom.

In the present application, the term “alkyl and alkoxy” is understood to mean straight or branched chains preferably of 1 to 10 carbon atoms.

The term alkenyl also refers to straight or branched chains, preferably of 2 to 10 carbon atoms.

The term aryl refers to the phenyl or substituted phenyl group.

The terms cycloalky or cycloalkenyl refer to rings having 5, 6 or 7 carbon atoms.

The term “5- or 6-membered heterocycle containing at least one atom” means nitrogen, one of the compounds represented by formula II or one of their dehydro derivatives.

<tb> CH2- (CH2) m
<tb><SEP> A <SEP> (Ir)
<tb><SEP> CH2-CH2 <SEP> /
<tb><SEP> CH2-C <SEP> 2
<tb> where m is 0 or I and
A is O, N-R6 or CH-R6 where R6 represents H, alkyl, aryl, optionally
substituted.

Such heterocycles are for example aromatic groups such as a pyrrolyl, imidazolyl, oxazolyl, pyrazolyl, pyridinyl, pyrimidinyl group.

They can be attached to the ligand of formula I by an unsaturated carbon adjacent to N or A.

In particular, the compounds correspond to formula III:

<SEP>IR;<SEP> / R3
<tb><SEP> (III)
<tb> C <SEP> R1
<tb><SEP> M
<tb>
As particularly advantageous ligands according to the present invention, mention may be made of the compounds of formula III where R1, R3 = CH3;
R2 = R4 = R4 = R5 = R5 = H, and n = 2 or R1 = CF3; R3 = CH3. R2 = R4 =
R4 = R5 = R5 = H and n = 2.

In general, the nature of the substituents of the compounds of formula I will be chosen according to the lipophilicity or the desired polarity for the ligand.

pour obtenir le composé relatif à l'invention.These compounds can be prepared by reacting a heterocycle X substituted with a formyl group of formula X-COH which is reacted with an alkylene diamine of formula NH2- (CRn4Rn5) n-NH2 in acetonitrile in the presence of NaBH4 . The product obtained is reacted with a dione of formula IV

to obtain the compound relating to the invention.

The compounds described in the invention have utility as ligands which can form complexes with metals. These complexes, when injected in vivo, may exhibit an affinity for brain or myocardial cells. They can also be used for labeling white blood cells, the labeled white blood cells being injectable in vivo for the detection of inflammatory sites. Depending on the isotope used for labeling, the compounds may be used as imaging agents or as control agents in targeted radiotherapy.

The compounds described in the invention can be used either directly or coupled to a transporter protein such as a monoclonal antibody. Their role is then reduced to coupling a metal to the protein.

A subject of the present invention is therefore also the coordination complexes of a compound described in the invention with a radioactive or paramagnetic metal ion.
111 113m 67
Mention may in particular be made of the isotopes In, In, Ga, 68Ga. 157 Gd. 201 Tl. 117m Sn. 64 Cu. 186 Re. 188Re 90Y. 212Ri. 99Tc.

99mTc, 97Ru, 51Cr, 57Co, 191Os.

The compounds according to the invention can be labeled with a radioactive isotope of halogen substituted on the molecule constituting said compound, in particular 123I, 125I, 131I,
The choice of the radioactive isotope depends on the use for which the ligand is intended.

For use as an imaging agent, ligands labeled with 99mTc, or alternatively 111In, 13mIn, 67Ga, 68Ga, 157Gd, 123I, 131I, 201TI, 117mSn, will be used, for example.

For targeted radiotherapy purposes, the ligands will for example be labeled with 1251, 131I 64Cu, 186Re 90y 212Bi
A subject of the present invention is therefore also kits comprising the ligands according to the invention and reagents making it possible to lead to the formation of coordination complexes between said ligands and the metals mentioned above.

The ligand can be in aqueous-alcoholic solution or in lyophilized form.

Said reagents are generally reducing agents, and stabilizing agents, some examples of which are provided in the detailed description which follows.

According to a preferred mode of use of the ocmposés according to the invention, these are used to complex 99mTc for the purposes of medical imaging of the brain, of the heart or of infections.

The kits then comprise the ligand and as reducing agent preferably a tin salt such as stannous chloride. Technetium is presumably found as Tc - 0 oxide in complex forms.

