A new [2 + 1] mixed ligand concept based on [99(m)Tc(OH2)3(CO)3]+: a basic study

Mixed ligand fac-tricarbonyl complexes of the general formula [M(L1)(L2)(CO)3](M = Re, 99(m)Tc, L1= imidazole, benzyl isocyanide, L2 = 1H-imidazole-4-carboxylic acid, pyridine-2,4-dicarboxylic acid, pyridine-2,5-dicarboxylic acid) have been prepared starting from the precursors [M(OH2)3(CO)3]+. The complexes can be obtained in good yield and purity in a two-step procedure by first attaching the bidentate ligand followed by addition of the monodentate. 99mTc compounds can also be prepared at the tracer level in one-pot procedures with L1 and L2 being concomitantly present. This [2 + 1] approach allows the labeling of bioactive molecules containing a monodentate or a bidentate donor site. Examples given in here are N-(tert-butoxycarbonyl)glycyl-N-(3-(imidazol-1-yl)propyl)phenylalaninamide, 5-((3-(imidazol-1-yl)propyl)aminomethyl)-2'-deoxyuridine and 4-(5-isonitrilpentyl)-1-(2-methoxyphenyl)-piperazine as L1 and N-((6-carboxypyridine-3-yl)methyl)glycylphenylalanine as L2. The corresponding second ligand can be used to influence the physico-chemical properties of the conjugate. The crystal structures of [99Tc(OH2)(imc)(CO)3], [Re(OH2)(2,4-dipic)(CO)3], [Re(bic)(2,4-dipic)(CO)3] and [Re(im)(2,5-dipic)(CO)3] are reported.     

Pyridine-tert-nitrogen-phenol ligands: N,N,O-Type tripodal chelates for the [M(CO)3]+ core (M = Re, Tc)

The design rationale, synthesis, and preliminary radiolabeling evaluation of new N,N,O-type pyridyl- tert-nitrogen-phenol ligands for the [M(CO) 3] (+) core, where M = (99m)Tc or Re, are described. The capability of the ligands to bind this technetium core is initially demonstrated by using the cold surrogate [Re(CO) 3] (+). NMR studies of the relevant rhenium tricarbonyl complexes indicate the formation of either a monomeric or a possible dimeric complex with each phenolic O atom bridging between two metal centers. Labeling with [ (99m)Tc(CO) 3] (+) provided further insight into the differences in complex formation on the dilute, no carrier added, level compared to the macroscopic scale at which the Re (I) counterparts were made. These new tridentate, monoanionic ligands are competent chelates in binding the [ (99m)Tc(CO) 3] (+) core because radiolabeling yields ranged from 85 to 99% and the resulting complexes were stable to cysteine and histidine challenges for as long as 24 h.     

Thiol- and thioether-based bifunctional chelates for the {M(CO)3}+ core (M = Tc, Re)

