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1.
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.  相似文献   

2.
Mixed ligand fac-tricarbonyl complex of [99mTc(CO)3-DMSA-MIBI] has been prepared starting from the precursor [99mTc(OH2)3(CO)3]+. The complex can be obtained in good yield and purity in a two-step procedure by first attaching meso-2,3-dimercaptosuccinic acid (DMSA, HOOCCH(SH)CH(SH)COOH) with [99mTc(OH2)3(CO)3]+, followed by addition of MIBI [tetrakis-2-methoxyisobutylisonitrile (CH3OC(CH3)2CH2-N≡C) copper(I) tetrafluoroborate] solution. The complex was characterized by TLC and HPLC and was studied by means of octanol-water partition coefficient, electrophoresis, stability in vitro, and normal mice experiment. Biodistribution in mice demonstrated that the complex showed higher myocardial uptake after 0.5-hour p.i. The ratios of heart/liver (%ID/g) in the case of 99mTc(CO)3-DMSA-MIBI was higher (1.88) than that observed in case of 99mTc-MIBI1 (0.93) after 0.5-hour p.i. (P<0.05). Results showed that the complex may be developed to a novel myocardial perfusion-imaging agent.  相似文献   

3.
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.  相似文献   

4.
We describe reactions of [99mTc(H2O)3(CO)3)]+ (1) with Diels-Alder products of cyclopentadiene such as “Thiele’s acid” (HCp-COOH)2 (2) and derivatives thereof in which the corresponding [(Cp-COOH)99mTc(CO)3)] (3) complex did form in water. We propose a metal mediated Diels-Alder reaction mechanism. To show that this reaction was not limited to carboxylate groups, we synthesized conjugates of 2 (HCp-CONHR)2 (4a-c) (4a, R = benzyl amine; 4b, R = Nα-Boc-l-2,3-diaminopropionic acid and 4c, R = glycine). The corresponding 99mTc complexes [(4a)99mTc(CO)3)] 6a, [(4b)99mTc(CO)3)] 6b and [(4c)99mTc(CO)3)] 6c have been prepared along the same route as for Thiele’s acid in aqueous media demonstrating the general applicability of this synthetic strategy. The authenticity of the 99mTc complexes on the no carrier added level have been confirmed by chromatographic comparison with the structurally characterized manganese or rhenium complexes.Studies of the reaction of 1 with Thiele’s acid bound to a solid phase resin demonstrated the formation of [(Cp-COOH)99mTc(CO)3)] 3 in a heterogeneous reaction. This is the first evidence for the formation of no carrier added 99mTc radiopharmaceuticals containing cyclopentadienyl ligands via solid phase syntheses. Macroscopically, the manganese analogue 5a and the rhenium complexes 5b-c have been prepared and characterized by IR, NMR, ESI-MS and X-ray crystallography for 5a (monoclinic, P21/c, a = 9.8696(2) Å, b = 25.8533(4) Å, c = 11.8414(2) Å, β = 98.7322(17)°) in order to unambiguously assign the authenticity of the corresponding 99mTc complexes.  相似文献   

5.
Dirk Rattat 《Tetrahedron letters》2006,47(27):4641-4645
Derivatives of ethylenediamine-N-acetic acid (EDAA = N-aminoethylglycine = AEG) and ortho-phenylenediamine-N-acetic acid (PDAA) with uncharged substituents on one or both of the amines form neutral complexes with a [99mTc(CO)3]+-moiety. We studied the influence of different modifications at the amines (e.g., with methyl, ethyl, butyl or benzyl groups) on the behaviour of the 99mTc(CO)3-complexes in vivo in mice, with special focus on blood-brain barrier (BBB) passage. The complexes have been characterised by reversed phase HPLC, log P, electrophoresis and some of them also by LC-MS. Log P values of the 99mTc-tricarbonyl complexes varied from −0.52 (AEG) to 2.5 (N,N′-dibenzyl-EDAA). With increasing lipophilicity, more of the activity was found in liver and intestines as compared to kidneys and urine for the more polar complexes. Brain uptake was found for the 99mTc(CO)3-complexes with N,N′-dibutyl-ethylenediamine-N-acetic acid (0.34% of I.D. after 2 min) and ortho-phenylenediamine-N-acetic acid (0.22% of I.D. after 2 min).  相似文献   