Other characteristics and advantages of the present invention will become apparent in the light of the exemplary embodiments of the invention which will follow.

Figure I shows a clearance graph of the 99mTc N [-2 (1H pyrolylmethyl) N '[- 4- (pentene-3-one-2 trifluoro)] ethylene 1,2 diamine (MRP2O) complex.

EXAMPLE 1: SYNTHESIS OF LIGAND Nt-2 (-1H-pyrrolylmethyll N '[- 4
(pentene-3one-2) j ethylene 1,2 diamine
Compound of formula I in which R1 = R3 = CH3 and R2 =
R4 = R4 = R5 = R5 = H and n = 2
1) Synthesis of N [-2 (-lH pyrrolylmethyl)] ethylene I, 2 diamine
Under an argon atmosphere, a solution of 0.1 mol (9.5 g) of pyrrol-2-carboxaldehyde in 50 ml of dry acetonitrile is added to a solution of 0.6 mol (40 ml) of ethylene 1.2 diamine in 80 ml of dry acetonitrile containing 2 g of molecular sieve. The mixture is left under stirring at ambient temperature overnight. The solvent is evaporated off in vacuo and the residue is redissolved in 100 ml of methanol. The solution obtained is placed in an ice bath and, with vigorous stirring, 0.1 mol of sodium borohydride is added thereto in small portions. The reaction mixture is then left under stirring for two hours.

A maximum of methanol is evaporated off under vacuum and the oil obtained is resolubilized in 100 ml of water. With vigorous stirring, this solution is placed in an ice bath and added with 20 g of potassium hydroxyl. After extracting the mixture with 5 times 5G ml of dichloromethane, the organic phases are combined, dried over anhydrous potassium carbonate, filtered and then evaporated to obtain an oily residue, which is then placed in a water bath at 60 ° C. and drawn under vacuum. Finally, 14 g of a yellow viscous oil are obtained (crude yield close to 100%). A control by TLC on silica with as eluent a mixture of 5% ammonia in methanol indicates the presence of a more polar main impurity, which is eliminated by selective precipitation of its hydrochloride in ethanol. Finally, 10 g (70% yield) of a yellow oil of satisfactory purity are obtained for the following stages.

2) Synthesis of N [-2 (-1H-pyrrolylmethyl)] N '[- 4- (pentene-3-one-2)]
ethylene 1,2 diamine
To a solution of 10 mmol (1.4 g) of 1) in 10 ml of acetonitrile is added 12 mmol (1.2 ml) of 2,4-pentanedione. The mixture is left under nitrogen for three hours at room temperature, then the solvent is evaporated off in vacuo. The residual oil is then re-extracted into a mixture of water and dichloromethane. The dried, filtered and then evaporated organic phases give a yellow oil which is purified on a silica column with as eluent a mixture of 0.5% of diethylamine in ethyl acetate. The final product obtained is a pale yellow oil which resolidifies after refrigeration. Recrystallization from diisopropyl ether gives 1.5 g of beautiful needle-shaped crystals (yield 66.0).

Analytical data
NMR: shifts in ppm 11.2 (s, br) NHc; 9.6 (s, br) NHa; 6.75 (qu) 6.08
(qu) 5.98 (tr) pyroll; 5.0 (s) CH; 3.8 (s) CH2; 3.29 (qu), 2.83 (tr)
CH2-CH2: 1.9 (s), 2.05 (s) Me, Me; 1.6 (s, br) NHb.

Infrared: NH, 3174 cm-1, C = O, 1598 cm-1. other bands are
detected at 3090, 2972, 2852, 1544, 1466, 1432, 1376, 1357,
1340, 1308, 1280, 1251, 1130, 1097, 1028, 998.

Mass spectrometry: ion corresponding to M / e 221.2: -Me 206.1
-C = O 178.1: peaks at 127, 113, 98, 95, 84, 80
representing various stages of fragmentation.

