State of the art The 99mTc-imido core has been only generically cited among a series of new cores suitable for the development of technetium radiopharmaceuticals (Archer C. et al. WO 91/03262 and references therein). Despite a few examples obtained at"carrier added (ca) "or, in other words, macroscopic level, using 99Tc and cold Re, in which the presence of the imido group was clearly established, the transfer of this chemistry at"no carrier added (nca)" or, in other words, microscopic level, has met severe obstacles so far. The terms"macroscopic"or"carrier added"level refer to chemical reactions occurring at concentrations ranging from 10-3 to 10-5 M. Reactions are performed in conventional laboratories (if necessary approved for low level radioactivity) using from 1 to 200 mg amounts of non-radioactive Re or radioactive 99Tc. The terms"microscopic"or"no carrier added"level refer to reactions occurring at concentrations ranging from 10-6 to 10-9 M with micrograms to nanograms amounts of radioactive 99mTc or of radioactive 188Re (see also IUPAC Compendium of Chemical Terminology, 2nd Edition (1997), wherein the following definition is provided for"no carrier added" :"... a preparation of a radioactive isotope which is essentially free from stable

isotopes of the element in question..."). These reactions are routinely performed in hospital Nuclear Medicine Departments for clinical purposes (Deutsch, E. , Libson, K., Recent advances in technetium chemistry : bridging inorganic chemistry and nuclear medicine, Comments Inorg. Chem. , 3, 83- 103, 1984).

Working at macroscopic level with 99Tc, only five crystal structures of Tc (V) -imido species have been reported. They include [Tc (NR) C13 (PPh3) 2], where R is phenyl (Nicholson T. et al. Inorg. Chim. Acta, 187 (1991) 51) or tolyl (Dilworth J. et al. in Technetium in Chemistry and Nuclear Medicine-3, Raven Press, New York, (1990), 109). By varying the bulkiness of both the halide (from Cl to Br) and/or the phosphine (from PPh3 to PMePh2 and PMe2Ph), three additional phenyl-imido compounds have been produced, i. e.: [Tc (NPh) Cl3 (PMePh2) 2], [Tc (NPh) Br3 (PMePh2) 2] (Rochon F. D. et al. Inorg.

Chem. 34 (1995) 2273) and [Tc (NPh) Cl2 (PMe2Ph) 3] + (Nicholson T. et al.

Inorg. Chim. Acta, 230 (1995) 205).

Nevertheless, no specific disclosure, nor even suggestions, have ever been made on the possibility of successfully transferring the above preparations also at microscopic level.

All the above species are six-coordinated compounds with slight distortion from the ideal octahedron. The co-ordination sphere is totally filled with monodentate ligands (halides and monophosphines) that do not impose heavy steric constraints. In this connection the Tc atom moves off the mean basal plane towards the imido unit by only 0.11 A. The imido core is essentially linear (mean Tc=N-C angle 175. 7°) with a marked portion of the Tc-N bond showing double bond character (mean value 1.71 A ; see G.

Bandoli et al., Coord. Chem. Rev., 214 (2001) 43).

The possibility to introduce chelate ligands in the co-ordination sphere of Tc (V) -imido compounds was demonstrated separately by different authors.

Nicholson et al. (Inorg. Chim. Acta, 196 (1992) 27) introduced a simple bidentate diphosphine, i. e. 1,2-bis (diphenylphosphine) ethane (dppe) to yield [Tc (NPh) Cl3 (dppe) ]. Tisato et al. (J. Organom. Chem. 637-639 (2001) 772) utilised the 1,2-bis (diphenylphosphine) ferrocenyl residue (dppf) to produce the analogous [Tc (NPh) Cl3 (dppf) ] complex. Similarly, rhenium (Re) complexes where synthesized, by using the bidentate (2-diphenylphosphine) benzeneamine (H2dpa), or the tetradentate N, N'- bis [ (2-diphenylphosphine) phenyl] propane-1, 3-diamine (Refosco F. et al, J.

Chem. Soc. Dalton Trans 1998, 923-930).

