共查询到20条相似文献,搜索用时 31 毫秒
1.
Kieffer DM Cleynhens BJ Vanbilloen HP Rattat D Terwinghe CY Mortelmans L Bormans GM Verbruggen AM 《Bioorganic & medicinal chemistry letters》2006,16(2):382-386
A new tropane derivative was synthesized by combining a tridentate ligand, N-(2-picolylamine)-N-acetic acid (2-PAA), and a phenyltropane derivative. It was labelled with a [(99m)Tc(CO)(3)](+) moiety, resulting in the formation of two stable and neutral lipophilic isomers. Their identity was confirmed using radio-LC-MS. In normal mice, no brain uptake was observed for any of the isomers and in vitro autoradiography using mouse brain sections showed no specific uptake in the striatal area. 相似文献
2.
Xin Chen Meng-Chao Cui Winnie Deuther-Conrad Ying-Feng Tu Teng Ma Ying Xie Bing Jia Yan Li Fang Xie Xia Wang Jörg Steinbach Peter Brust Bo-Li Liu Hong-Mei Jia 《Bioorganic & medicinal chemistry letters》2012,22(20):6352-6357
We report the design, synthesis and biological evaluation of a novel 99mTc 4-(4-cyclohexylpiperazine-1-yl)-butan-1-one-1-cyclopentadienyltricarbonyl technetium ([99mTc]5) as a potential SPECT tracer for imaging of σ2 receptors in tumors. [99mTc]5 was prepared in 25 ± 5% isolated radiochemical yield with radiochemical purity of >99% via double-ligand transfer (DLT) reaction from the ferrocene precursor 2b (4-(4-cyclohexylpiperazine-1-yl)-1-ferrocenylbutan-1-one). The corresponding Re-complex 4 and the ferrocenyl complex 2b showed relatively high affinity towards σ2 receptors in in vitro competition binding assay (Ki values of 4 and 2b were 64.4 ± 18.5 nM and 43.6 ± 21.3 nM, respectively) and moderate to high selectivity versus σ1 receptors (Kiσ1/Kiσ2 ratios were 12.5 and 95.5, respectively). The log D value of [99mTc]5 was determined to be 2.52 ± 0.33. Biodistribution studies in mice revealed comparably high initial brain uptake of [99mTc]5 and slow washout. Administration of haloperidol 5 min prior to injection of [99mTc]5 significantly reduced the radiotracer uptake in brain, heart, lung, and spleen by 40–50% at 2 h p.i.. Moreover, [99mTc]5 showed high uptake in C6 glioma cell lines (8.6%) after incubation for 1 h. Blocking with haloperidol to compete with [99mTc]5 significantly reduced the cell uptake. Preliminary blocking study in C6-brain-tumor bearing rats showed that [99mTc]5 binds to σ receptors in the brain-tumor specifically. These results are encouraging for further exploration of 99mTc-labeled probes for σ2 receptor tumor imaging in vivo. 相似文献
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《International journal of radiation applications and instrumentation. Part B, Nuclear medicine and biology》1992,19(4):481-489
The synthesis, radiochemical analysis and biological characteristics of some 1,8-diamine-3,6-dithiaoctane derivatives labelled with Tc-99m are reported. Analysis by HPLC shows that most of the 99mTc-chelates are multicomponent. Furthermore, almost all 99mTc-complexes isolated by HPLC are lipophilic and stable in vitro. The biodistributions of the most lipophilic of these complexes were evaluated in mice. The N-morpholinylethyl and N,N'′-bisalicylyl derivatives of 1,8-diamine-3,6-dithiaoctane yielded 99mTc-complexes which exhibit considerable uptake and retention in organs of interest, such as the heart and the brain. 相似文献
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Junbo Zhang Shijian Zhang Haixun Guo Xuebin Wang 《Bioorganic & medicinal chemistry letters》2010,20(12):3781-3784
The ciprofloxacin dithiocarbamate (CPFXDTC) was radiolabeled with [99mTc(CO)3(H2O)3]+ intermediate to form the 99mTc(CO)3–CPFXDTC complex in high yield. The 99mTc(CO)3–CPFXDTC complex was characterized by HPLC and its stability in serum was studied. Its partition coefficient indicated that it was a lipophilic complex. The bacterial binding efficiency of 99mTc(CO)3–CPFXDTC was almost the same as that of 99mTcN–CPFXDTC, and was higher than that of 99mTc–ciprofloxacin. Biodistribution results in induced infection mice showed 99mTc(CO)3–CPFXDTC had higher uptake at the sites of infection and better abscess/blood and abscess/muscle ratios than those of 99mTc–ciprofloxacin and 99mTcN–CPFXDTC. Single photon emission computed tomography (SPECT) static imaging study in infected rabbits demonstrated the uptake in the left thigh infection lesion was observable, while no accumulation in the right thigh muscle was found. These results suggested 99mTc(CO)3–CPFXDTC would be a promising candidate for further evaluation as infection imaging agent. 相似文献
7.