6.
The synthesis and structural characterization of the neutral rhenium complex fac-[Re(NSO)(CO)3], Re-1, where (NSO) is a tridentate bifunctional chelating agent, 3-(carboxymethylthio)-3-(1H-imidazol-4-yl)propanoic acid (1), is presented. The complex crystallized from methanol–water and its structure was assigned by IR and 1H, 13C NMR spectroscopies and X-ray crystallography. Furthermore, the analogous technetium complex fac-[99mTc(NSO)(CO)3], 99mTc-1, was synthesized in high yield by reacting ligand 1 with the fac-[99mTc(OH2)3(CO)3]+ precursor for 30 min at 85 °C. The tracer complex was found to be more than 95% stable in the L-histidine challenge experiment. Our data indicate that the bifunctional NSO chelating agent 1 can be successfully applied for the development of potential 99mTc-radiopharmaceuticals.  相似文献   

7.
Conventional 99mTc-radiopharmaceuticals for the detection of tumor hypoxia generally possess a single nitroimidazole moiety. Herein, we report the synthesis and evaluation of a 99mTc-complex with three-nitroimidazole moieties in an attempt to improve hypoxic cell detection. Isocyanide derivative of metronidazole (MetroNC) was synthesized and subsequently radiolabeled with [99mTc(CO)3(H2O)3]+ precursor complex, wherein the three labile water molecules were replaced with MetroNC ligand to form a pseudo-octahedral [99mTc(CO)3(MetroNC)3]+ complex. Analysis of corresponding Re(CO)3-analog prepared in macroscopic scale confirmed the formation of expected complex. Cyclic voltammetric studies of [Re(CO)3(MetroNC)3]+ complex showed no significant change in single-electron reduction potential (SERP) of MetroNC ligand (??0.96 V) upon forming the [Re(CO)3(MetroNC)3]+ complex (??0.90 V). In vitro studies in Chinese hamster ovary (CHO) cells showed three-fold preferential accumulation of [99mTc(CO)3(MetroNC)3]+ complex in hypoxic cells over normoxic cells. Biodistribution studies of [99mTc(CO)3(MetroNC)3]+ complex in Swiss mice bearing fibrosarcoma tumor showed tumor uptake and steady retention till 60 min post injection. Present study constitutes a novel design approach towards development of a 99mTc-radiopharmaceutical for hypoxia imaging application, which could be extended to other potential nitroimidazole ligands.  相似文献   

8.
The over-expression of folate receptors in variety of neoplastic tissues makes radiolabeled folate conjugates potential agents for imaging and therapy of such cancers. With the aim of preparing an imaging agent for targeting folate receptors, folic acid has been conjugated with homocysteine for complexation with [99mTc(CO)3(H2O)3]+ core. The radiolabeled complex of the homocysteine-folate could be obtained in >95% radiochemical yield as observed by HPLC. Stability of complex in saline was studied and challenge studies with histidine and cysteine revealed kinetic stability of the complex. Lipophilicity of the radiolabeled complex (log P) was found to be 0.45. In vitro uptake of 99mTc(CO)3-labeled folic acid derivative was studied in KB cells and inhibition studies were carried out using 3H-folic acid and cold homocysteine–folate conjugate. The in vitro studies indicated loss of binding affinity of the derivative towards folate receptors.  相似文献   

9.
To develop potential new Tc radiopharmaceuticals, a novel compound [99mTc(CO)2(NO)(EHIDA)]0 (EHIDA: 2,6-diethylphenylcarbamoylmethyliminodiacetic acid) has been prepared by reacting [99mTc(CO)3)(EHIDA)] with NOBF4 both in water and acetonitrile. The conversion of [99mTc(CO)3)(EHIDA)] to [99mTc(CO)2(NO)(EHIDA)]0 was supported by TLC, HPLC and eletrophoresis. The radiochemical purity (more than 99%) was proved by TLC and HPLC. The biodistribution in mice demonstrated that [Tc(CO)2(NO)(EHIDA)]0 showed higher uptake in blood, kidney and lung (15 min, blood: 19.24±2.95; kidney: 13.61±3.49; lung: 10.81±1.09.) but a lower uptake in liver (15 min, 5.73±0.74). The slower clearances (120 min, blood: 12.75±1.34; kidney: 13.61±3.49) from blood and kidney were also found. This research describes two methods for the conversion of [99mTc(CO)3]+ into [99mTc(CO)2)(NO)]2+ by using NOBF4 as the source of NO+ both in organic solvent and water. The latter method offers the possibility to introduce the NO-group in high yield in water.  相似文献   