By analogy to the recently described single amino acid chelate (SAAC) technology for complexation of the {M(CO)3}+ core (M = Tc, Re), a series of tridentate ligands containing thiolate and thioether groups, as well as amino and pyridyl nitrogen donors, have been prepared: (NC5H4CH2)2NCH2CH2SEt (L1); (NC5H4CH2)2NCH2CH2SH (L2); NC5H4CH2N(CH2CH2SH)2 (L3); (NC5H4CH2)N(CH2CH2SH)(CH2CO2R) [R = H (L4); R = -C2H5 (L5). The {Re(CO)3}+ core complexes of L1-L5 were prepared by the reaction of [Re(CO)3(H2O)3]Br or [NEt4]2[Re(CO)3Br3] with the appropriate ligand in methanol and characterized by infrared spectroscopy, 1H and 13C NMR spectroscopy, mass spectrometry, and in the case of [Re(CO)3(L2)] (Re-2) and [Re(CO)3(L1)Re(CO)3Br2] (Re-1a) by X-ray crystallography. The structure of Re-2 consists of discrete neutral monomers with a fac-Re(CO)3 coordination unit and the remaining coordination sites occupied by the amine, pyridyl, and thiolate donors of L2, leaving a pendant pyridyl arm. In contrast, the structure of Re-1a consists of discrete binuclear units, constructed from a {Re(CO)3(L1)}+ subunit linked to a {Re(CO)3Br2}- group through the sulfur donor of the pendant thioether arm. The series of complexes establishes that thiolate donors are effective ligands for the {M(CO)3}+ core and that a qualitative ordering of the coordination preferences of the core may be proposed: pyridyl nitrogen approximately thiolate > carboxylate > thioether sulfur > thiophene sulfur. The ligands L1 and L2 react cleanly with [99mTc(CO)3(H2O)3]+ in H2O/DMSO to give [99mTc(CO)3(L1)]+ (99m)Tc-1) and [99mTc(CO)3(L2)] (99mTc-2), respectively, in ca. 90% yield after HPLC purification. The Tc analogues 99mTc-1 and 99mTc-2 were subjected to ligand challenges by incubating each in the presence of 1000-fold excesses of both cysteine and histidine. The radiochromatograms showed greater than 95% recovery of the complexes.     

Very small and soft scorpionates: water stable technetium tricarbonyl complexes combining a bis-agostic (k(3)-H, H, S) binding motif with pendant and integrated bioactive molecules

The novel trihydro(mercaptoazolyl)borates Na[H(3)B(tim(Me))] (L(1)) (tim(Me) = 2-mercapto-1-methylimidazolyl), Na[H(3)B(tim(Bupip))] (L(2)) (tim(Bupip) = 1-[4-((2-methoxyphenyl)-1-piperazinyl)butyl]-2-mercaptoimidazolyl), and Na[H(3)B(bzt)] (L(3)) (bzt = 2-mercaptobenzothiazolyl) were synthesized by reaction of NaBH(4) with the corresponding azole. Ligands L(1)-L(3) represent a new class of light and soft scorpionates that stabilizes the [M(CO)(3)](+) core (M = (99)Tc, Re) by formation of the complexes fac-[M{kappa(3)-H(mu-H)(2)B(tim(Me))}(CO)(3)] (M = (99)Tc (1), Re (2)), fac-[Re{kappa(3)-H(mu-H)(2)B(tim(Bupip))}(CO)(3)] (3), and fac-[Re{kappa(3)-H(mu-H)(2)B(bzt)}(CO)(3)] (4), respectively. The soft scorpionates are coordinated to the metal in unique (kappa(3)-H, H', S) fashion, as confirmed by X-ray crystallography of 1, 2, and 4. These complexes with bis-agostic hydride coordination are formed in aqueous solution with the two hydrides replacing two coordinating aquo ligands. The agostic hydrogen atoms were located directly, confirming an unprecedented donor atom set combining one sulfur and two hydrogen atoms. Preliminary studies have shown the possibility of preparing some of these complexes at the no carrier added level ((99m)Tc), under conditions as required in radiopharmaceutical preparation. Due to their lipophilicity, small-size, and easy functionalization with adequate biomolecules, the trihydro(mercaptoazolyl)borate technetium tricarbonyl complexes are suitable for the design of CNS receptor ligand radiopharmaceuticals as exemplified with 3, comprising a pendant serotonergic 5-HT(1A) ligand. The integrated design of radiopharmaceuticals involving a bis-agostic scorpionate ligand is demonstrated by the synthesis of 4, with an integrated benzothiazolyl fragment for the recognition of beta-amyloid plaques.     