André Luís Branco de Barros Valbert Nascimento Cardoso Luciene das Graças Mota Ricardo José Alves 《Bioorganic & medicinal chemistry letters》2010,20(1):315-317
Three carbohydrate derivatives, MAG3-Gl, MAG3-Ga, MAG3-NG, were synthesized and radiolabeled in high yields. These substances were injected in health Swiss mice and their biodistribution were evaluated. Among them, 99mTc-MAG3-Ga displayed higher accumulation in hepatic tissue, due to the presence of specific receptors in the liver for this carbohydrate. Thus, the use of 99mTc-MAG3-Ga to assess hepatic function can be considered. 相似文献
8.
Cappelli A Mancini A Sudati F Valenti S Anzini M Belloli S Moresco RM Matarrese M Vaghi M Fabro A Fazio F Vomero S 《Bioconjugate chemistry》2008,19(6):1143-1153
Potential receptor imaging agents based on Tc-99m for the in vivo visualization of the peripheral benzodiazepine receptor (PBR) have been designed on the basis of the information provided by the previously published structure-affinity relationship studies, which suggested the existence of tolerance to voluminous substituents in the receptor area interacting with 3-position of the quinoline nucleus of 2-quinolinecarboxamides 5. In the first step of the investigation, the stereoelectronic features of the above-indicated receptor area were also probed by means of 4-phenyl-3-[(1-piperazinyl)methyl]-2-quinolinecarboxamide derivatives bearing different substituents on the terminal piperazine nitrogen atom (compounds 6a-f). The structure-affinity relationship data confirmed the existence of a tolerance to bulky lipophilic substituents and stimulated the design of bifunctional ligands based on the 4-phenyl-3-[(1-piperazinyl)methyl]-2-quinolinecarboxamide moiety (compounds 6h,j,k,m). The submicromolar PBR affinity of rhenium complexes 6j,m suggests that the presence of their metal-ligand moieties with encaged rhenium is fairly compatible with the interaction with the PBR binding site. Thus, in order to obtain information on the in vivo behavior of these bifunctional ligands, (99m)Tc-labeled compounds 6h,k were synthesized and evaluated in preliminary biodistribution and single photon emission tomography (SPET) studies. The results suggest that both tracers do not present a clear preferential distribution in tissues rich in PBR, probably because of their molecular dimensions, which may hamper both the intracellular diffusion toward PBR and the interaction with the binding site. 相似文献
9.