Notwithstanding the above results, successive extensive efforts to stabilize the 99mTc-imido core have surprisingly failed, because no appropriate combinations of donor atoms was found to support this group, while, on the contrary, this target was successfully achieved in the case of the somewhat similar 99mTc-oxo and 99mTc-nitrido cores. Oxo [99mTc (O) ] 3+, imido <BR> <BR> <BR> [99mTc (NR) ] 3+ and nitrido [99mTc (N) ] 2+ moieties are isoelectronic cores, the metal being in the 5+ oxidation state, and, in this connection, the technetium- imido group can be considered as intermediate between oxo and nitrido cores.

Previous investigations have established that Tc (V) -oxo groups are readily stabilized by tetradentate ligands, as shown by N4-hexamethylpropylene amine oxime (HM-PAO), N3S-mercaptoacetyltriglycyl (MAG3) and N2S2-ethylcysteine dimer (ECD) in the clinically used Ceretece, Technescan and Neurolite radiopharmaceuticals. On the other hand, the Tc (V) -nitrido group prefers a combination of two different polydentate ligands. Previous studies on 99Tc- imido complexes have shown that distorted octahedral environments are usually achieved, the coordination being supported by monodentate ligands, preferably tertiary monophosphines and halides. Attempts to replace the monodentate P-based donors present in the prototype precursor [Tc (NPh) Cl3 (PPh3) 2] with various polydentate chelates were not successful,

thus indicating that the imido group should be stabilized only by the presence of monodentate monophosphine ligands.

Description of the invention It has now surprisingly been found that it is possible to replace the two monodentate triphenylphosphine substituents with a tridentate hetero- diphosphine ligand Li which comprises an electron donor heteroatom in the spacer chain linking said two phosphine groups, without affecting the stability of the imido group in the resulting [(Me=N-R) Y2 (Ll)] +Y~ compounds, wherein Y is a leaving group, such as a halogen atom, an hydroxy or an alkoxy group.

The facial configuration of the tridentate hetero-diphosphine chelate induces a cis-coordination of the two Y groups, which in turn can be easily substituted with suitable bidentate ligands L2 to give the final desired [(Me=N-R) LlL2] +Z~ metal heterocomplex.

Accordingly, the present invention primarily provides a radioactive transition metal-imido hetero-diphosphine complex compound of formula (I) : [(Me=N-R) L L] Z (I), wherein: Me is a radioactive transition metal selected from the group consisting of 99mTC l86Re, l88Re ; R is a Cl-Cl5 linear or branched alkyl or alkenyl residue, optionally interrupted by-O-,-S-,-N (R') -, where R'is H or Cl-C6 alkyl, and/or optionally substituted with halogen, hydroxy, C1-C5 alkoxy, carboxy, ester, thiol, primary or secondary amino or amido groups, or R is phenyl or an aryl residue, being R optionally substituted with a biologically active substance, wherein said biologically active substance is selected among sugars, amino acids, fatty acids, vitamins, hormones, peptides, catecholamines, said catecholamines being optionally conjugated, via peptidic bond, to the other above mentioned biologically active substances;

Li is a tridentate hetero-diphosphine ligand of formula (II) : <BR> <BR> <BR> <BR> R1 R3<BR> P-(CH2)n-X-(CH2)n-P<BR> <BR> <BR> <BR> <BR> R2 R4<BR> 4<BR> <BR> <BR> <BR> <BR> <BR> <BR> <BR> (il), wherein: R1, R2, R3 and R4, which may be the same or different, have the same meanings as R; X is oxygen, sulphur, NR, wherein R is hydrogen or R; n is an integer ranging from 1 to 5; L2 is a bidentate ligand, which comprises a combination of two donor atoms, selected from the group consisting of oxygen, sulphur and nitrogen, said atoms being preferably negatively charged and being separated by a spacer of 2 to 4 members, said spacer being an aliphatic chain or part of an aromatic ring, L2 being optionally conjugated to a biologically active substance as above defined; Z-is a mononegative counter-ion selected from the group consisting of Cl-, Br, OH-, C104-, alkoxylate, preferably EtO-, tetrafluoroborate.

Preferred R are methyl, ethyl, propyl, isopropyl, butyl, isobutyl, octyl, decyl, dodecyl, propenyl, butenyl, pentenyl, phenyl, benzyl, tolyl, 4-methoxy- benzyl, 4-ethoxy-benzyl, salicyl.

