Reactivity of the [M(PS)₂]⁺ Building Block (M = Re^III and ^99mTc^III; PS = Phosphinothiolate) toward Isopropylxanthate and Pyridine-2-thiolate

The coordination properties of isopropylxanthate (<i>i</i>-Pr-Tiox) and pyridine-2-thiolate (PyS) toward the [M­(PS)₂]⁺ moiety (M = Re and ^99mTc; PS = phosphinothiolate) were investigated. Synthesis and full characterization of [Re­(PS2)₂(<i>i</i>-Pr-Tiox)] (<b>Re1</b>), [Re­(PSiso)₂(<i>i</i>-Pr-Tiox)] (<b>Re2</b>), [Re­(PS2)₂(PyS)] (<b>Re3</b>), and [Re­(PSiso)₂(PyS)] (<b>Re4</b>), where PS2 = 2-(di­phenyl­phosphino)­ethane­thiolate and PSiso = 2-(di­isopropyl­phosphino)­ethane­thiolate, and the structural X-ray analysis of complex <b>Re3</b> were carried out. ^99mTc analogues of complexes <b>Re2</b> (^<b>99m</b><b>Tc2</b>) and <b>Re4</b> (^<b>99m</b><b>Tc4</b>) were obtained in high radiochemical yield following a simple one-pot procedure. The chemical identity of the radiolabeled compounds was confirmed by chromatographic comparison with the corresponding rhenium complexes and by dual radio/UV HPLC analysis combined with ESI­(+)-MS of ^99g/99mTc complexes prepared in carrier-added conditions. The two radiolabeled complexes were stable with regard to trans chelation with cysteine, glutathione, and ethylene­diamino­tetra­acetic acid and in rat and human sera. This study highlights the substitution-inert metal-fragment behavior of the [M­(PS)₂]⁺ framework, which reacts with suitable bidentate coligands to form stable hexacoordinated asymmetrical complexes. This feature makes it a promising platform on which to develop a new class of Re/Tc complexes that are potentially useful in radiopharmaceutical applications

Reactivity of the [M(PS)₂]⁺ Building Block (M = Re^III and ^99mTc^III; PS = Phosphinothiolate) toward Isopropylxanthate and Pyridine-2-thiolate

The coordination properties of isopropylxanthate (<i>i</i>-Pr-Tiox) and pyridine-2-thiolate (PyS) toward the [M­(PS)₂]⁺ moiety (M = Re and ^99mTc; PS = phosphinothiolate) were investigated. Synthesis and full characterization of [Re­(PS2)₂(<i>i</i>-Pr-Tiox)] (<b>Re1</b>), [Re­(PSiso)₂(<i>i</i>-Pr-Tiox)] (<b>Re2</b>), [Re­(PS2)₂(PyS)] (<b>Re3</b>), and [Re­(PSiso)₂(PyS)] (<b>Re4</b>), where PS2 = 2-(di­phenyl­phosphino)­ethane­thiolate and PSiso = 2-(di­isopropyl­phosphino)­ethane­thiolate, and the structural X-ray analysis of complex <b>Re3</b> were carried out. ^99mTc analogues of complexes <b>Re2</b> (^<b>99m</b><b>Tc2</b>) and <b>Re4</b> (^<b>99m</b><b>Tc4</b>) were obtained in high radiochemical yield following a simple one-pot procedure. The chemical identity of the radiolabeled compounds was confirmed by chromatographic comparison with the corresponding rhenium complexes and by dual radio/UV HPLC analysis combined with ESI­(+)-MS of ^99g/99mTc complexes prepared in carrier-added conditions. The two radiolabeled complexes were stable with regard to trans chelation with cysteine, glutathione, and ethylene­diamino­tetra­acetic acid and in rat and human sera. This study highlights the substitution-inert metal-fragment behavior of the [M­(PS)₂]⁺ framework, which reacts with suitable bidentate coligands to form stable hexacoordinated asymmetrical complexes. This feature makes it a promising platform on which to develop a new class of Re/Tc complexes that are potentially useful in radiopharmaceutical applications