Curcumin as the OO bidentate ligand in "2 + 1" complexes with the [M(CO)3]+ (M = Re, 99mTc) tricarbonyl core for radiodiagnostic applications

The synthesis and characterization of "2 + 1" complexes of the [M(CO)(3)](+) (M = Re, (99m)Tc) core with the β-diketones acetylacetone (complexes 2, 8) and curcumin (complexes 5, 10 and 6, 11) as bidentate OO ligands, and imidazole or isocyanocyclohexane as monodentate ligands is reported. The complexes were synthesized by reacting the [NEt(4)](2)[Re(CO)(3)Br(3)] precursor with the β-diketone to generate the intermediate aqua complex fac-Re(CO)(3)(OO)(H(2)O) that was isolated and characterized, followed by replacement of the labile water by the monodentate ligand. All complexes were characterized by mass spectrometry, NMR and IR spectroscopies, and elemental analysis. In the case of complex 2, bearing imidazole as the monodentate ligand, X-ray analysis was possible. The chemistry was successfully transferred at (99m)Tc tracer level. The curcumin complexes 5 and 6, as well as their intermediate aqua complex 4, that bear potential for radiopharmaceutical applications due to the wide spectrum of pharmacological activity of curcumin, were successfully tested for selective staining of β-amyloid plaques of Alzheimer's disease. The fact that the complexes maintain the affinity of the mother compound curcumin for β-amyloid plaques prompts for further exploration of their chemistry and biological properties as radioimaging probes.     

(S)-(2-(2'-Pyridyl)ethyl)cysteamine and (S)-(2-(2'-pyridyl)ethyl)-d,l-homocysteine as ligands for the "fac-[M(CO)(3)](+)" (M = Re, (99m)Tc) core

The reaction of fac-[NEt(4)](2)[Re(CO)(3)Br(3)] with (S)-(2-(2'-pyridyl)ethyl)cysteamine, L(1), in methanol leads to the formation of the cationic fac-[Re(CO)(3)(NSN)][Br] complex, 1, with coordination of the nitrogen of the pyridine, the sulfur of the thioether, and the nitrogen of the primary amine. When fac-[NEt(4)](2)[Re(CO)(3)Br(3)] reacts with the homocysteine derivative (S)-(2-(2'-pyridyl)ethyl)-d,l-homocysteine, L(2), the neutral fac-Re(CO)(3)(NSO) complex, 2, is produced with coordination of the nitrogen of the primary amine, the sulfur of the thioether, and the oxygen of the carboxylate group, while the pyridine ring remains uncoordinated. The analogous technetium-99m complexes, 1' and 2', were also prepared quantitatively by the reaction of L(1) and L(2) with the fac-[(99m)Tc(CO)(3)(H(2)O)(3)](+) precursor at 70 degrees C in water. Given that both (S)-(2-(2'-pyridyl)ethyl)cysteamine and homocysteine can be easily N- or S-derivatized by a bioactive molecule of interest, both the NSN or NSO ligand systems could be used to develop target-specific radiopharmaceuticals for diagnosis and therapy.     

N-(2-Mercaptoethyl)picolylamine as a diaminomonothiolate ligand for the "fac-[Re(CO)3]+" core

N-(2-Mercaptoethyl)picolylamine (MEPAH) was studied as a potentially biologically relevant ligand for the "fac-[M(CO)(3)](+)" core (M = Re, (99)Tc, (99m)Tc). To this end, the complex Re(CO)(3)(MEPA) was synthesized. The reaction of MEPAH with fac-[Re(CO)(3)(MeCN)(3)](+) took place over the course of seconds, showing the high affinity possessed by this ligand for the "fac-[Re(CO)(3)](+)" core. A single-crystal X-ray diffraction study was performed confirming the nature of Re(CO)(3)(MEPA), a rare mononuclear rhenium(I) thiolate complex. Additional exploration into derivatization of the ligand backbone has afforded the analogous N-ethyl complex, Re(CO)(3)(MEPA-NEt). The high affinity of the ligand for the metal coupled with the ease of its derivatization implies that utilization of this ligand system for the purposes of (99m)Tc-radiopharmaceutical development is promising.     