Preferred tridentate hetero-diphosphine ligands L1 of formula (II) are those where n = 2. Most preferred ligands Li are selected from the group consisting of : (C6Hs) 2PCH2CH2N (H) CH2CH2P (C6H5) 2; (C6Hs) 2PCH2CH2N (CH3) CH2CH2P (C6Hs) 2; (CH3) 2PCH2CH2N (CH3) CH2CH2P (CH3) 2; (C6H5) 2PCH2CH2SCH2CH2P (C6H5) 2; (C6H5) 2PCH2CH20CH2CH2P (C6H5) 2;

(C6H5) 2PCH2CH2N (CH2CH20CH3) CH2CH2P (C6H5) 2.

Bidentate ligands L2 preferably comprise a 2 or 3 membered spacer as defined above between the two electron-donor atoms. Suitable combinations of electron-donor atoms, preferably negatively charged, are [O-, 0-], [N-, O-], [S-, O-], [N-, N-], [N-, S-] and [S-, S-]. Preferred bidentate ligands are catecholate (2-) ; carbonate (2-) ; 1, 2-aminophenolate (2-) ; 1, 2-benzenedithiolate (2~) ; ethyleneglycolate (2-) ; ethylenediaminate(2-) ; ethylenedithiolate (2~) ; 1, 2-phenylenediaminate(2-); 1, 2-aminothiophenolate (2-) thiosalicylate (2-) ; 1, 2-aminoethanolate(2-) and the like.

The bidentate ligands L2 preferably carry a biologically active substance as defined above. Among said biologically active substances, preferred are catecholamines, like dopamine, L-DOPA and 3-hydroxythyramine. Catecholamines may, in turn, be conjugated, via peptidic bond, to other physiologically active substances. In a preferred embodiment of the invention, vitamin H is conjugated to dopamine.

The radioactive compounds of formula (I) can be obtained by reacting an intermediate compound of formula (III): [ (Me=N-R) Y2 (L1)] +Y' (III), with a bidentate ligand L2, wherein Me, R, Ll and L2 are as defined above and Y is halogen, preferably chlorine, or bromine, hydroxy or alkoxy, preferably ethoxy, or a leaving group which easily undergoes nucleophilic substitution.

The reaction is usually carried out in an organic solvent, in the presence of an organic base, or under buffered conditions, preferably in phosphate buffer. Preferred solvents are alcohols and chlorinated solvents. Preferred organic bases are tertiary amines, more preferred is triethylamine. The reaction temperature ranges from room temperature to the reflux temperature of the solvent.

The final product is separated and purified with conventional techniques like salification, crystallization, chromatography as described in detail in the following experimental section.

Intermediate compounds of formula (III) are in turn synthesized as described in Scheme 1 below from oxides of radioactive transition metals, preferably 99mTcO4-, ls6Re04 or lssRe04-, more preferably 99mTcO4-, which are treated with an excess of tertiary monophosphines, preferably PPh3, in acidic hydro-alcoholic solutions and in the presence of a suitable imido donor (D), to give an imido complex of formula (IV), wherein Me, R and Y are as defined above. Successive treatment with an above described ligand Li affords the desired intermediates of formula (III).

Scheme 1 Suitable imido donors D according to the invention are preferably 1-substituted-2-acetyl hydrazine, most preferably 1-phenyl-2-acetyl hydrazine (PAH).

The reaction of L1 with imido complexes of formula (IV) is preferably carried out in organic solvents like alcohols, chlorinated solvents, acetonitrile or a mixture thereof, optionally in the presence of an organic base like triethylamine, at a temperature ranging from room temperature to the reflux temperature of the solvent. The final purification of the desired intermediate of formula (III) is thoroughly described in the following experimental section.

It has finally been demonstrated that the preferred 99mTc-imido heterocomplexes according to the invention can be obtained at microscopical level via a three-step approach starting from pertechnetate sodium salt eluted

from a commercial 99Mo/99mTc generator. In the first step pertechnetate is treated with an excess of tertiary monophosphine in hydro-alcoholic solutions acidified with hydrochloric acid and in the presence of 1-phenyl-2-acetyl hydrazine. In the second step, addition of the tridentate hetero-diphosphine ligand in an organic solvent affords the intermediate species [99mTc (NPh) Cl2 (Ll)] +Y-. By adjusting pH at 7.4 with phosphate buffer, and by adding the preferred bidentate ligand L2, the desired imido heterocomplex is produced in high radiochemical yield (see Table 1).