《International journal of radiation applications and instrumentation. Part B, Nuclear medicine and biology》1992,19(8):831-840
The binding of 99mTc to negatively-charged and neutral unilamellar lipid vesicles was investigated in the absence and presence of the ligand diethylenetriaminepentaacetic acid (DTPA) covalently attached to the headgroup of phosphatidylethanolamine at the surface of the membrane. Even in the absence of DTPA on the membrane surface, 99mTc reduced by Sn bound to the membrane surface but rapidly dissociated from the vesicles in the presence of plasma in vitro. When DTPA was present on the membrane surface, dissociation of 99mTc from the vesicle surface in plasma was much reduced. The dissociation of 99mTc from the surface of negatively-charged vesicles was less than for neutral vesicles in the absence of ligand but was markedly greater than for vesicles containing the ligand DTPA, suggesting that the binding of 99mTc to vesicles with surface-attached DTPA could not be explained solely on the basis of the negative charge provided by the DTPA. In vitro experiments using 14C-labeled lipids as well as in vivo imaging studies indicated that dissociation of 99mTc from the surface of the vesicle did not arise predominantly because of lipid exchange with plasma components or due to cleavage of Tc-DTPA from the vesicle surface. For vesicles with surface-attached DTPA, 99mTc dissociation from the vesicle surface in plasma was further reduced by addition of the antioxidant ascorbate. 相似文献
10.
Novel organometallic 99mTc(I)-folate derivatives have been synthesized and evaluated in vitro and in vivo in order to assess the influence of the overall charge of the radioconjugates and the spacer entity on the affinity and pharmacokinetic profile. Folic acid has been functionalized at the gamma-carboxylate group of the glutamate moiety with (i) a hydrophilic diethoxyethyl spacer bearing a picolylamine monoacetic acid chelate, (ii) a hexyl spacer bearing an iminodiacetic acid chelate, and (iii) a hexyl spacer with a bis(pyridylmethyl)amine chelating system. Coordination of the 99mTc(CO)3-core resulted in neutral complex 21, anionic complex 22, and cationic complex 23 in excellent yields (>90%) at ligand concentrations of 10(-4) M. Complexes 21-23 were HPLC purified for in vitro and in vivo experiments. In the case of 23, separation from the unlabeled folate analogue was incomplete, leading to low specific activity and, hence, significantly inferior in vivo uptake in folate-receptor-positive (FR-positive) organs and tissues (tumors and kidneys). Time dependent in vivo studies were performed in female, athymic nude mice bearing subcutaneous FR-positive human KB cell xenografts at 1, 4, and 24 h post injection (p.i.) of the radiotracers. Tumor uptake ranged between 1.9-2.7% ID/g, 4 h p.i. and 1.6-2.2% ID/g, 24 h p.i. for 21 and 22, and 0.9% ID/g, 4 h p.i. and 1.1% ID/g, 24 h p.i. for 23. Blood clearance was fast for all derivatives (< or =0.2% ID/g 1 h p.i.). Significant fractions of radioactivity were found in nontargeted and FR-negative organs and tissues (particularly in the liver and the intestines/intestinal contents) at early time points p.i. Coadministration of folic acid reduced radioactivity in FR-positive tissues and organs to background levels. In conclusion, overall charge and the nature of the spacer entity seemed to have a relatively minor influence on receptor affinity and the in vivo pharmacokinetic profile of the tested radiofolates. 相似文献
11.
Stable one-step technetium-99m labeling of His-tagged recombinant proteins with a novel Tc(I)-carbonyl complex. 总被引:3,自引:0,他引:3
R Waibel R Alberto J Willuda R Finnern R Schibli A Stichelberger A Egli U Abram J P Mach A Plückthun P A Schubiger 《Nature biotechnology》1999,17(9):897-901
We have developed a technetium labeling technology based on a new organometallic chemistry, which involves simple mixing of the novel reagent, a 99m Tc(I)-carbonyl compound, with a His-tagged recombinant protein. This method obviates the labeling of unpaired engineered cysteines, which frequently create problems in large-scale expression and storage of disulfide-containing proteins. In this study, we labeled antibody single-chain Fv fragments to high specific activities (90 mCi/mg), and the label was very stable to serum and all other challenges tested. The pharmacokinetic characteristics were indistinguishable from iodinated scFv fragments, and thus scFV fragments labeled by the new method will be suitable for biodistribution studies. This novel labeling method should be applicable not only to diagnostic imaging with 99mTc, but also to radioimmunotherapy approaches with 186/188 Re, and its use can be easily extended to almost any recombinant protein or synthetic peptide. 相似文献
12.