Cell-specific and nuclear targeting with [M(CO)(3)](+) (M=(99m)Tc, Re)-based complexes conjugated to acridine orange and bombesin

Receptor-specific nuclear targeting requires trifunctional metal complexes. We have synthesized [M(L(2)-pept)(L(1)-acr)(CO)(3)] (pept=peptide; acr=acridine-based agent) in which the fac-[M(CO)(3)](+) moiety (1st function, M=(99m)Tc, Re) couples an acridine-based nuclear-targeting agent (2nd function, L(1)-acr) and the specific cell-receptor-binding peptide bombesin (3rd function, L(2)-pept). The metal-mediated coupling is based on the mixed ligand [2+1] principle. The nuclear targeting agents have been derivatised with an isocyanide group for monodentate (L(1)) and bombesin (BBN) with a bidentate ligand (L(2)) for complexation to fac-[M(CO)(3)](+). For nuclear uptake studies, the model complexes [Re(L(2))(L(1)-acr)(CO)(3)] (L(2)=pyridine-2-carboxylic acid and pyridine-2,4-dicarboxylic acid) were synthesized and structurally characterized. We selected acridine derivatives as nuclear-targeting agents, because they are very good nucleus-staining agents and exhibit strong fluorescence. Despite the bulky metal complexes attached to acridine, all [Re(L(2))(L(1)-acr)(CO)(3)] showed high accumulation in the nuclei of PC3 and B16F1 cells, as evidenced by fluorescence microscopy. For radiopharmaceutical purposes, the (99m)Tc analogues have been prepared and radioactivity distribution confirmed the fluorescence results. Coupling of BBN to L(2) gave the receptor-selective complexes [M(L(2)-BBN)(L(1)-acr)(CO)(3)]. Whereas no internalization was found with B16F1 cells, fluorescence microscopy on PC3 cells bearing the BBN receptor showed high and rapid uptake by receptor-mediated endocytosis into the cytoplasm, but not into the nucleus.     

Carboranes as ligands for the preparation of organometallic Tc and Re Radiopharmaceuticals. Synthesis of [M(CO)(3)(eta-2,3-C(2)B(9)H(11))](-) and rac-[M(CO)(3)(eta-2-R-2,3-C(2)B(9)H(10))](-) (M = Re, (99)Tc; R = CH(2)CH(2)CO(2)H) from [M(CO)(3)Br(3)](2-)

A new and high yielding method for the synthesis of [M(CO)(3)(eta(5)-2,3-C(2)B(9)H(11))](-) and the bifunctional metal complexes, rac-[M(CO)(3)(eta(5)-2-R-2,3-C(2)B(9)H(10))](-) (R = CH(2)CH(2)CO(2)H), from [M(CO)(3)Br(3)](2)(-) (M = Re, (99)Tc) was developed. The general approach entailed the addition of nido-[(C(2)B(9)H(12))(-)], or the acid substituted analogue, to [M(CO)(3)Br(3)](2)(-) (M = Re, (99)Tc) in the presence of TlOEt in THF. It was also possible to prepare the reported products in water using sodium carbonate in place of TlOEt. The reported approach led to the preparation, and X-ray crystallographic structure determination, of the first Tc-carborane complex reported to date (a = 13.606(17) A, b = 10.685(13) A, c = 15.534(16) A, alpha = gamma = 90 degrees, beta = 111.84(2) degrees). Because of the stabilities of the metal complexes, and the fact that the compounds can be prepared in water, the bifunctional derivatives can be considered as novel synthons for the preparation of organometallic (99m)Tc and (186/188)Re radiopharmaceuticals.     