Preferred complexes of the invention are: [99mTc (NPh) (PNHP) (0, N-ap) ]; [99mTc (NPh) (PNHP) (O, O-car)] ; [99mTc (NPh) (PNMeP) (O,N-ap)] ; [99mTc (NPh) (PNMeP) (S, N-atp) ] ; [99mTc (NPh) (PNMeP) (O, O-cat)] ; [99mTc (NPh) (PNMeP) (S, O-tsal)] ; [99mTc (NPh) (PNMeP) (S, S-bdt) ] ; wherein PNHP means (C6H5) 2PCH2CH2N (H) CH2CH2P (C6H5) 2 ; PNMeP means (C6H5) 2PCH2CH2N (CH3) CH2CH2P (C6H5) 2; O, N-ap means 2-aminophenolate (2-) ; S, N-atp means 2-aminothiophenolate (2-) O, O-cat means catecholate (2-) O, O-car means carbonate (2-) S, O-tsal means thiosalicylate S, S-bdt means 1, 2-benzenedithiolate(2-) The reactivity of imido-containing species has been thoroughly studied at macroscopic level using [99Tc (NPh) Cl3 (PPh3) 2] and [Re (NPh) Cl3 (PPh3) 2] as precursors.

These precursors react with tridentate hetero-diphosphine ligands L1 to yield intermediate compounds of the type [Me (NPh) Cl2Ll)] [Cl]. The hetero- diphosphine ligand acts as a tridentate donor due to the presence of the electron-donor X heteroatom interposed in the diphosphine chain and gives rise to three different octahedral configurations, shown by the following formulas (IIIA): fac, cis (IIIB) mer, cis and (IIIC) mer, trans.

R R R # # # axa a a (IIIA) (IIIB) (IIIC) fac, cis mer, cis mer, trans In formulae (IIIA), (IIIB) and (IIIC) a denotes the positions occupied by ligand L1 and b denotes the positions occupied by ligand Y.

The halide group, positioned trans with respect to the imido core in the intermediate mer, cis- [Me (NPh) Cl2 (Ll)] + compounds, easily undergoes substitution with nucleophilic ligands (such as ethanolate), indicating that halide ligands are labile and good leaving groups. In similar substitution reactions, cis-positioned halides are replaced by bidentate nucleophilic ligands such as ethyleneglycol or catechol or the like to yield imido heterocomplexes of the type [Me (NPh) L'L 2] +Z-. Thus, both mer, cis-[Me (NPh) Cl2Ll] + and fac, cis- [Me (NPh) Cl2L1]+ isomers are useful intermediates for the production of mixed imido heterocomplexes. On the contrary, the mer, trans- [Me (NPh) Cl2Ll] + isomers give rise to the heterocomplexes in a negligible yield, as a result of heavy steric constraints imposed by the meridional co- ordination of the Ll diphosphine combined with the trans-halide configuration. Thus, a reciprocal cis-position of the halide groups in the intermediate compounds is an essential pre-requisite for obtaining

heterocomplexes of the invention.

The stereochemistry of the L1 ligand in the final heterocomplex is always facial, the bidentate ligand L2 filling the residual two positions on the equatorial plane of the octahedron.

The present invention is illustrated in further detail in the following examples.

EXAMPLES The tridentate hetero-diphosphine ligands Li and the bidentate ligands L2 used in the following examples are abbreviated as follows: Tridentate hetero-diphosphine ligands L1 : PNHP; (C6H5) 2PCH2CH2N (H) CH2CH2P (C6H5) 2 PNMeP ; (C6H5) 2PCH2CH2N (CH3) CH2CH2P (C6H5) 2 MePNMePMe; (CH3) 2PCH2CH2N (CH3) CH2CH2P (CH3) 2 PNOMeP ; (C6H5) 2PCH2CH2N (CH2CH2OCH3) CH2CH2P (C6H5) 2 POP ; (C6H5) 2PCH2CH20CH2CH2P (C6H5) 2 PSP; (C6Hs) 2PCH2CH20CH2CH2P (C6H5) 2 Bidentate ligands L2 : O, O-cat ; catecholate (2-) O, O-car ; carbonate (2~) N, N-pda; 1, 2-phenylenediaminate(2-) S, S-bdt; 1, 2-benzenedithiolate(2-) O, O-eg ; ethyleneglycolate (2-) N, N-en; ethylenediaminate (2-) S, S-edt; ethylenedithiolate (2-) O, N-ap; 1, 2-aminophenolate(2-) S, N-atp; 1, 2-aminothiophenolate(2-) O, S-tsal; thiosalicylate (2-) O, N-ae; 1, 2-aminoethanolate(2-)