EXAMPLE 2: SYNTHESIS OF LIGAND N [-2 (-1H-pyrrolylmethyl)] N '[- 4
(-5-trifluoropentene-3-one-2) 1 ethylene 1,2 diamine
Compound of formula I in which R1 = CF3, R3 = CH3,
R2 = R4 = R4 = R5 = R5 = H in n = 2
To a solution of 10 mmol (1.4 g) of the product obtained in Example 1, 1) in 15 ml of dichloromethane, 1 g of molecular sieve is added and the whole is placed in an ice bath. Then added and with stirring, 12 mmol (1.4 ml) of 1,1,1 trifluoro-2,4-pentanedione. the mixture is left under argon overnight. After washing with water, the dichloromethane phase is dried and then evaporated to give a yellow oil. The product is purified by chromatography on silica with a mixture of 0.5% of diethylamine in ethyl acetate as eluting. A pale yellow oil is obtained which resolidifies in the cold. The
product is then recrystallized from a mixture of 5% ether.
diisopropyl in hexane. We obtain 0.9 g of white crystals in the form
fine needles (30% yield).

Analytical data
MN:: displacements in ppm 10.9 (s, br) NHc; 9.4 (s, br) NHa; 6.75 (qu).

6.08 (qu), 5.98 (tr) pyroll; 5.35 (s) CH; 3.85 (s) CH2; 3.38 (qu), 2.9
(tr) CH2-CH2; 2.08 (5) Me; 1.6 (s, br) NHb.

Infrared: NH 3365/3350 cm-1, C = O 1554 cm-1. Other bands were
observed at 2863, 1605, 1372, 1252. 1125. 1021 cm-I.

Mass spectroscopy: the molecular ion m / e 275 is accompanied by a
fragment at 255 (loss of HF). The diagram of
fragmentation clearly shows the presence
of the pyrrole nucleus and of the ethylene backbone
diamine, while the collision spectra
indicate further losses of R.

EXAMPLE 3 TECHNETIUM COMPLEX
The ligands described above react in an ethanolic-saline solution with pertechnetate (obtained from a commercial generator) and in the presence of a reducing agent (with or without a base or stabilizing agent such as paraaminobenzoic acid) to give complexes technetium ligand. The reducing agents can be chosen from the following: tin (II), sodium dithionite, formamidine sulphinic acid, hydrazine or any other usual reducing agent with an appropriate redox potential.

1) Dissolution of the complex of N [-2 (-1H-pyrrolylmethyl)] N '[- 4- (pentene-
3-one-2)] ethylene 1,2 diamine and 99mTc
In a 10 ml flask, successively introduce 4 mg of ligand, 1 ml of ethanol, 1 ml of an aqueous saline solution (NaCl 0.9 o), a maximum of 0.5 ml of an aqueous saline solution of 99mTcO4- and 20 g of
Freshly dissolved SnCi2 in degassed water. Leave to react for 30 min at room temperature. Analysis of the reaction products by TLC on silica gel (ITLC-SG) shows the presence of a lipophilic product which migrates with MEK (methyl ethyl ketone) and does not migrate with an aqueous saline solution. The lipophilic compound can be chromatographed by HPLC and is retained on a reverse phase chromatographic medium.

2) Synthesis of the complex 1) in the presence of a non-coordinating base
In a 10 ml solution, successively introduce 4 mg of ligand 5 mg of l, 2'-bipyridyl, 1 ml of ethanol, 1 ml of an aqueous saline solution, a maximum of 0.5 ml of a solution of 99m-TcO4 and 20 g of
Freshly dissolved SnCl7 in degassed water. The reaction is carried out as in Example 3.1).

3) Synthesis of complex I) in the presence of hydroxyl ions
In a 10 ml flask, successively introduce 4 mg of ligand, 1 ml of ethanol, I ml of an aqueous saline solution. Adjust the pH to 9.5 with NaOH. add a maximum of 0.5 ml of 99mTcO4- and 20 µg of SnCl2- The reaction is carried out as in example 3.1).

4) Synthesis of complex 1) in the presence of paraaminibenzoic acid
In a 10 ml flask, successively introduce 4 mg of ligand, 80 μg of paraaminobenzoic acid, 1 ml of ethanol, 1 ml of an aqueous saline solution, a maximum of 0.5 ml of a saline solution of 99mTcO40 and 20 g of SnCl2. The reaction is carried out as in the example
5) Synthesis of complex I) with tin tartrate
In a 10 ml flask, successively introduce 4 mg of ligand, 1 ml of ethanol, 1 ml of an aqueous saline solution, a maximum of 0.5 ml of an aqueous saline solution of 99mTcO4- and 50 g of tartrate tin (II) in solution. The reaction is carried out as for example 3.1).