1-(4-Nitroimidazole-1-yl)-propanhydroxyiminoamide (N4IPA) was synthesized. The biodistribution of 99mTc-N4IPA in mice bearing S180 tumor demonstrated that the complex showed accumulation in tumor and slow clearance from it. The tumor-to-tissue uptake ratios increase with time. These results suggest that 99mTc-N4IPA would be a marker for imaging tumor hypoxia. 相似文献
13.
Wen-Yi Chang Hao-Wen Kao Hsin-Ell Wang Jenn-Tzong Chen Wuu-Jyh Lin Shyh-Jen Wang Chuan-Lin Chen 《Bioorganic & medicinal chemistry letters》2013,23(23):6486-6491
Two galactose derivatives, a monovalent 99mTc-MAMA-MGal galactoside and a divalent 99mTc-MAMA-DGal galactoside, were synthesized and radiolabeled in high radiochemical purity (>98%). Dynamic microSPECT imaging and biodistribution study of two traces in normal and liver fibrosis mice showed that the 99mTc-MAMA-DGal revealed higher specific binding to asialoglycoprotein receptors in liver and then rapidly excreted via both hepatobiliary system and renal clearance. The results suggest that 99mTc-MAMA-DGal may be used as SPECT probes for noninvasive evaluation of asialoglycoprotein receptor-related liver dysfunction. 相似文献
14.
A Boschi C Bolzati E Benini E Malagò L Uccelli A Duatti A Piffanelli F Refosco F Tisato 《Bioconjugate chemistry》2001,12(6):1035-1042
A new labeling approach for incorporating bioactive peptides into a technetium-99m coordination complex is described. This method exploits the chemical properties of the novel metal-nitrido fragment [99mTc(N)(PXP)]2+, composed of a terminal Tc[triple bond] N multiple bond bound to an ancillary diphosphine ligand (PXP). It will be shown that this basic, molecular building block easily forms in solution as the dichloride derivative [99mTc(N)(PXP)Cl2], and that this latter complex selectively reacts with monoanionic and dianionic, bidentate ligands (YZ) having soft, pi-donor coordinating atoms to afford asymmetrical nitrido heterocomplexes of the type [99mTc(N)(PXP)(YZ)]0/+ without removal of the basic motif [99mTc(N)(PXP)]2+. The reactions of the amino acid cysteine was studied in detail. It was found that cysteine readily coordinates to the metal fragment [99mTc(N)(PXP)]2+ either through the [NH2, S-] pair of donor atoms or, alternatively, through the [O-, S-] pair, to yield the corresponding asymmetrical complexes in very high specific activity. Thus, these results were conveniently employed to devise a new, efficient procedure for labeling short peptide sequences having a terminal cysteine group available for coordination to the [99mTc(N)(PXP)]2+ fragment. Examples of the application of this novel approach to the labeling of the short peptide ligand H-Arg-Gly-Asp-Cys-OH (H(2)1) and of the peptidomimetic derivative H-Cys-Val-2-Nal-Met-OH (H2) will be discussed. 相似文献
15.