Chemistry at macroscopic (ca) level by using 99Tc and Re Example 1: Synthesis of iii er, cis-199Tc (NPh) Cl2 (PNHP)] [Cl] To a solution of [Tc (NPh) Cl3 (PPh3) 2] (45 mg) in dichloromethane/ methanol (5 mL/1 mL) a 1.1 equivalent of solid PN (H) P was added under stirring. The brown mixture, in 2 minutes, turned brown-green. After 3 h the solution was taken to dryness with a flow of nitrogen. The oily residue was treated with diethyl ether and the resulting brown-green solid filtered. The crude solid was washed on the filter with acetone (2 mL). The light green solid was dried under nitrogen (yield 22 mg, 60%). The product is soluble in chlorinated solvents and acetonitrile, slightly soluble in alcohols, insoluble in diethyl ether.

31P-NMR (300 MHz, CDCl3, ppm): 31.6 (bs).

1H-NMR (300 MHz, CDC13, ppm) : 9.70 (bs, 1H; N-H), 8.06 (m, 4H, PPh2), 7.51 (m, 13H, PPh2 + NPhy, a), 7.02 (m, 6H, PPh2), 6.86 (t, 2H, NPhp), 3.97 (bt, 2H, CH2), 3.34 (bm, 6H, CH2).

Example 2: Synthesis of mer, cis-[Re (NPh) C12 (PNHP)] [Cl] To a suspension of [Re (NPh) Cl3 (PPh3) 2] (104 mg, 0.11 mmol) in CH2C12, an excess of PNHP HCl (75 mg, 0.16 mmol) dissolved in CH2C12 with 50 jj. l of NEt3 (0.38 mmol) was added dropwise. The reaction mixture was refluxed for 2 hours and then stirred overnight at room temperature. The resulting solution was olive-green. The solvent was removed and the green solid washed with diethyl ether, water and dried under vacuum. The 31P-NMR spectrum of such solid in CDC13 showed two peaks at 4.3 an 8.4 ppm, which suggest the presence of two new products. A pure product was obtained by crystallization from a CH2Cl2/n-hexane mixture. Grey-blue crystals were obtained (final yield 30-40%) and the compound was identified as [Re (NPh) Cl2 (PN (H) P)] Cl. The product is stable in air and soluble in CH2Cl2, CHCl3, quite soluble in EtOH and MeOH, insoluble in H2O, hexane and Et20.

31P-NMR (300 MHz, CDC13, ppm): 8.48 (s).

H-NMR (300 MHz, CDC13, ppm): 8.07 (m, 4H, PPh2), 7.71 (d, 2H, ), 7.50 (m, 11H, PPh2 + NPhy), 7.03 (m, 6H, PPh2), 6.87 (t, 2H, NPhß), 4.01 (bt, 2H, CH2), 3.39 (bm, 2H, CH2), 3.22 (bm, 4H, Chez), 9.5 (b, 1H, NH).

Example 3: Synthesis of mer,cis-[Re (NPh) (OEt) Cl (PNHP)] [Cl] To a suspension of [Re (NPh) Cl3 (PPh3) 2] (52 mg, 0.057 mmol) in EtOH, an excess of PNHP HCl (43 mg, 0.089 mmol) dissolved in EtOH with 25 gel of NEt3 (0.19 mmol) was added dropwise. The reaction mixture was refluxed for 4 hours: the resulting solution was green-yellowish. The volume was reduced under a nitrogen stream and Et2O was added: after few hours large bright blue crystals of [Re (NPh) (OEt) Cl (PNHP) ] Cl had been formed.

31P-NMR (300 MHz, CDC13, ppm) : -0.20 (s).

