两种新型99mTcN核标记的甲硝唑类乏氧显像剂的制备及生物性能评价

为研制新的肿瘤乏氧显像剂, 设计合成了2-(2-甲基-5-硝基咪唑基)乙基氨荒酸钾(MNIE-DTC)和4-(2-甲基-5-硝基咪唑基)丁基氨荒酸钾(MNIB-DTC)两种氨荒酸盐配体, 并制得了相应的99mTcN核配合物99mTcN(MNIE-DTC)2和99mTcN(MNIB-DTC)2. 所获得的两种99mTcN核配合物均为电中性, 具有较高的体外稳定性. 在荷乳腺癌的TA-2小鼠体内分布实验结果显示, 两种配合物均具有一定的肿瘤摄取, 给药1 h后, 99mTcN(MNIE-DTC)2和99mTcN(MNIB-DTC)2的肿瘤摄取率分别为(0.50±0.01)%ID/g和(0.64±0.10)%ID/g. 注入肼苯哒嗪后, 两种配合物的肿瘤摄取明显增高, 表明这两种配合物都具有对乏氧肿瘤的选择性.     

99mTc(CO)3-labeled pamidronate and alendronate for bone imaging

Bone scintigraphy with (99m)Technetium-methylenediphosphonate ((99m)Tc-MDP) or (99m)Technetium-hydroxymethylenediphosphonate ((99m)Tc-HMDP) presents several limitations, namely low specificity, uncertainty in the radiopharmaceutical's molecular structure and long acquisition time after injection. Aiming to find bone-seeking radiotracers based on the core fac-[(99m)Tc(CO)(3)](+) with improved chemical and biological properties, we synthesized new conjugates (pz-PAM and pz-ALN), comprising a pyrazolyl-diamine chelating unit (pz: N,N,N donor atom set) for metal stabilization and a pendant pamidronate (PAM) or alendronate (ALN) moiety for bone targeting. The reaction of the conjugates with fac-[(99m)Tc(CO)(3)](+) yielded (> 95%) the stable complexes fac-[(99m)Tc(CO)(3)(pz-PAM)](-) (2a) and fac-[(99m)Tc(CO)(3)(pz-ALN)](-) (3a), which have been characterized by comparing their HPLC gamma-traces with the UV-vis traces of the Re surrogates 2 and 3, respectively. 2a and 3a bind strongly onto hydroxyapatite. The biodistribution studies in Balb-c mice have shown that 2a and 3a presented an high bone uptake (2a 18.3 ± 0.6% I.D./g, 3a 17.3 ± 6.1% I.D./g, at 1 h post injection), similar to (99m)Tc-MDP (17.1 ± 2.4% I.D./g, at 1 h post injection), with comparable clearance from most tissues and increased total excretion (2a 66% I.D., 3a 67% I.D. and (99m)Tc-MDP 49% I.D., at 1 h post injection). The bone-to-blood (2a 86.2, 3a 74.7) and the bone-to-muscle ratios (2a 77.7, 3a 79.0) are higher than the ones found for (99m)Tc-MDP (70.9, 47.9), at 4 h post injection. Planar whole-body gamma camera images of the rats injected with the (99m)Tc(CO)(3)-labeled pamidronate (2a) and alendronate (3a) confirmed the overall adequate biological profile of the new radiotracers for bone imaging.     