Uncommon Anionic Dioxorhenium(V) and Neutral Monooxorhenium(V) Mixed-Ligand Complexes Containing Heterofunctionalized Phosphine Ligands: Syntheses and Structural Characterization

The potentially bidentate hybrid ligand (o-hydroxyphenyl)diphenylphosphine, abbreviated POH, reacted via ligand-exchange with pentavalent rhenium precursors to give a series of six-coordinate mono- and dioxo complexes. Accurate control of the metal:ligand stoichiometric ratio allowed for the isolation of the mono-substituted [ReOCl3(PO)]- (1) and [ReOCl2(PO)(PPh3)] (2) derivatives. 1 was found to be the key intermediate for the syntheses of three more types of bis-substituted compounds:  anionic dioxo [ReO2(PO)2][A] (A = NBu4 (3), AsPh4 (4)), neutral monooxo [ReOX(PO)2] (X = Cl (5), Br (6), I (7)), and neutral monooxo mixed-ligand [ReOX(PO)(PNH)] [PNH = (o-amidophenyl)diphenylphosphine; X = Cl (8), Br (9), I (10)] complexes. In the mono-substituted complexes, the P,O-donors of the bidentate ligand spanned an equatorial (P) and the apical position (O) trans to the ReO linkage in a distorted octahedral arrangement. In all of the bis-substituted monooxo compounds, the second chelate ligated on the equatorial plane almost orthogonally positioned with respect to the first one, the two phosphorus donors showing a mutual cis-(P,P) orientation. Dioxo complexes retained the cis-(P,P) configuration with the bidentate ligands symmetrically coordinated on the equatorial plane normal to the trans-ReO2 core. All the complexes were characterized by various physical techniques, including IR, MS, and 1H/31P{1H} NMR. The X-ray structure of a representative compound for each category, namely [ReOCl3(PO)][NBu4] (1), [ReO2(PO)2][AsPh4] (4), [ReOCl(PO)2] (5), and [ReOCl(PO)(PNH)] (8), were determined. Crystals of 1 were monoclinic, P21/n, a = 10.840(3) Å, b = 22.167(6) Å, c = 15.210(4) Å, β = 95.91(2)°, and Z = 4; those of 4 were triclinic, P1̄, a = 12.679(7) Å, b = 13.082(7) Å, c = 19.649(8) Å, α = 82.64(4)°, β = 81.16(4)°, γ = 62.27(3)°, and Z = 2; those of 5 were orthorhombic, a = 10.225(4) Å, b = 14.208(6) Å, c = 21.771(9) Å, P212121, and Z = 4; and those of 8 were orthorhombic, a = 10.199(2) Å, b = 14.147(4) Å, c = 21.772(6) Å, P212121, and Z = 4. The four structures were solved by the Patterson method and refined by full-matrix least-squares procedures to R = 0.050, 0.063, 0.043, and 0.039 for 1, 4, 5 and 8, respectively. Both solution state (31P{1H} NMR) and solid state (X-ray) demonstrated a cis-(P,P) arrangement for each bis-substituted complex, with the Re atom at the center of a highly distorted octahedron. Detailed analyses of the IR spectra of this series of Re(V) compounds in the region 900−580 cm-1 allowed us the possibility to distinguish between symmetrical and asymmetrical bis-substituted complexes

Technetium and Rhenium in Five-Coordinate Symmetrical and Dissymmetrical Nitrido Complexes with Alkyl Phosphino-thiol Ligands. Synthesis and Structural Characterization

