Yvon Coulais

A click procedure with heterogeneous copper to tether technetium-99m chelating agents and rhenium complexes. Evaluation of the chelating properties and biodistribution of the new radiolabelled glucose conjugates.

An efficient protocol was developed to tether chelating agents and rhenium complexes onto a glucoside scaffold with a heterogeneous copper catalyst via click chemistry. The supported catalyst avoids the formation of unwanted copper complexes during the cyclisation step. The possibility to graft a pre-chelated M(CO)(3) core by click chemistry onto a biomolecule was highlighted for the first time. (99m)Tc(CO)(3)-glucoconjugates displayed excellent in vitro stability, a fast in vivo blood clearance and a low specific organ uptake or long-term retention in spleen and stomach.

Neutral oxo and nitrido complexes of technetium(V) and rhenium(V) with an unsaturated tetradentate (N2S2) ligand. Crystal structure of [N,N′-ethylenebis(thioacetylacetonylideneiminato](2–)S,S′,N,N′) nitridotechnetium(V)

Ligand-exchange reactions of the tetradentate unsaturated N2S2Schiff-base ligand N,N′-ethylenebis (thioacetylacetonylideneimine)(H2L) with labile monooxo-technetium(V) and -rhenium(V) compounds ([NBu4][TcOCl4]; [NBu4][ReOCl4] or [ReOCl3(PPh3)2]) gave two types of neutral six-co-ordinated species [MO(L)Cl] and [{MO(L)}2O](M = Tc or Re). The monooxo monomeric complexes rearrange to the µ-oxo dimeric species via a charged labile intermediate in wet organic solvents or when solution are kept in contact with air. Reaction of H2L with [NBu4][TcVINCl4] follows a reduction–substitution route to give another neutral, but five-co-ordinated species, [TcN(L)] which contains the [TcVN]2+ nitride core. All complexes have been characterized by means of standard spectroscopic techniques. The influence of the metal on ligand 1H NMR chemical shifts is discussed. The technetium centre shifts all the ligand protons more downfield than does rhenium. This behaviour is in general agrement with the stronger acidity of the [TcO]3+ core with respect to [ReO]3+. The five-co-ordination of the nitrido complex [TcN(L)] is confirmed by its X-ray structure determination: monoclinic, space group P21/n, a= 14.654(7), b= 12.62(5), c= 7.819(4)A, β= 92.60(3)° and Z= 4. The co-ordination sphere around the Tc centre is nearly square pyramidal with an apical multiply bonded nitrogen atom [TcN 1.621(8)A].

Bidentate phosphinophenol ligands. Preparation and electrochemistry of the Re(III) complexes of 2-(diphenylphosphinomethyl)-4-methylphenol (P1OH) and 2-diphenylphosphinophenol (P2OH). Crystal and molecular structure of mer-Re[P1O]3

Abstract The reaction of 2-(diphenylphosphinomethyl)-4-methylphenol (P1OH) and 2-diphenylphosphinophenol (P2OH) on ReCl3(MeCN)(PPh3)2 in a 3:1 ratio leads to the formation of the homoleptic Re(III) complexes Re(P1O)3 (1) and Re(P2O)3 (2) in high yield. 1 is reasonably stable in air in the solid state and in solution, which is not the case for 2. Orange–red crystals of 1 contain distorted octahedral Re entities in which the metal is coordinated to three bidentate phosphinophenolato ligands in the mer configuration. Cyclic voltammetry of 1 and 2 shows two well defined monoelectronic quasi-reversible redox waves, one reductive attributed to the Re(III)/Re(II) couple and one oxidative due to the Re(III)/Re(IV) one. A second oxidative wave, attributed to the Re(IV)/Re(V) couple, is reversible only for 1, indicating the lower stability of 2 toward oxidation. In agreement with this, 2 gives, in air, the Re(V)-oxo species ReO(OP2O)(P2O)2 (3) quantitatively, whose structure is confirmed by X-ray diffraction.