6) Synthesis of the complex of N [-2 (-1H-pyrrolylmethyl) N '[- 4 (-5-
trifluoropentene-3-one-2)] ethylene 1,2 diamine and 99mTc
Using 4 mg of ligand, carry out the reaction as in Example 3.1). The retention time of the lipophilic compound obtained by
HPLC is different from that of complex 1).

7) Synthesis of complex I) at different temperatures
In a 10 ml flacton, successively introduce 4 mg of ligand, 1 ml of ethanol, 1 ml of an aqueous saline solution, a maximum of 0.5 ml of an aqueous saline solution of 99mTcO4- and 20 g of SnCl2.

Put in a water bath at 20 C, 40 C and 100 C for 30 min. Perform the analyzes as in Example 3.1).

8) Synthesis of the complex 1) by varying the quantities of reagents
a) Carry out the reaction described in Example 3.1) by
using 1.4 mg of ligand instead of 4 mg of ligand.

b) Carry out the reaction described in Example 3.1) by
using 5, 10, 20 and 50 µg of SnCl2.

EXAMPLE 4: BIODISTRIBUTION
A biodistribution study was performed on female Wistar rats using the 99mTc - N [-2 (-1H-pyrrolylmethyl)] complex.
N '[- 4- (pentene-3-one-2)] ethylene 1,2 diamine. The animals were injected into the femoral vein and were killed at different times after the injection: 5 min, 15 min, 30 min, 60 min and 180 min. Three animals were sacrificed during these different periods. Organs of interest were removed, cleaned, blood stripped, and scintigraphic evaluation performed using a gamma counter from a standard sample prepared from the injected solution. The percentages of injected doses per organ and per gram of tissue were calculated and are presented in Tables I and 2, a clearance graph is presented in Figure 1.

Although the initial uptake in the brain appears to be slow. the complex is retained for three hours and reaches a maximum of 2.35% of the dose injected per organ. This percentage is very satisfactory given what is commonly accepted for a brain tracer. namely 2 to 3 o of fixation in the brain of the rat, which corresponds in general for primates to a rate of fixation greater than -5
TABLE 1: Percentage of the injected dose per organ

<tb><SEP> MR26 / RAT / DOSE / ORGAN
<tb> OGANE
<tb><SEP> 5 <SEP> min <SEP> 15 <SEP> min <SEP> 36 <SEP> min <SEP> 60 <SEP> min <SEP> 180 <SEP> mm
<tb> blood <SEP> 14.70 <SEP> 11.58 <SEP> 13.22 <SEP> 12.44 <SEP> 9.27
<tb> brain <SEP> 1.05 <SEP> 0.77 <SEP> 2.35 <SEP> 2.08 <SEP> 1.68
<tb> core <SEP> 1.11 <SEP> 0.86 <SEP> 1.43 <SEP> 1.31 <SEP><SEP> 0.88 <SEP>
<tb> liver <SEP> 5.9 <SEP> 4.08 <SEP> 13.2 <SEP> 8.98 <SEP> 4.27
<tb> kidneys <SEP> 2.41 <SEP> 3.66 <SEP> 5.84 <SEP> 6.45 <SEP> 7.95
<tb> lung <SEP> 1.97 <SEP> 1.23 <SEP> 2.21 <SEP> 2.05 <SEP> 1.31
<tb> stomach <SEP> 5.88 <SEP> 1.14 <SEP> 2.85 <SEP> 2.51 <SEP> 1.73
<tb> intestine <SEP> 2.69 <SEP> 5.67 <SEP>, <SEP><SEP> 9.32 <SEP> 9.89 <SEP> 15.27 <SEP>
<tb>
TABLE 2: Percentage of the dose injected per gram of tissue