Microwave-assisted synthesis of organometallic complexes of ⁹⁹mTc(CO)₃ and Re(CO)₃: its application to radiopharmaceuticals

(99m)Tc-tricarbonyl [(99m)Tc(CO)(3)] complexes have been conventionally synthesized by heating [(99m)Tc(CO)(3)(H(2)O)(3)](+) and a tridentate chelating ligand under atmospheric pressure; however, this method is poor in terms of chemical yield and reproducibility. Moreover, since the half-life of (99m)Tc is very short (6 h), the development of facile and rapid methods of synthesizing (99m)Tc-labeled compounds, which could be used as radioactive tracers for single photon emission computed tomography (SPECT), is required. Thus, we initiated a study on the application of a microwave reaction to the synthesis of (99m)Tc(CO)(3)-2-picolylamine monoacetic acid (PAMA) [(99m)Tc(CO)(3)-PAMA] complexes on the basis of the fact that synthesis of metal complexes proceeds rapidly by microwave irradiation owing to an efficient exothermic phenomenon and heat conduction effect. Formation of by-products could be markedly suppressed by comparison with that in conventional methods. In the present study, rhenium (Re), an element belonging to the same group in the periodic table as technetium (Tc), and which also forms bipyramidal complexes, was first used to investigate the synthetic reaction because no stable isotopes exist for Tc. As a result, when water was used as the solvent under the irradiation of microwaves within 1 min, the Re(CO)(3)-PAMA complex could be directly synthesized from ethyl ester of PAMA (PAMAEE) and [Re(CO)(3)(H(2)O)(3)]Br in one step and with a high yield (94%). Finally, the (99m)Tc(CO)(3)-PAMA complex was successfully synthesized at a high radiochemical yield (>99%) within 1 min of reaction using (99m)Tc instead of Re under the same conditions.     

Trifunctional 99mTc based radiopharmaceuticals: metal-mediated conjugation of a peptide with a nucleus targeting intercalator

The development of molecular imaging agents with multiple functions has become a major trend in radiopharmaceutical chemistry. We present herein the syntheses of trifunctional compounds, combining an acridine orange (AO) based intercalator with a GRP receptor specific bombesin like peptide (BBN). Metal-mediated conjugation of these two functions via the [2 + 1] approach to the third function, the [M(CO)(3)](+) (M = (99m)Tc, Re) moiety, yielded the final trifunctional molecules. The strongly fluorescent acridine orange, a nuclear targeting agent, has been derivatised with 4-imidazolecarboxylate as a bidentate ligand and bombesin with an isonitrile group as a monodentate ligand. For cell and nuclear uptake studies, [Re(L(1)-BBN)(L(2)-Ical)(CO)(3)] type complexes were synthesized and characterized. For radiopharmaceutical purposes, the (99m)Tc analogues have been prepared in a stepwise synthesis. Fluorescence microscopy studies on PC-3 cells, bearing the BBN receptor, showed high and rapid uptake into the cytoplasm. For the bifunctional molecule, lacking the BBN peptide, no internalization was observed.     

Characterization of 99mTc(CO)3-iminodiacetic acid (IDA) and its comparison with 99mTc-(IDA)2 using compounds for hepatobiliary scintigraphy

The organometallic precursor of fac-[^99mTc(CO)₃(H₂O)₃]⁺ has attracted much attention because of the robustness and small size of Tc(I)-tricarbonyl complexes compared to Tc(V) complexes and the good labeling affinity with a variety of donor atoms. Among various ligand systems, an iminodiacetic acid (IDA) was proven as a good chelating group to form a Tc(III)-compelx as well as has been shown its potential as a chelating system for fac-[^99mTc(CO)₃] precursor. In an attempt to confirm the similarity and the difference between ^99mTc(CO)₃-IDA and ^99mTc-(IDA)₂-complex, M(CO)₃-IDA (M = ^99mTc, Re) complexes of disofenin, mebrofenin and N-(3-iodo-2,4,6-trimethyl phenylcarbamoylmethyl) iminodiacetic acid were prepared, and the biological evaluation of ^99mTc(CO)₃-disofenin was performed. The ^99mTc(CO)₃-IDA complexes were prepared with a high radiolabeling yield (>98%) in a quantitative manner and showed a negative charge. The in vivo pharmacokinetic behavior of ^99mTc(CO)₃-disofenin showed a similar biological activity to ^99mTc-(disofenin)₂ in that those complexes were quickly cleared from the blood by the hepatocytes and excreted into the gallbladder and intestine. Accordingly, the ^99mTc(CO)₃-IDA derivatives of disofenin and mebrofenin might be used as hepatobiliary imaging agents. Since an IDA is a promising chelator for ^99mTc-based radiopharmaceutical and the biological properties of ^99mTc(CO)₃-IDA derivative shows similar to that of ^99mTc-complex, a biomolecule containing IDA can be freely radiolabeled with fac-[^99mTc(CO)₃]-precursor or ^99mTc. However, the radiolabeling efficiency and the biological behavior demonstrates the favorable properties of ^99mTc(CO)₃-IDA compound for the development of a new imaging agent.     