Bidentate phosphinophenol ligand: synthesis and characterization of oxo and phenylimido rhenium(V) complexes of 2-diisopropylphosphinophenol

Abstract Six-coordinate, monosubstituted and disubstituted phosphinophenol complexes ReYX2(PPh3)(P∼O) and ReYX(P∼O)2 (Y=O, NPh; X=Cl, Br, I) were obtained by reacting 2-diisopropylphosphinophenol (P∼OH) with ReOX3(PPh3)2 and Re(NPh)X3(PPh3)2 in toluene. A mixture of the monosubstituted and disubstituted complexes ReYX2(PPh3)(P∼O) and ReYX(P∼O)2 was precipitated when the reactions were performed with a 2:1 ligand to metal ratio. Excess ligand (4 equiv.) was needed to obtain quantitatively the disubstituted complexes. 1H and 31P{1H} NMR show that all monosubstituted and disubstituted complexes exist as single isomers with a trans-P,P ‘twisted’ octahedral geometry, the site trans to the multiple bond being filled by the oxygen donor of one P∼O ligand. The compounds were also characterized by microanalysis, IR and mass spectrometry.

A simplified route to the synthesis of new 99mTc-specific tetradentate ligands

Abstract The synthesis of two new N 2 S 2 or N 2 SO tetradentate ligands and the preparation of their technetium-99m complexes are reported. Each ligand leads to a unique 99m Tc-complex with an excellent radiochemical yield. The in vivo stability of these complexes was determined by serum stability and cysteine challenge studies.

Synthesis, molecular and crystal structure of the zwitterionic Re(V)–oxo complex ReOCl3(L)(PPh3) with L=2-(diethylaminomethyl)-4-methylphenol

Abstract Ligand exchange between 2-(diethylaminomethyl)-4-methylphenol (N ∩ OH) and ReOCl 3 (PPh 3 ) 2 yields green crystals of the zwitterionic complex ReOCl 3 (O ∩ NH)(PPh 3 ). The X-ray diffraction study reveals that the structure consists of monomeric units in which the distorted octahedral coordination around Re is provided by the oxo group, the three Cl atoms in a mer arrangement, the PPh 3 ligand and the phenolate oxygen trans to the oxo group. The amino–phenol is monodentate via the phenolate oxygen, whereas the amine in the side-arm has been quaternized by migration of the phenol proton. The resulting ammonium group forms an intramolecular NH⋯Cl hydrogen bond with an adjacent Cl ligand, making the complex highly resistant to deprotonation. The 1 H NMR spectra indicate that the NH proton is not labile in CDCl 3 . Electron delocalisation along the OReOC(phenolate) moiety via the sp-hybridised oxygen of the end-on coordinated phenolate would be consistent with the short ReO(phenolate) distance of 1.915(3) A observed.

Synthesis and physicochemical characterization of oxo and phenylimido Re(V), Re(III) and Ni(II) complexes with the 2-[bis(ethoxyethyl)phosphino]phenolato ligand and derivatives

2-[Bis(ethoxyethyl)phosphino]phenol P1–OH reacts in basic refluxing solvents with ReOCl3(PPh3)2, in a 2/1 molar ratio, to give the green ReOCl(P1–O)2 complex. Structure elucidation by 31P NMR is consistent with a cis-PP “twisted” octahedral complex, which is the preferred conformation on electronic grounds. The complex is unique in toluene while several species were present in ethanol. When the reaction is performed with Re(NPh)Cl3(PPh3)2, a mixture of trans-PP (major) and cis-PP(minor) species in a 3/1 ratio is obtained. These geometric isomers were distinguished by their 2JPP coupling constants. Only cis-PP-Re(NPh)Cl(P1–O)2, less soluble, could be isolated and its molecular structure determined by physicochemical measurements. This is the first example of cis-PP phosphinophenolato complex with the [ReNPh]3+ core, thus illustrating the importance of the steric demand of the phosphine substituent. Reaction of P1–OH with NiCl2 gives Ni(P1–O)2 as an orange oily solid with a cis-PP square planar structure. This structure is the most probable based on the 31P, 13C NMR data.