Synthesis and biological evaluation of EC20: a new folate-derived, (99m)Tc-based radiopharmaceutical
Leamon CP Parker MA Vlahov IR Xu LC Reddy JA Vetzel M Douglas N 《Bioconjugate chemistry》2002,13(6):1200-1210
A new peptide derivative of folic acid was designed to efficiently coordinate (99m)Tc. This new chelate, referred to as EC20, was found to bind cultured folate receptor (FR)-positive tumor cells in both a time- and concentration-dependent manner with very high affinity (K(D) approximately 3 nM). Using an in vitro relative affinity assay, EC20 was also found to effectively compete with (3)H-folic acid for cell binding when presented either alone or as a formulated metal chelate. Following intravenous injection into Balb/c mice, (99m)Tc-EC20 was rapidly removed from circulation (plasma t(1/2) approximately 4 min) and excreted into the urine in a nonmetabolized form. Data from gamma scintigraphic and quantitative biodistribution studies performed in M109 tumor-bearing Balb/c mice confirmed that (99m)Tc-EC20 predominantly accumulates in FR-positive tumor and kidney tissues. These results suggest that (99m)Tc-EC20 may be clinically useful as a noninvasive radiodiagnostic imaging agent for the detection of FR-positive human cancers. 相似文献
16.
Zhang Y Chu T Gao X Liu X Yang Z Guo Z Wang X 《Bioorganic & medicinal chemistry letters》2006,16(7):1831-1833
1-(3-1,2,4-Nitrotriazole-1-yl)-propanhydroxyiminoamide and 1-(6-nitrobenzoimidazole-1-yl)-propanhydroxyiminoamide were synthesized and radiolabeled with (99m)Tc. The (99m)Tc labeled complexes continuously accumulated in hypoxic murine sarcoma S180 cells in vitro but not in aerobic cells. Biodistribution results in mice bearing S180 tumor indicated that the tracers could localize in tumor and eliminate from it slowly. These results suggested that the (99m)Tc labeled nitrobenzoimidazole and nitrotriazole might be the novel tumor hypoxia markers. 相似文献
17.
Three deoxyglucose (DG) derivatives, S-DG, MAG(3)-DG and MAMA-BA-DG, were synthesized and labeled successfully with high labeling yields and high radio-chemical purities. Biodistribution in tumor-bearing mice demonstrated that these three new (99m)Tc-deoxyglucose derivatives showed accumulation in tumor and high tumor-to-muscle ratios. Among them, the (99m)Tc-MAG(3)-DG showed the best characteristics as a potential tumor marker for single photon emission computed tomography (SPECT). 相似文献
18.
Synthesis of a diaminedithiol bifunctional chelating agent for incorporation of technetium-99m into biomolecules 总被引:1,自引:0,他引:1
The synthesis of a bifunctional chelating agent (BCA), 1, based on the diaminedithiol (DADT) ligand system, is described. The six-step synthetic sequence has been accomplished in 16% overall yield, affording 1, which contains a thiolactone as a reactive moiety, which permits direct coupling to nucleophiles without the formation of byproducts. The reactivity of 1 toward benzylamine and subsequent labeling of the ligand with technetium-99m has been evaluated as a model for preparation of various bioconjugates. Both coupling and exchange labeling occur in high yield under mild conditions, and competition reactions with diethylenetriaminepentaacetic acid (DTPA) indicate the superior stability of the technetium-99m-DADT complex. Preparation of BCA 1 thus provides a new avenue into technetium-labeled radiopharmaceuticals. 相似文献
19.