Iron oxide-filled micelles as ligands for fac-[M(CO)3]+ (M = (99m)Tc, Re)

Magnetite-filled micelles capture fac-[M(OH(2))(3)(CO)(3)](+) complexes (M = (99m)Tc, Re), creating versatile self-assembled constructs for multimodal SPECT/MR/optical imaging and radiopharmaceutical guided delivery.     

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 x 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 x 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) x 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.     

Syntheses and reactivity of 'sulfur rich' Re(iii) and Tc(iii) complexes containing trithioperoxybenzoate, dithiobenzoate and dithiocarbamate ligands

Reduction-substitution reactions of [M(O)Cl(4)](-)(M=Re, (99)Tc) precursors with an excess of substituted dithiobenzoate ligands (R-PhCS(2))(-) in dichloromethane/methanol mixtures afford a series of six-coordinated neutral mixed-ligand complexes of the type M(III)(R-PhCS(3))(2)(R-PhCS(2))(M=Re; Rel--9; M=99)Tc; Tel--9). The coordination sphere is entirely filled by sulfur donor atoms, and the complexes adopt a distorted trigonal prismatic arrangement, as assessed by the X-ray crystal structure analysis of Re(4-Me-PhCS(3))(2)(4-Me-PhCS(2)), Re 2. These compounds show sharp proton and carbon NMR profiles, in agreement with the diamagnetism typical of low spin d(4) trigonal prismatic configurations. The red-ox processes involve reduction of the metal from Re(v) to Re(iii) and oxidation of dithiobenzoate to trithioperoxybenzoate. M2--9 complexes contain a substitution-inert [M(R-PhCS(3))(2)](+) moiety including the metal and two trithioperoxybenzoate fragments, while the third dithiobenzoate ligand is labile. The latter is efficiently replaced by reaction with better nucleophiles such as diethyldithiocarbamate giving a further class of mixed ligand complexes of the type M(III)(R-PhCS(3))(2)(Et(2)NCS(2))(M=Re; Re 10--18; M=(99)Tc; Tc--18), which retain the trigonal prismatic arrangement, as determined by the X-ray analyses of the representative compounds Re(PhCS(3))(2)(Et(2)NCS(2)), Re 10 and (99)Tc(PhCS(3))(2)(Et(2)NCS(2)), Tc 10.     

[M(CO)2(NO)], a new core in bioorganometallic chemistry: model complexes of [Re(CO)2(NO)] and [Tc(CO)2(NO)]