New Bioconjugated Technetium and Rhenium Folates Synthesized by Transmetallation Reaction with Zinc Derivatives

The zinc dithiocarbamates functionalized with folic acid 2_Zn and 3_Zn were synthesized with a simple straightforward method, using an appropriated folic acid derivative and a functionalized zinc dithiocarbamate (1_Zn). Zinc complexes 2_Zn and 3_Zn show very low solubilities in water, making them useful for preparing Tc-99m radiopharmaceuticals with a potentially high molar activity. Thus, the transmetallation reaction in water medium between the zinc complexes 2_Zn or 3_Zn and the cation fac-[^99mTc(H₂O)₃(CO)₃]⁺, in the presence of the monodentate ligand TPPTS, leads to the formation of the 2 + 1 complexes fac-[^99mTc(CO)₃(SS)(P)] bioconjugated to folic acid (2_Tc and 3_Tc). In spite of the low solubility of 2_Zn and 3_Zn in water, the reaction yield is higher than 95%, and the excess zinc reagent is easily removed by centrifugation. The Tc-99m complexes were characterized by comparing their HPLC with those of the homologous rhenium complexes (2_Re and 3_Re) previously synthesized and characterized by standard methods. Preliminary in vivo studies with 2_Tc and 3_Tc indicate low specific binding to folate receptors. In summary, Tc-99m folates 2_Tc and 3_Tc were prepared in high yields, using a one-pot transmetallation reaction with low soluble zinc dithiocarbamates (>1 ppm), at moderate temperature, without needing a subsequent purification step.     

The Relationship Between Relative Hydration Free Energies of 99mTcON2S2 Complexes and Their Brain Uptakes

A thermodynamic integration dual-transform method was firstly applied to calculating the relative hydration free energies of ^99mTcON2S2 complexes. The relationship between the brain uptakes(B, U. ) of ^99mTcON2S2 complexes with different substituted functional groups and their relative hydration free energies was investigated. The simulation results show that the experiment brain uptake(B. U. ) data are strongly influenced by the relative hydration free energies of ^99mTcON2S2 complexes, thus the simulations can provide the useful information for the medicine design of ^99mTc brain imaging agents.     

The first nitro-substituted heteroscorpionate ligand

The new dihydridobis(3-nitro-1,2,4-triazolyl)borate ligand, [H2B(tzNO2)2]-, has been synthesized in dimethylacetamide solution, using 3-nitro-1,2,4-triazole and KBH4 through careful temperature control, and characterized as its potassium salt. The zinc(II) and cadmium(II) complexes, {M[H2B(tzNO2)2]Cl(H2O)2}, have been prepared by metathesis of [H2B(tzNO2)2]K with ZnCl2 and CdCl2, respectively. The complexes likely contain a metal core in which the ligand is coordinated to the metal ions in the K2-N,N' or K4-N,N',O,O' fashion. A single-crystal structural characterization is reported for the potassium dihydrobis(3-nitro-1,2,4-triazolyl)borate. The potassium salt is polymeric and shows several K...N and K...O interactions.     

Reactions of 3-nitro-1,2,4-triazoles with alkylating agents. 6*. Alkylation of a neutral heterocycle by alcohols in acid media*

Reaction of 3-nitro-1,2,4-triazole and 5-methyl-3-nitro-1,2,4-triazole with secondary and tertiary alcohols in conc. H₂SO₄ takes place at the N(2) atom. Alkylation by 2-propanol occurs regioselectively to form the 1-isopropyl-3-nitro-and 1-isopropyl-3-methyl-5-nitro-1,2,4-triazoles. As a consequence of isomerization the alkylation using cyclohexyl or tert-butyl alcohols gives respectively a mixture of regioisomers substituted at atom N(1) (1-cyclohexyl-3-nitro-and 1-cyclohexyl-5-methyl-3-nitro-1,2,4-triazoles) and at atom N(2) (5-nitro-1-cyclohexyl-and 1-cyclohexyl-3-methyl-5-nitro-1,2,4-triazoles) and, in the second case, to 1-tert-butyl-3-nitro-1,2,4-triazole. * For Communication 5 see [1]. Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 11, pp. 1680–1687, November, 2008.     