1H-NMR (300 MHz, CDC13, ppm) : 9.5 (b, 1H, NH), 8.00 (m, 4H, PPh2), 7.53 (m, 13H, PPh2 + NPh), 7.07 (m, 6H, PPh2), 6.87 (t, 2H, NPhß), 3.99 (bt, 2H, CH2), 3.41 (m, 2H, CH2), 3.18 (m, 2H, CH2), 2.98 (m, 2H, Chia), 2.64 (q, 2H ; O-CH2-CH3),-0. 13 (t, 3H; O-CH2-CH3).

Example 4: Synthesis offac, cis- [Re (NPh) C12 (PNMeP)] [CI] To a suspension of [Re (NPh) Cl3 (PPh3) 2] in CH2C12 a slight excess of PNMeP (86 mg, 0.19 mmol) was added. The reaction mixture was refluxed for 24 h. The volume of the resulting green-yellowish solution was reduced and Et2O was added. A TLC analysis of the precipitate showed a mixture of different products, so separation by means of a cromatographic column was performed (silica gel, CHC13/EtOH 3/2). Two yellow and a green fraction <BR> <BR> <BR> <BR> were collected. The green product was identified as [Re (NPh) Cl2 (PNMeP) ] Cl.

31P {H}-NMR (300 MHz, CDC13, ppm) : 19. 9 (s).

1H-NMR (300 MHz, CDC13, ppm): 4.08, 3.45 and 2.95 (m, 8H CH2), 2.61 (s, 3H, CH3).

Example 5: Synthesis of mer, trans-[Re (NPh) Cl2 (PNMeP)] [Cl] [Re (NPh) Cl3 (PPh3) 2] (100 mg, 0.11 mmol) and PNMeP#HCl (86 mg, 0.17 mmol) were mixed in acetonitrile. By refluxing for 15 minutes the reaction mixture became light green. Additional reflux deposited a green solid within a few hours. After 4 h the mixture was allowed to reach room temperature and filtered. The green powder was washed with Et2O and resulted soluble in CH2C12, quite soluble in CHC13 and almost insoluble in Et2O and benzene. NMR analysis evidenced the presence of two isomers in <BR> <BR> <BR> <BR> <BR> solution (yield 70%), then characterised as cis- [Re (NPh) Cl2 (PNMeP) ] Cl#HCl.

1H-NMR (300 MHz, CD2C12, ppm): 6.59 (d); 6.74 (t); 7.45 (t) (5H, NPh) ; 7.10 (m); 7.24 (m); 7.37 (m); 7.55 (m); 7.70 (m); 7.85 (m); 7. 96 (m) (20H, PPh2) ; 3.74 (m); 3.35 (m); 3.08 (m) (8H, CH2) ; 2.99 (d); 2.69 (d) CH3. 31P {H} NMR (300 MHz, CD2Cl2, ppm) : -25.1 (s);-26. 9 (s). The pale-green powder <BR> <BR> <BR> <BR> <BR> (cis- [Re (NPh) Cl2 (PNMeP) ] Cl#HCl) was dissolved in CH2C12 in the presence of an excess of NEt3. NMR analysis evidenced the quantitative conversion into the mer, trans- [Re (NPh) Cl2 (PNMeP) ] Cl complex.

31P-NMR (300 MHz, CDCl3, ppm) : 19. 9 (s) 1H-NMR (CDC13, ppm) = 7.6-7. 1 (20H; PPh2) 4.08, 3.45 and 2.95 (m, 8H; methylene protons); 2.61 (s, 3H; CH3).

Example 6: Synthesis of fac- [99Tc (NPh) (O, O-cat) (PNHP)] [C104] To a solution of [99Tc (NPh) Cl2 (PNHP) ] [Cl], prepared according to Example 1, (26 mg, 0.04 mmol) in methanol (5 mL), catechol (5.2 mg, 0.047 mmol) and triethylamine (6.7 pL, 0. 047 mmol) were added. The colour of the mixture turned immediately deep purple. The solution was stirred for 4 h and concentrated to 2 mL by a nitrogen flow. A drop of a saturated NaC104 solution in MeOH was added to the solution. After 1 day, dark-grey crystals were formed; they were collected on a filter and washed with a lx2 mL of MeOH.