<tb><SEP> MRP20 / DOSE / GRAM
<tb><SEP> ORGAN
<tb><SEP> 5 <SEP> min <SEP> 30 <SEP> min <SEP> 60 <SEP> min <SEP> 180 <SEP> min
<tb> blood <SEP> 1.49 <SEP> 1.14 <SEP> 1.10 <SEP> 0.77
<tb> brain <SEP> 0.97 <SEP> 1.74 <SEP> 1.31 <SEP> 1.34
<tb> core <SEP> 2.18 <SEP> 2.98 <SEP> 2.07 <SEP> 1.64
<tb> liver <SEP> 0.65 <SEP> 2.48 <SEP> 1.34 <SEP> 5.78 <SEP>
<tb> kidneys <SEP> 1.69 <SEP> 4.74 <SEP> 4.65 <SEP> 5.92
<tb> lung <SEP> 2.4 <SEP> 2.5 <SEP> 1.79 <SEP> 1.62
<tb> stomach <SEP> 0.36 <SEP> 0.92 <SEP> 0.79 <SEP> 0.79
<tb> intestine <SEP> 0.12 <SEP> 0.92 <SEP> 0.68 <SEP> 1.32
<tb>

Claims (11)

CLAIMS 1) Compounds corresponding to the following general formula <SEP> 7 <tb> c <SEP> I <tb> x <tb> <SEP> R1 <tb> in which R1 and R3 represent independently of one another H, an alkyl, alkenyl, cycloalkyl, aryl, arylalkyl, heterocycle, groups optionally substituted, in particular with one or more hydroxy, alkoxy or halogen groups. R2, R4n and R5n represent independently of one another H, an alkyl, aikenyl, aryl, alkoxy, carboxyalkyl (or a salt or an alkyl ester), hydroxyalkyl, alkoxyalkyl, amide or carboxylic acid (or a salt or an alkyl ester). n represents an integer from 1 to 5. X represents a 5 or 6 membered heterocycle containing at least one nitrogen atom, one of the compounds represented by formula II or one of their dehydro derivatives <tb> <SEP> vCH2- (CH2) m <tb> HN <SEP> A <SEP> II <tb> M <SEP> M <tb> <SEP> \ <SEP> CH2-CH2 <SEP> / <tb> where m is 0 or I and A is O, N-R6 or CH-R6 where R6 represents H, alkyl, aryl, optionally substituted. 2) Compounds according to claim 1, characterized in that they correspond to the general formula III:

<tb> <SEP> C <SEP> / R3 <tb> <SEP> I <tb> <SEP> wNH <SEP> HllQ <tb> <SEP> NH <SEP> It! <tb> / <SEP> \ <SEP> e <R <tb> <SEP> M <tb> where R1, R2, R3, R4n and R5n have the meanings given above. 3) Compounds according to claim 2, characterized in that R1, R3 = CH3; R2 = R4 = R4 = R5 = R5 = H and n = 2 or R1 = CF3; R3 = CH3 and R2 = R4 = R4 = R5 = R5 = H and n = 2. 4) All the acid-base forms of the compounds according to claims I, 2 and 3. 5) Coordination complex of a compound according to one of the preceding claims with a metal. 6) Coordination complex according to the preceding claim characterized in that the metal is IIIIn, 113mIn, 67Ga, 68ga, 157Gd, 201Tl, 117m5n, 64Cu, 186Re, 188Re, 90Y, 212Bi, 99Tc, 99mTc. 97Ru, 51Cr, 57 @@ 191 @@ Co, Os. 7) Coordination complex according to the preceding claim, characterized in that the metal is 99mTc. 8) Kit consisting of a ligand consisting of a compound according to one of claims 1, 2, 3 and 4 and reagents allowing the formation of metal complexes according to claims 5, 6 and 7 when said kit is reconstituted in the presence of compounds of said metals. 9) Kit according to the preceding claim, characterized in that the metal compound is 99mTc pertechnetate, the reagents leading to the formation of coordination complex comprise a reducing agent, such as a tin salt. 15) Kit according to one of the preceding claims, characterized in that the compound according to claims 1 to 4 is in hydroalcoholic solution or in lyophilized form. 11) Kit according to claims 8 to 10, characterized in that the reagents also comprise a stabilizing agent such as paraaminobenzoic acid or a base. 12) Kit according to one of the preceding claims, useful for medical imaging of the brain or of the heart, or the marking of lymphocytes for imaging of inflammatory sites. 13) Kit intended for imaging the brain or for labeling white blood cells according to one of the preceding claims, characterized in that the metal compound used for reconstituting the kit is pertechnetate 99mTcO4- and that the ligand is the compound represented in formula III with R1 = R3 = CH3; n = 2; R2 = R4 = R4 = R5 = R5 = H.