10.
This study reports the synthesis, radiolabeling and preliminary biodistribution results of [99mTc(CO)3(MN-TZ-BPA)]+ in tumor-bearing mice. The novel nitroimidazole derivative was successfully synthesized by conjugation of bis(pyridin-2-ylmethyl)amine (BPA) to 2-methyl-5-niroimidazole via “click” reaction. The ligand could be labeled by [99mTc(CO)3]+ core in high yield to get [99mTc(CO)3(MN-TZ-BPA)]+, which was very hydrophilic and was stable at room temperature. Biodistribution studies in tumor-bearing mice showed that [99mTc(CO)3(MN-TZ-BPA)]+ accumulated in the tumor with certain initial uptake while poor retention. The rapid clearance from normal organs with favorable tumor/muscle ratios warrants further research to improve tumor targeting efficacy and pharmacokinetic profile of radiolabeled nitroimidazoles by structural modification.  相似文献   

11.
Summary The organometallic precursor fac-[99mTc(CO)3(H2O)3]+ was reacted with N-ethoxy, N-ethyl dithiocarbamate (NOET) in phosphate buffered saline (pH 7.4) at room temperature for 30 minutes to produce the 99mTc(CO)3-NOET complex. The radiochemical purity (RCP) of the product was over 90% as measured by thin layer chromatography (TLC). No decomposition of the complex at room temperature (RT) was observed over a period of 6 hours. Its partition coefficient indicated that it was a lipophilic complex. The biodistribution comparison in mice of the 99mTc(CO)3-NOET complex and the 99mTcN-NOET complex showed that the former had a lower heart and brain uptake as compared to that of the latter, suggesting the incorporation of the [99mTc(CO)3]+ core into the NOET ligand does not improve the biological features as a myocardial imaging agent.  相似文献   

12.
A novel quinoline derivative, 2,2′-[(5-chloro-8-hydroxyquinoline-7-yl) methylazanediyl] diacetic acid (CHQMADA) was labeled with 99mTc using SnCl2·2H2O as a reducing agent to give a complex with a labeling yield 94 %. Also [99mTc(H2O)3(CO)3]+ was prepared by heating at 100 °C for 30 min using 2 mg CHQMADA at pH 8 to give a labeling yield >99 %. 99mTc-(CO)3 CHQMADA and 99mTc-Sn(II)-CHQMADA showed tissue uptake (target to non target T/NT = 6.80 ± 0.22) and (T/NT = 5.65 ± 0.34) respectively in Escherichia coli induced infection, which is higher than the commercially available 99mTc-ciprofloxacin (T/NT = 3.80 ± 0.80). In conclusion, both complexes were able to differentiate between septic and aseptic inflammation with superiority of [99mTc-(CO)3 CHQMADA].  相似文献   

13.
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.  相似文献   

14.
A novel electrochemical process to avail clinical grade 99mTc from (n,γ)99Mo has been demonstrated. The electrochemical parameters were optimized to maximize the 99mTc yield with minimal 99Mo contamination. 99Mo/99mTc generators containing up to 29.6 GBq (800 mCi) 99Mo were developed and their performance were extensively evaluated for 10 days without changing the operating conditions. Very high radioactive concentration of 99mTcO4 of acceptable quality, commensurate with hospital radiopharmacy requirements could be availed from the system with >90% yield. The compatibility of the product for the formulation of 99mTc labeled radiopharmaceuticals such as 99mTc-DMSA and 99mTc-EC was found to be satisfactory in terms of high labeling yields. The proposed route represents an important step for enhancing the scope of accessing clinical grade 99mTc from low specific activity (n, γ)99Mo.  相似文献   

15.
The reaction of [NEt4]2[Re(CO)3Br3] with equimolar amount of a tridentate NSO ligand in methanol leads to the formation of neutral tricarbonyl rhenium(I) complexes of the general formula Re(CO)3(NSO), where the NSO ligand is o-C5H4N-CH2CH2-S-CH2CH(NHCOCH3)COOH (L1H), complex 1 or o-C5H4N-CH2CH2-S-C(CH3)2CH(NHCOCH3)COOH (L2H), complex 2. Both complexes have been characterized by elemental analysis and spectroscopic methods, while complex 2 has also been characterized by X-rays analysis. At technetium-99m level, the corresponding fac-[99mTc(CO)3(NSO)] complexes 3 and 4, were obtained in high yield by reacting ligands L1H or L2H with the fac-[99mTc(CO)3(H2O)3]+ precursor in water. Their structure was established by chromatographic comparison to the prototype rhenium complex using high-performance liquid chromatographic techniques.  相似文献   