In this study selected bidentate (L²) and tridentate (L³) ligands were coordinated to the Re(I) or Tc(I) core [M(CO)₂(NO)]²⁺ resulting in complexes of the general formula fac-[MX(L²)(CO)₂(NO)] and fac-[M(L³)(CO)₂(NO)] (M = Re or Tc; X = Br or Cl). The complexes were obtained directly from the reaction of [M(CO)₂(NO)]²⁺ with the ligand or indirectly by first reacting the ligand with [M(CO)₃]⁺ and subsequent nitrosylation with [NO][BF₄] or [NO][HSO₄]. Most of the reactions were performed with cold rhenium on a macroscopic level before the conditions were adapted to the n.c.a. level with technetium (^99mTc). Chloride, bromide and nitrate were used as monodentate ligands, picolinic acid (PIC) as a bidentate ligand and histidine (HIS), iminodiacetic acid (IDA) and nitrilotriacetic acid (NTA) as tridentate ligands. We synthesised and describe the dinuclear complex [ReCl(μ-Cl)(CO)₂(NO)]₂ and the mononuclear complexes [NEt₄][ReCl₃(CO)₂(NO)], [NEt₄][ReBr₃(CO)₂(NO)], [ReBr(PIC)(CO)₂(NO)], [NMe₄][Re(NO₃)₃(CO)₂(NO)], [Re(HIS)(CO)₂(NO)][BF₄], [⁹⁹Tc(HIS)(CO)₂(NO)][BF₄], [^99mTc(IDA)(CO)₂ (NO)] and [^99mTc(NTA)(CO)₂(NO)]. The chemical and physical characteristics of the Re and Tc-dicarbonyl-nitrosyl complexes differ significantly from those of the corresponding tricarbonyl compounds.     

Novel carbohydrate-appended metal complexes for potential use in molecular imaging

Seven discrete sugar-pendant diamines were complexed to the {M(CO)(3)}(+) ((99m)Tc/Re) core: 1,3-diamino-2-propyl beta-D-glucopyranoside (L(1)), 1,3-diamino-2-propyl beta-D-xylopyranoside (L(2)), 1,3-diamino-2-propyl alpha-D-mannopyranoside (L(3)), 1,3-diamino-2-propyl alpha-D-galactopyranoside (L(4)), 1,3-diamino-2-propyl beta-D-galactopyranoside (L(5)), 1,3-diamino-2-propyl beta-(alpha-D-glucopyranosyl-(1,4)-D-glucopyranoside) (L(6)), and bis(aminomethyl)bis[(beta-D-glucopyranosyloxy)methyl]methane (L(7)). The Re complexes [Re(L(1)-L(7))(Br)(CO)(3)] were characterized by (1)H and (13)C 1D/2D NMR spectroscopy which confirmed the pendant nature of the carbohydrate moieties in solution. Additional characterization was provided by IR spectroscopy, elemental analysis, and mass spectrometry. Two analogues, [Re(L(2))(CO)(3)Br] and [Re(L(3))(CO)(3)Br], were characterized in the solid state by X-ray crystallography and represent the first reported structures of Re organometallic carbohydrate compounds. Conductivity measurements in H(2)O established that the complexes exist as [Re(L(1)-L(7))(H(2)O)(CO)(3)]Br in aqueous conditions. Radiolabelling of L(1)-L(7) with [(99m)Tc(H(2)O)(3)(CO)(3)](+) afforded in high yield compounds of identical character to the Re analogues. The radiolabelled compounds were determined to exhibit high in vitro stability towards ligand exchange in the presence of an excess of either cysteine or histidine over a 24 h period.     

Synthesis and characterization of organometallic rhenium(І) and technetium(І) bile acid complexes

Eight bile acid derivatives have been synthesized with alkyl chains of various length based tridentate ligand chelating system. These derivatives have been reacted with the precursor [Et₄N]₂[Re(CO)₃Br₃] and fac-[M(CO)₃(H₂O)₃]⁺ (M = ^99mTc, Re) in ethanol or ethanol–aqueous media to form water-soluble and stable organometallic complexes in good yields. ¹H NMR, ¹³C NMR, IR and elemental analysis or HRMS spectroscopic analyses confirmed the tridentate complexation of the metal–tricarbonyl fragment exclusively via the tridentate chelates. In addition, the corresponding radioactive technetium-99m complexes were prepared successfully and challenged for stability in physiological phosphate buffer at 37 °C for 24 h. No decomposition of the complexes could be detected under the condition proving the stability of these complexes.     