Technetium-99m complexes with steroid-2-aminooxyethyliminodiacetic acid conjugates

Conjugates of 2-aminooxyethyliminodiacetic acid with estrone, testosterone, epiandrosterone, 17-alpha-hydroxy-progesterone and progesterone were synthesized and their complexes with Tc-99m were successfully prepared in good yields, which indicated the agent to be promising for metal-labeling of biomolecules and related substances containing one or more carbonyl groups. The biodistribution and scintigraphic studies in mice bearing Ehrlich tumor and mammary tumor showed that the radioactivity accumulated considerably in the tumor tissues, but the tumor images were somewhat obscured.     

Synthesis and biological evaluation of novel technetium-99m-labeled HYNIC-d-glucose as a potential tumor imaging agent

A conjugate of 6-hydrazinopyridine-3-carboxylic acid (HYNIC) with the d-Glucosamine Hydrochloride (DG) was synthesized though a multiple-step reaction. HYNIC-DG could be labeled successfully and efficiently with ^99mTc using N-[2-hydroxy-1,1-bis(hydroxymethyl)ethyl]glycine (tricine) and ethylenediamine-N,N′-diacetic acid (EDDA) or tricine and triphenylphosphine-3,3′,3″-trisulfonic acid trisodium salt (TPPTS) as co-ligands to form two ^99mTc-HYNIC-DG complexes ^99mTc-(t/E)HYNIC-DG and ^99mTc-(t/T)HYNIC-DG in high yields (>95 %). The partition coefficient and electrophoresis results indicated they were very hydrophilic and electronegative. The biodistribution studies of two ^99mTc-HYNIC-DG complexes in Kunming mice bearing S 180 tumor showed that ^99mTc-(t/T)HYNIC-DG has more favorable characteristics than ^99mTc-(t/E)HYNIC-DG. High tumor uptake, low or negligible accumulation in non-target organs, and good retention, suggesting ^99mTc-(t/T)HYNIC-DG would be a novel potential tumor imaging agent.     

Technetium complexes with ligands of pharmacological interest

The synthesis and scintigraphic studies in rats of^99mTc-amino acid complexes containing the TcN multiple bond are reported. Chromatographic analysis shows the formation of a multicomponent system affected by tertiary phosphines employed as reducing agents of pertechnetate-99m in the systhesis of the complexes with cysteine (CYS) and cysteine ethyl ester (CYS-OEt), while no influence of them is observed in^99mTc-complexes having cysteamine (CSA) as ligand. Electrophoresis stresses a strong anionic character in all these compounds. It has not been possible to define their chemical identity by a comparison with the neutral technetium-99 nitrido complexes characterized by spectroscopic and X-ray crystallographic data due to the complexity of the^99mTc-system. These complexes are stable at 80 °C over a period of 2 hours. Time-activity curves indicate a renal tissue retention only for the^99mTc-(CSA) complexes.     

Paper chromatographic and paper elettrophoretic study of the solution chemistry of Tc-99m-methylendiphosphonate and of Tc-99m-dimercaptosuccinate for improving the tumour-affinity of Tc-99m during scintigraphic imaging of cancer

In order to find the conditions under which Tc-99m-methylenediphosphonate (Tc-99m-MDP) and Tc-99m(V)-dimercaptosuccinate (Tc-99m(V)-DMSA) may become tumour-seeking agents, leaving healthy organs free from the radionuclide uptake, the solution chemistry of these radiopharmaceuticals was studied by paper chromatography and paper electrophoresis in distilled water, in physiological saline, in NAHCO3, and ascorbic acid solutions. Both radiopharmaceuticals are anionic in the radiopharmaceutical solution but get easily hydrolysed to form cationic Tc-99m species which concentrates in healthy bone and in some bone metastases. Tc-99m (V)-DMSA being more stable remains long in the blood pool giving undesirable presence of the radionuclide in lung, heart and kidneys, in addition to its reduced uptake in bone metastases and in some primaries. We are trying to eliminate these drawbacks of healthy organ uptake of Tc-99-m(V)-DMSA not only to get a clean scintigraphic image of the tumour with this radiopharmaceutical but to extend its formulation, thus obtained, to prepare radiopharmaceutical with Re-188, which is the higher homologue of Tc-99m, for systemic therapy of cancer. Essentially similar solution chemistry of both radiopharmaceuticals suggests that like Tc-99m-MDP, technetium-99m-dimercaptosuccinate is also a complex of tetravalent Tc-99m and not of pentavalent Tc-99m as so far supposed to be.     