16.
A PNA monomer containing thymine as nucleobase (1) was synthesized, characterized and coupled to the pyrazolyl containing ligand 3,5-Me2pz(CH2)2N((CH2)3COOH)(CH2)2NHBoc (2) and to a modified cysteine S-(carboxymethyl-pentafluorphenyl)-N-[(trifluor)carbonyl]-l-cysteine methyl ester (3) yielding the bifunctional chelators 6 and 7, respectively. Reactions of 6 and 7 with the Re(I) tricarbonyl starting material [Re(CO)3(H2O)3]Br afforded the complexes fac-[Re(CO)33-6)]+ (8) and fac-[Re(CO)33-7)] (9), respectively. The identity of 8 and 9 has been established based on IR spectroscopy, elemental analysis, ESI-MS spectrometry and HPLC. The multinuclear NMR spectroscopy (1H, 13C, g-COSY, g-HSQC) has also been very informative in the case of complex 8, showing the presence of rotamers in solution. For 9 the NMR spectrum was too complex due to the presence of rotamers and diastereoisomers. The radioactive congeners of complexes 8 and 9, fac-[99mTc(CO)33-6)]+ (8a) and fac-[99mTc(CO)33-7)] (9a), have been prepared by reacting the precursor fac-[99mTc(CO)3(H2O)3]+ with the corresponding ligands being their identity established by comparing their HPLC chromatograms with the HPLC of the rhenium surrogates.  相似文献   

17.
This work reports the synthesis, radiolabeling and preliminary biodistribution results in tumor-bearing mice of 99mTc(CO)3-labeled pegylated (PEG) 2-nitroimidazoles for tumor hypoxia imaging. The novel 2-nitroimidazole derivatives were successfully synthesized by conjugation of tridendate chelators to 2-nitroimidazole via PEG3 linker. Radiolabeling was performed in high yield with [99mTc(CO)3]+ core to get cationic [99mTc(CO)3(BPA-PEG3-NIM)]+, neutral [99mTc(CO)3(AOPA-PEG3-NIM)] and anionic [99mTc(CO)3(IDA-PEG3-NIM)]? respectively, all of which were hydrophilic and stable at room temperature. Biodistribution studies in tumor-bearing mice showed that 99mTc(CO)3-labeled pegylated 2-nitroimidazoles accumulated in the tumor with low uptake. 99mTc-chelate and charge had significant impact on partition coefficient, radiotracer tumor uptake and pharmacokinetic properties. The results indicate the need for synthetic modification of the parent 2-nitroimidazole derivatives and the 99mTc-chelate with a view to improve the tumor targeting efficacy and in vivo kinetic profiles.  相似文献   

18.
The 99mTc(CO)3(H2O)-DEDT complex was prepared by a two-step procedure involving the preparation of the precursor fac-[99mTc(CO)3(H2O)3]+, followed by the addition of sodium salt of diethyl dithiocarbamate (DEDT). The radiochemical purity (RCP) of the product was over 90% as measured by thin layer chromatography (TLC). No decomposition of the complex at room temperature was observed over a period of 6 hours. Its partition coefficient indicated that it was a lipophilic complex. The electrophoresis results showed the complex was neutral. Biodistribution in mice demonstrated that the complex can penetrate the intact blood-brain barrier (BBB) and the brain uptake (ID%/g) was 4.22 at 5-minute post-injection, suggesting the complex may lead to a further development of the radiopharma ceutical as a brain perfusion tracer.  相似文献   

19.
The confirmation that N-substituted imidodiacetic acids, as small and simple ligand systems containing amines and carboxylic acids, could be coordinated to the tricarbonyl core and form inert complexes with [99mTc (CO)3(H2O)3]+, is demonstrated. The HPLC quality control results of 99mTc-carbonyl tagged IDA molecules, performed by gradient HPLC, have shown that HIDA, EHIDA and p-butyl-IDA form complexes with [99mTc(CO)3(H2O)3]+, with a labeling yield of ~90% for each of 99mTc(CO)3 IDA derivatives. However, the changes in the structure of labeled compounds, e.g., EHIDA, influence the changes in the biological behavior. In comparison with 99mTc-EHIDA, the biliary excretion of 99mTc(CO)3 EHIDA was lower, but the urinary excretion higher. This revised version was published online in July 2006 with corrections to the Cover Date.  相似文献   

20.
In this study we have compared different ligands containing three or more hetero-atoms (N, O and/or S) with respect to their ability to form tridentate complexes with a Tc-tricarbonyl moiety. Comparison of each ligand in a competition reaction with histidine first and then with each other compound allowed to rank the ligands according to their ability of complex formation with the [99mTc(CO)3]+ precursor from diethylenetriamine (most efficient of the studied ligands) to nitrilotriacetic acid (weakest complexing properties). The results provide insight in the structural requirements for the formation of stable Tc-tricarbonyl complexes and suggest preferred combinations and arrangements of the hetero-atoms involved in the complex formation. They also give a good indication which type of ligand is most appropriate to modify biomolecules for an efficient and stable labelling with a Tc-tricarbonyl moiety.  相似文献   

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