Korde A Satpati D Mathur A Mallia M Banerjee S Kothari K Sarma HD Choudhari P Venkatesh M 《Bioorganic & medicinal chemistry》2006,14(3):793-799
Multidrug resistance (MDR) mediated by over-expression of P-glycoprotein (Pgp) is one of the major causes of failure of chemotherapy in cancer treatment. Colchicine, a naturally occurring alkaloid, is a Pgp substrate and acts as an antimitotic agent by binding to microtubules. Hence, Colchicine and its analogues radiolabeled with 99mTc may have potential for visualization of MDR in tumors. Here we report 99mTc-labeling of colchicine derivatives using [99mTc(CO)3(H2O)3]+ and [99mTc triple bond N]2+ cores. Trimethylcolchicinic acid synthesized from colchicine was used as the precursor to prepare iminodiacetic acid and dithiocarbamate derivatives which were then radiolabeled with [99mTc(CO)3(H2O)3]+ and [99mTc triple bond N]2+ cores, respectively. Radiolabeling yield for both the complexes was > 98% as observed by HPLC and TLC patterns. In vitro studies in tumor cell lines showed significant uptake for 99mTc-carbonyl as well as for 99mTc-nitrido colchicine complexes. Biodistribution studies in Swiss mice bearing fibrosarcoma tumor showed 4.1 +/- 1.2% ID/g of uptake at 30 min pi for 99mTc(CO)3-complex as against 0.42 +/- 0.24% ID/g for the 99mTcN-complex. 99mTc(CO)3-colchicine complex exhibited better pharmacokinetics with lower liver accumulation as compared to the 99mTcN-complex. Thus, colchicine radiolabeled with [99mTc(CO)3(H2O)3]+ core is more promising with respect to in vivo distribution characteristics in tumor model. 相似文献
20.
Liu G Dou S He J Vanderheyden JL Rusckowski M Hnatowich DJ 《Bioconjugate chemistry》2004,15(6):1441-1446
Labeling biomolecules with (99m)Tc(CO)(3)(+) ((99m)Tc tricarbonyl) is attracting increasing attention. Although histidine is often considered an ideal bifunctional chelator for (99m)Tc (or (188)Re) tricarbonyl, the family of dipicolylamine carboxylate chelators may be a useful alternative because of the expected ease of synthesis and because the structure provides a pendent carboxylate for potential conjugation to biomolecules. The dipicolylamine chelator N,N-bis(2-pyridylmethyl)-4-aminobutyric acid (BPABA) was synthesized using 4-aminobutyric acid in place of glycine or aminopropionic acid in the literature, to avoid possible involvement of the carboxylate in the complex formation process by forming five- or six-membered chelation rings. Using a commercial tricarbonyl kit (Mallinckrodt), the complex formation properties of both BPABA and commercial histidine with (99m)Tc tricarbonyl were investigated, and the in vitro complex stabilities in saline and in serum were compared. Stability in vivo was also examined following i.v. administration to normal mice. BPABA was synthesized simply and quantitatively by reacting picolyl chloride with aminobutyric acid in one step. On RP HPLC, the product eluted essentially in one peak and the structure was confirmed by ESI-MS. After labeling, both BPABA and histidine were shown by RP HPLC to form tricarbonyl complexes. In both cases, after incubation at 100 degrees C for 20 min, only one predominant peak of (99m)Tc(CO)(3)(+)-histidine or (99m)Tc(CO)(3)(+)-BPABA was apparent, and both complexes were stable at room temperature in saline for at least 24 h. After incubation for 24 h in 37 degrees C serum, by SE HPLC, 20% of the (99m)Tc(CO)(3)(+)-histidine was bound to serum protein compared to less than 10% for (99m)Tc(CO)(3)(+)-BPABA. A 5000 molar excess of histidine at 100 degrees C for 6 h was unable to dissociate (99m)Tc(CO)(3)(+)-BPABA. By contrast, BPABA easily dissociated (99m)Tc(CO)(3)(+)-histidine under the same conditions. Both complexes were stable in vivo in mice, and (99m)Tc(CO)(3)(+)-BPABA showed rapid and specific hepatobiliary clearance while (99m)Tc(CO)(3)(+)-histidine was cleared through the kidneys. In conclusion, BPABA was easily synthesized and was shown to possess properties comparable to histidine for labeling of biomolecules with (99m)Tc tricarbonyl. However, it was found that the chelator concentration required for quantitative (99m)Tc tricarbonyl labeling with both BPABA and histidine were 2 orders higher than that required with more conventional labeling using MAG(3). Finally, the complex (99m)Tc(CO)(3)(+)-BPABA itself was found to clear exclusively via the hepatobiliary pathway and may have value as a potential hepatobiliary imaging agent. 相似文献