The reactivity of bulky alkylphosphino-thiol ligands (PSH) toward nitride-M(V, VI) (M = Tc/Re) precursors was investigated. Neutral five-coordinate monosubstituted complexes of the type [M(N)(PS)Cl(PPh3)] (Tc1−4, Re1−2) were prepared in moderate to high yields. It was found that these [M(N)(PS)Cl(PPh3)] species underwent ligand-exchange reactions under mild conditions when reacted with bidentate mononegative ligands having soft donor atoms such as dithiocarbamates (NaLn) to afford stable dissymmetrical mixed-substituted complexes of the type [M(N)(PS)(Ln)] (Tc5,8−10, Re5−9) containing two different bidentate chelating ligands bound to the [MN]2+ moiety. In these reactions, the dithiocarbamate replaced the two labile monodentate ligands (Cl and PPh3) leaving the [M(N)(PS)]+ building block intact. In the above reactions, technetium and rhenium were found to behave in a similar way. Instead, under more drastic conditions, reactions of PSH with [M(N)Cl2(PPh3)2] gave a mixture of monosubstituted [M(N)(PS)Cl(PPh3)] and bis-substituted species [M(N)(PS)2] (Tc11−14) in the case of technetium, whereas only monosubstituted [M(N)(PS)Cl(PPh3)] complexes were recovered for rhenium. All isolated products were characterized by elemental analysis, IR and multinuclear (1H, 13C, and 31P) NMR spectroscopies, ESI MS spectrometry, and X-ray crystal structure determination of the representative monosubstituted [Tc(N)(PStbu)Cl(PPh3)] (Tc4) and mixed-substituted [Re(N)(PScy)(L3)] (Re7) and [Re(N)(PSiso)(L4)] (Re9) complexes. The latter rhenium complexes represent the first example of a square-pyramidal nitrido Re species with the basal plane defined by a PS3 donor set. Monosubstituted [M(N)(PS)Cl(PPh3)] species bearing the substitution-inert [M(N)(PS)]+ moieties act as suitable building blocks proposed for the construction of new classes of dissymmetrical nitrido compounds with potential application in the development of essential and target specific 99mTc and 188Re radiopharmaceuticals for imaging and therapy, respectively

[^99mTc][Tc(N)(DASD)(PNP<i>n</i>)]⁺ (DASD = 1,4-Dioxa-8-azaspiro[4,5]decandithiocarbamate, PNP<i>n</i> = Bisphosphinoamine) for Myocardial Imaging: Synthesis, Pharmacological and Pharmacokinetic Studies

[99mTc]­[TcN-DBODC­(5) is the lead candidate of a class of cationic complexes proposed as myocardial imaging agents (MPIAs). Phase I clinical studies showed that its clinical properties were comparable to those of the commercially available agents. Thus, modification of [99mTc]­TcN-DBODC­(5), directed to obtain an ideal myocardial imaging without interference from the adjacent organ activities, is desirable. This work describes the pharmacological and pharmacokinetic development of four new complexes of general formula [99mTc]­[Tc­(N)­(DASD)­(PNPn)]+, [99mTc]­TcN-DASD­(n) (DASD = 1,4-dioxa-8-azaspiro­[4,5]­decandithiocarbamate; PNPn = bisphosphinoamine), proposed as improved MPIAs. Among the tested compounds, [99mTc]­TcN-DASD­(5) and [99mTc]­TcN-DASD­(7) showed enhanced heart uptake compared with the gold standards, with a rapid liver washout and superior heart-to-liver ratio. These features might shorten the duration of imaging procedures below 30 min, consenting the early acquisition of high-quality images. In addition, mechanistic studies were performed in cellulo by using human drug-sensitive and drug-resistant cancer cell lines, obtaining results which might be conveniently applied to tumor imaging

Novel [^99mTc^III(PS)₂(Ln)] Mixed-Ligand Compounds (PS = Phosphino-thiolate; L = Dithiocarbamate) Useful in Design and Development of Tc^III-Based Agents: Synthesis, in Vitro, and ex Vivo Biodistribution Studies