New neutral and lipophilic technetium complexes based on a cytectrene moiety: synthesis, characterization and biological evaluation

Abstract The synthesis, characterization and biological evaluation of five neutral and lipophilic 99mTc-complexes, so-called cytectrenes, obtained from N-substitutedferrocenecarboxamide derivatives are reported. N-substitutedferrocenecarboxamide starting materials were obtained in two steps, with good yield and were fully characterized by classical spectroscopic methods including X-ray diffraction analysis for one of them. Using a microwave strategy for the 99mTc-radiolabelling step, each cytectrene were obtained quickly (radiolabelling time < 5 min), from modest to good yield. The 99mTc-complexes, characterized by HPLC comparison with cold rhenium complex analogues, are stable, neutral and lipophilic (log Po/w ranged between 1.8 and 2.9). Unfortunately, despite such suitable features, in vivo studies of two of them gave poor results, in terms of brain uptake. Both radiocompounds exhibited the maximum brain accumulation of 0.31% ID/g and 0.26% ID/g at 5 min post-injection, respectively, followed by a very fast washout from the brain (0.06% ID/g and 0.07% ID/g at 30 min post-injection, respectively). Although our ligand systems exhibited high stability against exchange reactions with blood proteins, the high radioactivity level in stomach, increasing with time, suggests in vivo decomposition of our complex to pertechnetate.

Synthesis and characterisation of oxo- and phenylimido-rhenium(V) complexes containing bidentate phosphinoenolato ligands

Reacting 1-phenyl-2-(diphenylphosphino)ethanone (P1∼OH), 1-tert-butyl-2-(diphenylphosphino)ethanone (P2∼OH) and 1-phenyl-2-(diphenylphosphino)propanone (P3∼OH) with ReOCl3(PPh3)2 and Re(NPh)Cl3(PPh3)2 in toluene and ethanol in the presence of NEt3 yields complexes in which these ligands bind as monoanionic enolato chelating agents. Bromo and iodo analogues are prepared similarly. The reactions are solvent dependent. The disubstituted ReOCl(P∼O)2 compounds obtained in toluene adopt the ‘twisted’ cis-(P,P) octahedral structure. With Re(NPh)Cl3(PPh3)2, P1∼OH and P2∼OH give the corresponding Re(NPh)Cl(P∼O)2 compounds and the trans-(P,P)-trans-(Cl,Cl) isomer of monosubstituted Re(NPh)Cl2(PPh3)(P∼O) as the major products, together with small amounts of ‘twisted’ trans-(P,P) Re(NPh)Cl(P∼O)2. The monosubstituted complex is the only species isolated with P3∼OH. The major structural difference between the two systems is the small stability gap between the cis- and the trans-(P,P) isomers of the imido complexes. In ethanol, unexpected cis-ethoxo-oxo complexes ReO(OEt)(P∼O)2 are isolated, resulting from stereoselective substitution of the halide in the ‘twisted’ cis-(P,P) octahedral complexes. The reactions with Re(NPh)Cl3(PPh3)2 are less selective and give rise to mixtures of complexes. The trans-ethoxo-phenylimido compound Re(NPh)(OEt)(P1∼O)2 is obtained in good yield. A crystallographic study reveals an unexpected ‘equatorial’ trans-(P,P) structure with the ethoxo ligand trans to the ReNPh bond. 1H NMR indicates that the ethoxo ligand acts as an electron reservoir in these complexes, since its protons are strongly deshielded in the cis-oxo-ethoxo species and strongly shielded in the trans-phenylimido-ethoxo complex.