31P-NMR (300 MHz, CDC13, ppm): 46.5 (bs).

1H-NMR (300 MHz, CDC13, ppm): 7.77 (t, 4H), 7.49 (t, 4H, ), 7.40 (t, 4H), 7.22 (m, 6H) 7.02 (m, 7H), 6.87 (m, 2H), 6,71 (m, 2H), 3.5-2. 7 (8H).

Example 7: Synthesis offac- [Re (NPh) (O, O-cat) (PNHP)] [Cl] To a bluish solution of [Re (NPh) Cl2 (PNHP) ] Cl, prepared according to Example 2, in CH2C12 (40 mg, 0.05 mmol) catechol (H2cat) (5 mg, 0.045 mmol) and 20 ul of NEt3 were added at room temperature. The reaction mixture immediately turned red. The solution was stirred overnight at room temperature. After 15 h the solvent was removed, the residue was treated with diethyl ether and the resulting red-brown solid filtered and washed several times with n-hexane, diethyl ether and water. [Re (NPh) (O, O-cat) (PNHP) ] Cl was obtained with a final yield of 53%. 1H-NMR (300 MHz, CDC13) : 7.85-7. 07 (m, 25H, NPh and PPh2), 6.91-6. 73 (m, 4H, catH). 31P-NMR : 19.5 (s). A stoichiometric amount of NBu4BF4 was added to a CH2C12 solution of [Re (NPh) (O, O-cat) (PNHP) ] Cl and by addition of n-hexane a red-orange product precipitated. Accoprding to the elemental analysis, this powder was characterized as the tetrafluoroborate salt of [Re (NPh) (O, O-cat) (PNHP)].

31P-NMR : 19.5 (s).

El. Anal.: ReN2C4oH3802P2BF4, MW 913.7 Calcd. C 52.6, N 3.2, H 5.1 Found: C 52. 9, N 3. 2, H 5.1.

Example 8: Synthesis of ac-[Re (NPh) (O, O-eg) (PNHP)] [Cl] To a bluish solution of [Re (NPh) Cl2 (PNHP) ] Cl of Example 2 in CH2C12 (40 mg, 0.05 mmol) 30 p. l ofethylene glycol and 20 p1 of NEt3 were added at room temperature. The reaction mixture was refluxed for 1 h and then stirred at room temperature for 24 h. The solution became grey. After removal of the solvent with a gentle nitrogen stream, the oily residue was treated with diethyl ether and the resulting grey solid filtered. The crude solid was purified

washing, on the filter, with n-hexane and water. Grey crystals of <BR> <BR> <BR> <BR> [Re (NPh) (O, O-eg) (PNHP) ] Cl, suitable also for X-ray diffractometric analysis, were obtained by crystallization from a CH2Cl2/n-hexane solution. 31 {H} NMR (300 MHz, CD2C12) 17. 2. 1H-NMR (300 MHz, CDC13) : 7.74-6. 91 (m, 25H, NPh and PPh2), 4.98 (b, 1H, NH), 4.78 (d, 2H, CH2), 4. 60 (d, 2H, CH2), 3.2-2. 9 (m, 8H, PCH2CH2N).

Example 9: Synthesis of fac-[Re (NPh) (O, O-eg) (PNMeP)][Cl] To a solution of fac, cis- [Re (NPh) Cl2 (PNMeP) ] Cl of Example 4 in CH3CN (50 mg, 0.06 mmol) 30 p1 of ethylene glycol and 20 1 ofNEts were added. The reaction mixture was refluxed for 24 h. The volume of the dark green solution was reduced and the oily residue was dissolved in CH2C12 The excess of ethylene glycol was removed by water extraction. The organic phase was dried and a green powder, characterised as fac- [Re (NPh) (O, O- eg) (PNMeP) ] Cl was recovered (yield 43%).

1H-NMR (300 MHz, CDC13, 6 ppm): 6.98-7. 48 (m, 25H, NPh and PPh2) ; 4.91-4. 76 (m, 4H CH) ; 3.58 (m), 3.27 (m) e 2.27 (m) (8H,-CH2CH2-PNP ; 2.34 (s, 3H, N-CH3).

3lp (CDC13) : = 24. 3 (s).