Exploring the nitrosyl-approach: “Re(CO)2(NO)”- and “Tc(CO)2(NO)”-complexes provide new pathways for bioorganometallic chemistry

Nitrosylation reactions are rare in the context of low valent Re(I)- and Tc(I)-tricarbonyl complexes so far. We herein describe a method for the conversion of a “M(CO)₃-moiety” (M = Re, Tc) into a dicarbonyl-nitrosyl moiety “M(CO)₂NO”, the synthesis of important precursor complexes and intermediates and possible applications for this new kind of Re- and Tc-chemistry.The behavior of the complex [ReCl₃(CO)₂(NO)]⁻ in water was studied in detail and compared to that of [ReCl₃(CO)₃]²⁻. Contrary to the conversion of [ReCl₃(CO)₃]²⁻ to the mixed aquo-carbonyl complex [Re(OH₂)₃(CO)₃]⁺ in water, one chloride remains initially bound to the metal center in the dicarbonyl-nitrosyl complex, making [ReCl(OH₂)₂(CO)₂(NO)]⁺ the main species for further reactions. In this context, we isolated and characterized the complex [Re(μ₃-O)(CO)₂(NO)]₄. Examples of complexes with different bi- and tridentate ligands based on ReCl₃(CO)₂(NO)]⁻ are discussed.For the development of potential new radiopharmaceuticals we also adapted the nitrosylation technique to the n.c.a. level with ^99mTc. [^99mTc(OH₂)₃(CO)₃]⁺ served as starting material to form a ^99mTc(CO)₂(NO)-core. Labelling reactions with ligands such as iminodiacetic acid (IDA), nitrilotriacetic acid (NTA) and diethylenetriamine pentaacetic acid (DTPA) were performed, resulting in the complexes [^99mTc(IDA)(CO)₂(NO)], [^99mTc(NTA)(CO)₂(NO)] and [^99mTc(DTPA)(CO)₂(NO)]. In this way, the “nitrosyl-approach” adds a new and challenging synthetic tool to the already established organometallic chemistry of Re- and Tc-tricarbonyl complexes.     

fac-[Re(CO)(3)L](+) complexes with N-CH(2)-CH(2)-X-CH(2)-CH(2)-N tridentate ligands. synthetic, X-ray crystallographic, and NMR spectroscopic investigations

Polyamine ligands (L) have excellent binding characteristics for the formation of fac-99mTc(CO)3-based radiopharmaceuticals. Normally, these L are elaborated so as to leave pendant groups designed to impart useful biodistribution characteristics to the fac-[99mTc(CO)3L] imaging agent. Our goal is to lay a foundation for understanding the features of the bound elaborated ligands by using the fac-[Re(CO)3L]-analogue approach with the minimal prototypical ligands, diethylenetriamine (dien) or simple dien-related derivatives. Treatment of the fac-[Re(CO)3(H2O)3]+ cation with such triamine (NNN) ligands afforded fac-[Re(CO)3L]+ complexes. Ligand variations included having a central amine thioether donor, thus allowing X-ray crystallographic and NMR spectroscopic comparisons of fac-[Re(CO)3L]+ complexes with NNN and NSN ligands. fac-[Re(CO)3L]+ complexes with two terminal exo-NH groups exhibit unusually far upfield exo-NH NMR signals in DMSO-d6. Upon the addition of Cl-, these exo-NH signals move downfield, while the signals of any endo-NH or central NH groups move very little. This behavior is attributed to the formation of 1:1 ion pairs having selective Cl- hydrogen bonding to both exo-NH groups. Base addition to a DMSO-d6 solution of meso-exo-[Re(CO)3(N,N',N'-Me3dien)]PF6 led to isomerization of only one NHMe group, producing the chiral isomer. The meso isomer did not form. The [Re(CO)3(N,N,N',N',N'-pentamethyldiethylenetriamine)]triflate.[Re(CO)3(mu3-OH)]4.3.35H2O crystal, the first structure with a fac-[Re(CO)3L] complex cocrystallized with this well-known cluster, provided parameters for a bulky NNN ligand and also reveals CO-CO interlocking intermolecular interactions that could stabilize the crystal.