A general procedure for the preparation of a new class of neutral six-coordinated mixed ligand [^99mTc^III(PS)₂(Ln)] compounds (PS = trisalkyl-phosphino-thiolate; Ln = dithiocarbamate) is reported as well as their in vitro stability and the ex vivo tissue distribution studies. [^99mTc­(PS)₂(Ln)] complexes were prepared in high yield in nearly physiologic conditions following a one-pot procedure. For instance, the chemical identity of [^99mTc­(PSiso)₂(L1)] (PSiso = 2-(diisopropylphosphino)­ethanethiol; L1 = pyrrolidine dithiocarbamate) was determined by HPLC comparison with the corresponding ^99gTc-complex. All complexes comprise the stable [^99mTc^III(PS)₂]⁺ moiety, where the remaining two coordination positions are saturated by a dithiocarbamate chelate, also carrying bioactive molecules (e.g., 2-methoxyphenylpiperazine). [^99mTc­(PS)₂(Ln)] complexes were inert toward ligand exchange reactions. No significant in vitro and in vivo biotransformation were observed, underlining their remarkable thermodynamic stability and kinetic inertness. These results could be conveniently utilized to devise a novel class of ^99mTc^III-based compounds useful in radiopharmaceutical applications

Geometrically Controlled Selective Formation of Nitrido Technetium(V) Asymmetrical Heterocomplexes with Bidentate Ligands

Geometrically Controlled Selective Formation of Nitrido Technetium(V) Asymmetrical Heterocomplexes with Bidentate Ligand

Geometrically Controlled Selective Formation of Nitrido Technetium(V) Asymmetrical Heterocomplexes with Bidentate Ligands

Geometrically Controlled Selective Formation of Nitrido Technetium(V) Asymmetrical Heterocomplexes with Bidentate Ligand

New Approach to the Chemistry of Technetium(V) and Rhenium(V) Phenylimido Complexes: Novel [M(NPh)PNP]³⁺ Metal Fragments (M = Tc, Re; PNP = Aminodiphosphine) Suitable for the Synthesis of Stable Mixed-Ligand Compounds

Ligand-exchange reactions of the aminodiphosphine ligand bis[(2-diphenylphosphino)ethyl]amine hydrochloride (PNHP·HCl) with labile M(NPh)Cl3(PPh3)2 precursors (M = Re, Tc) in the presence of triethylamine yield monocationic phenylimido mer,cis-[M(NPh)Cl2(PNHP)]Cl (M = Re, 1; Tc, 2) intermediate complexes. X-ray analyses show that in both compounds the aminodiphosphine acts as a tridentate ligand dictating a mer,cis arrangement. Two chloride ligands, respectively in an equatorial and in the axial position trans to the linear M−NPh moiety, fill the remaining positions in a distorted-octahedral geometry. The chloride trans to the metal−imido core is labile, and is replaced by an alcoholate group, without affecting the original geometry, as established in mer,cis-[Re(NPh)(OEt)Cl(PNHP)]Cl 4. Otherwise, ligand-exchange reactions involving the aminodiphosphine bis[(2-diphenylphosphino)ethyl]methylamine (PNMeP), in which the central secondary amine has been replaced by a tertiary amine function, or its hydrochloride salt (PNMeP·HCl) give rise to three different species, depending on the experimental conditions:  fac,cis-[Re(NPh)Cl2(PNMeP)]Cl 3a, cis,fac-Re(NPh)Cl3(PNMeP)·HCl 3b, and mer,trans-[Re(NPh)Cl2(PNMeP)]Cl 3c, which are characterized in solution by multinuclear NMR studies. The monodentate groups incorporated in these intermediate compounds, either halides and/or ethoxide, undergo substitution reactions with bidentate donor ligands such as catechol, ethylene glycol, and 1,2-aminophenol to afford stable mixed ligand complexes of the type [M(NPh)(O,O-cat)(PNP)]Cl [PNP = PNHP M = Re 5, Tc 6; PNP = PNMeP M = Re 7], [Re(NPh)(O,O-gly)(PNP)]Cl [PNP = PNHP 8, PNMeP 9] and [Re(NPh)(O,N-ap)(PNMeP)]Cl 10. X-ray diffraction analyses of the representative compounds 5 and 8 reveal that the aminodiphosphine switches from the meridional to the facial coordination mode placing the heteroatom of the diphosphine trans to the phenylimido unit and the bidentate ligand in the equatorial plane. Solution-state NMR studies suggest an analogous geometry for 6, 7, 9, and 10. Comparison with similar mixed ligand complexes including the terminal nitrido group is discussed