Example 10: Synthesis of fac-[Re (NPh) (O, N-ap) (PNMeP)] [CI] To a suspension of [Re (NPh) Cl3 (PPh3) 2] in CH2C12 (90 mg, 0. 1 mmol) PNMeP (53 mg, 0.11 mmol) was added at room temperature. After 5 minutes 1,2 aminophenol (17 mg, 0.16 mmol) and 20 p, l ofNEts were added and the reaction mixture was refluxed. After 10 minutes the solution turned from green to dark brown. After refluxing for 30 min the solution was stirred overnight at room temperature. The solvent was removed and the residue treated with diethyl ether. The red brown solid was filtered and re-dissolved in CH2C12. Elution from a silica column with CHC13/MeOH 85/15 separated a yellow by-product and the red fac- [Re (NPh) (O, N-ap) (PNMeP) ] Cl.

31P (CDCl3) : =17. 8 (d), 10.1 (d).

Chemistry at microscopic (nca) level by employing 99mTc) Example 11: Synthesis of the intermediate [99mTc (NPh) CI, L1)] +Y-.

0.1 mL of saline physiological solution containing [99mTcO4]- (50 Mbq) were added to a vial containing 10 mg of PAH, 3 mg of PPh3 0. 1 mL of 1 M HC1 and 1.5 mL of MeOH. The resulting solution was heated at 65°C for 30 min. After this, 0.2 mL of an alcoholic solution containing 3 mg of an appropriate L1 hetero-diphosphine ligand (PNHP or PNMeP or PNOMeP) was added. The resulting solution was maintained at 65°C for further 30 min.

TLC analysis of the intermediate [99mTc (NPh) Cl2 Ll)] + species showed a mixture of different products. This behaviour is in agreement with the evidences produced at macroscopic level, where some intermediate species were characterised.

Example 12: Synthesis of [99mTc (NPh) L1L2]+Z-.

This three-step preparation involves the preliminary formation of a mixture of intermediate complexes of general formula [99mTc (NPh) Y2 Ll] (Y = halides, water, hydroxyl, alkoxy) followed by its conversion into the final asymmetrical compound by reactions with the bidentate ligand L2. In detail, 0.250 mL of phosphate buffer 1 M, pH 7.4, followed by 0.2 mL of methanol solution containing 5 mg of an appropriate bidentate ligand L2 were added to the vial containing the intermediate compound, obtained as reported above. The mixture was heated at 65°C for lh. The radiochemical yields evaluated by TLC chromatography are reported in Table 1.

Table 1: TLC Si02 : a EtOH/CHC13/C6H6 (1/2/1.5) ; bCHCl3/MeOH (2% NH40H 20%) 85/15 ;'CHC13/MeOH (2% NH40H 20%) 90/10 ; dCHCl3/MeOH (2% NH40H 20%) 95/5 Complexes TLC, Rf Yield % [99mTc (NPh) (PNHP) (O, N-ap) ] 0. 42b 62 [99mTc (NPh) (PNMeP) (O, N-ap) ] 0. 24a ; 0. 45b ; 0. 14c 97 [99mTc (NPh) (PNMeP) (S, N-atp) ] 0. 28a ; 0. 28c 85 [99mTc (NPh) (PNMeP) (O, O-cat)] 0. 85a ; 0. 85c ; 0. 5d 91 [99mTc (NPh) (PNMeP) (S, O-tsal)] 0.78a ; 0. 75c, 0. 35d 90 [99mTc (NPh) (PNMeP) (S, S-bdt) ] 0. 74a ; 1b,c,d 98 Rf values shown by the compounds of Table 1 are in full accord with the ones shown by the corresponding compounds obtained at macroscopic level, using 99Tc, thus confirming that for the compounds of the invention the transfer from macro to micro level is possible.

The metal-imido hetero-diphosphine complexes of the present invention proved useful in the radiopharmaceutical field, either in radiodiagnostic imaging, when 99mTc is the employed radioactive metal, or in radiotherapy, when 186Re and libre are the radioactive metals.

Accordingly, the invention encompasses also the use of these complexes in the diagnostic and/or therapeutic radiopharmaceutical field and the pharmaceutical compositions comprising said compounds in admixture with pharmaceutically acceptable carriers and/or excipients.