Picryl derivatives of 5-nitro-2,4-dihydro-3H-1,2,4-triazol-3-one

Treatment of 5-nitro-2,4-dihydro-3H-1,2,4-triazol-3-one ( 1 ) with picryl fluoride (PkF) in 1-methyl-2-pyrrolidinone (NMP) gave a mixture of a monopicryl and a dipicryl derivative of 1 in a ratio of 2 :1 , respectively, regardless of the initial concentrations of 1 and PkF. The products were identified as 5-nitro-2-picryl-2,4-dihydro-3H-1,2,4-triazol-3-one ( 2 ) by X-ray crystallography and 5-nitro-2,4-dipicryl-2,4-dihydro-3H-1,2,4-triazol-3-one ( 4 ) by ¹⁵N labeling experiments.     

α-Oxides in reaction with N-H acids of the heterocyclic series

Anumber of 1-methyl-4-(2-hydroxyalkyl)-3-nitro-1,2,4-triazol-5-ones and their derivatives were obtained by reaction of 1-methyl-3-nitro1,2,4-triazol-5-one with -epoxides. The fact of intramolecular nucleophilic substitution of the nitro group in hydroxy derivatives of 3-nitro-1,2,4-triazol-5-one with cyclization to 2-methyl-3-oxo-5,6-dihydrooxazolo[3,2-b]-1,2,4-triazoline was established.See [1] for communication III.Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 10, pp. 1407–1410, October, 1977.     

Nitraminomethylation of silylated polynitrogen heterocyclic compounds in nonaqueous solutions

Trimethylsilyloxy derivatives of 1,2,4-triazole, 3(5)-nitro-1,2,4-triazole, and tetrazole are inert toward 2-nitro-1-trimethylsilyloxy-2-azapropane, but they react with 1-chloro-2-nitro-2-azapropane to give the corresponding nitraminomethyl derivatives. Silyiated 1,2,4-triazole undergoes bis-nitraminomethylation to give a triazolium salt.Translated fromIzvestiya Akademii Nauk. Seriya Khimicheskaya, No. 9, pp. 1666–1668, September, 1993.     

Heterocyclic nitro compounds

A number of triazolylpropanones were synthesized by oxidation of 1-(2-hydroxypropyl)-3-nitro-5-R-1,2,4-triazoles obtained by condensation of 3-nitro-5-R-1,2,4-triazoles with propylene oxide. Similar triazolylbutanones were obtained by reaction of 3-nitro-5-R-1,2,4-triazoles with methyl vinyl ketone.See [1] for communication XIX.Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 7, pp. 991–994, July, 1976.     

Synthesis and properties of energetic salts based on 3-nitro-5-nitroimino-1,2,4-oxadiazole

A series of 3-nitro-5-nitroimino-1,2,4-oxadiazole-based energetic salts were synthesized from 3-nitro-5-nitroimino-1,2,4-oxadiazole anion and nitrogen-rich cations. They were fully characterized by IR,elemental analysis and NMR spectroscopy. The structure of triaminoguanidinium salt(1-e) was confirmed by single crystal X-ray diffraction. All salts showed good thermal stability with decomposed temperature ranging from 155 8C to 258 8C, and positive heats of formation from 226.0 k J/mol to554.1 k J/mol. Thus, the theoretic detonation pressure was predicted from 28.70 GPa to 37.60 GPa and velocities from 8526 m/s to 9354 m/s. Among them, guanidinium salt(1-c) exhibited both high decomposition temperature(258 8C) and detonation velocity(9319 m/s).     

Reactions of 3-nitro-1,2,4-triazoles with alkylating agents. 3. Alkylation of a neutral heterocycle by diethyl sulfate

The reaction of 3-nitro-5-R-1,2,4-triazoles with diethyl sulfate gives 1-ethyl-3-R-5-nitro-, 4-ethyl-3-nitro-5-R-1,2,4-triazoles, 1,4-diethyl-, 1,4-diethyl-3-methyl-1,2,4-triazol-5-ones, and 1,4-diethyl-3-nitro-5-R-1,2,4-triazolium salts. When compared with the use of dimethyl sulfate as alkylating agent the ethylation products have a markedly increased fraction of triazolones (up to 30–37%) and a somewhat lowered yield of nitrotriazolium salts (up to 6–10%). The reaction time is increased by an order. __________ Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 9, pp. 1378–1381, September, 2006.     

α-Oxides in reactions with N-H acids of the heterocyclic series

The reaction of epoxides with 3-nitro-5-bromo-1,2,4-triazole gave a series of 1-(β-hydroxyalkyl)-3-nitro-5-bromo-1,2,4-triazoles, which, under the influence of bases, undergo intramolecular cyclization with HBr elimination to give an ew heterocyclic system — 2-nitro-5,6-dihydrooxazolo[2,3-e]-1,2,4-triazole.     

Heterocyclic nitro compounds. 26. Reaction of 1-substituted 3,5-dinitro-1,2,4-triazoles with anions of heterocyclic NH acids

1-Substituted 3-nitro-5-(N-azolyl)-1,2,4-triazoles mixed with 1-substituted 3-nitro-1,2,4-triazol-5-ones are obtained in the reaction of 1-substituted 3,5-dinitro-1,2,4-triazoles with anions of heterocyclic NH acids (1,2,4-triazole, 1,2,3-triazole, pyrazole, benzotriazole, benzimidazole, and indazole derivatives). 1-Methyl-3-nitro-5-amino-1,2,4-triazole is formed instead of the expected 5-tetrazolyl derivative in the reaction of 1-methyl-3,5-dinitro-1,2,4-triazole with tetrazole in alkaline media. See [1] for communication 25. Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 2, pp. 257–261, February, 1980.     

Synthesis and structure of new ditopic ligands containing tetrazole and 3-nitro-1,2,4-triazole fragments

Alkylation of 3-nitro-1,2,4-triazole with haloalkyltetrazoles has afforded in high yields previously unknown 1-[2-(3-nitro-1H-1,2,4-triazol-1-yl)ethyl]-1H-tetrazole and 2-tert-butyl-5-(3-nitro-1H-1,2,4-triazol-1-ylmethyl)-2H-tetrazole. The molecular and crystal structure of these compounds has been established by X-ray diffraction analysis (XRD).     

Cu K-edge EXAFS on copper(I) complexes containing dihydridobis(3-nitro-1,2,4-triazol-1-yl)borate and bis(1,2,4-triazol-1-yl)acetate ligand: Evidence for the Cu–O interaction

X-ray absorption spectroscopy (XAS) has been used to probe the local structure of copper(I) complexes containing the dihydridobis(3-nitro-1,2,4-triazol-1-yl)borate and the bis(1,2,4-triazol-1-yl)acetate ligands. The material is polycrystalline and no crystal structure is available in the literature. The EXAFS analysis has permitted the identification of the local environment of the copper site. Copper is found to be 4-fold coordinated with two sets of Cu–N and Cu–P interactions describing a quasi planar figure. An additional coordination is revealed for the copper(I) complex of bis(1,2,4-triazol-1-yl)acetate due to the interaction of the copper with the acetate of the scorpionate ligand. XANES spectra of the studied samples show a resolved pre-edge peak at about 8983 eV which is assigned to the 1s → 4p transition, whose intensities can be explained considering the copper in a 4-fold coordination.