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1.
张亚东  陆洁 《化学进展》2010,22(4):603-609
叶酸受体在许多源于上皮组织的恶性肿瘤中高度表达,是目前肿瘤放射性显像研究的一个新的靶点。由于叶酸对于叶酸受体具有很高的亲和性,作为重要的特异性靶向介导分子,99mTc标记叶酸肿瘤显像剂已成为当前放射性药物的研究热点之一。本文对不同类型的99mTc标记的叶酸类放射性肿瘤显像剂的研究进展、应用情况和存在的问题进行了评述,探讨了99mTc标记叶酸显像剂的一般设计方法,并对其未来发展方向进行了展望。  相似文献   

2.
Prostate-specific membrane antigen (PSMA) is a well-established biological target that is overexpressed on the surface of prostate cancer lesions. Radionuclide-labeled small-molecule PSMA inhibitors have been shown to be promising PSMA-specific agents for the diagnosis and therapy of prostate cancer. In this study, a glutamate-urea-based PSMA-targeted ligand containing an isonitrile (CNGU) was synthesized and labeled with 99mTc to prepare [99mTc]Tc-CNGU with a high radiochemical purity (RCP). The CNGU ligand showed a high affinity toward PSMA (Ki value is 8.79 nM) in LNCaP cells. The [99mTc]Tc-CNGU exhibited a good stability in vitro and hydrophilicity (log P = −1.97 ± 0.03). In biodistribution studies, BALB/c nude mice bearing LNCaP xenografts showed that the complex had a high tumor uptake with 4.86 ± 1.19% ID/g, which decreased to 1.74 ± 0.90% ID/g after a pre-injection of the selective PSMA inhibitor ZJ-43, suggesting that it was a PSMA-specific agent. Micro-SPECT imaging demonstrated that the [99mTc]Tc-CNGU had a tumor uptake and that the uptake was reduced in the image after blocking with ZJ-43, further confirming its PSMA specificity. All of the results in this work indicated that [99mTc]Tc-CNGU is a promising PSMA-specific tracer for the imaging of prostate cancer.  相似文献   

3.
Isocyanide is a strong coordination ligand that can coordinate with [99mTc(I)(CO)3]+ core and [99mTc(I)]+ core to produce stable 99mTc complexes, therefore developing a 99mTc-labeled isocyanide complex for single-photon emission computed tomography (SPECT) imaging is considered to be of great interest. In order to develop potential tumor imaging agents with satisfied tumor uptake and suitable pharmacokinetic properties in vivo, a novel d -glucosamine isocyanide derivative, 4-isocyano-N-(2,4,5-trihydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-3-yl)butanamide (CN3DG), was synthesized and radiolabeled with [99mTc(I)]+ and [99mTc(CO)3]+ cores to obtain [99mTc(CN3DG)6]+ and [99mTc(CO)3(CN3DG)3]+ in high radiolabeling yields (>95%). Both of the complexes showed good hydrophilicity and great stability in vitro. Cell uptake studies performed in S180 cells demonstrated they were transported into cells by glucose transporters. Biodistribution studies of the two complexes in mice bearing S180 tumor showed they had high tumor uptakes and rapid clearance from muscle and blood so that the tumor/blood and tumor/muscle ratios were high. By comparison, [99mTc(CN3DG)6]+ was superior to [99mTc(CO)3(CN3DG)3]+ in regard to tumor uptake, tumor/blood and tumor/liver ratios. S180 tumors could be seen clearly from the SPECT/CT images with [99mTc(CN3DG)6]+. Considering its favorable properties, [99mTc(CN3DG)6]+ would be a promising tumor imaging agent and needs to be further studied.  相似文献   

4.
A novel 99mTc labeled complex, [N-[2-((2-oxo-2-(4-(3-phenylpropyl)piperazin-1-yl)ethyl) (2-mercaptoethyl)amino)acetyl]-2-aminoethanethiolato]Technetium(V) oxide (PPPE-MAMA’-99mTcO) ([ 99m Tc]-2) has been designed and prepared based on the integrated approach. The corresponding rhenium complex (PPPE-MAMA’-ReO)(Re-2) has been prepared and characterized. In vitro competition binding assays show moderate affinity of Re-2 towards σ1 and σ2 receptors with K i values of 8.67 ± 0.07 and 5.71 ± 1.88 μmol, respectively. Planar images obtained at 0.5 h, 4 h, 20 h after i.v. injection indicate the accumulation of [ 99m Tc]-2 in MCF-7 human breast tumor bearing mice at 20 h. Furthermore, the accumulation of [ 99m Tc]-2 has been inhibited at 20 h after co-injection of [ 99m Tc]-2 plus haloperidol (1 mg/kg). Biodistribution studies of [ 99m Tc]-2 display an in vivo tumor uptake of 0.14% ± 0.01% ID/g at 24 h post i.v. injection with a tumor/muscle ratio of 6.02 ± 0.87. The above results suggest that [ 99m Tc]-2, derived from a previously published lead compound, retains certain tumor uptake and affinity for σ receptors. [ 99m Tc]-2 may be used as a basis for further structural modifications to develop tumor imaging agents with high affinity for σ receptors.  相似文献   

5.
A novel C3′‐functionalized thymidine dithiocarbamate derivative (3’DTC‐TdR) was successfully synthesized and labelled using [99mTcO]3+ core and [99mTc(CO)3(H2O)3]+ core with high yields. The structures of the 99mTc complexes were verified by preparation and characterization of the corresponding stable rhenium complexes. Both of the complexes were lipophilic and stable in vitro. Cell internalization experiments indicated that the uptakes of 99mTcO‐3’DTC‐TdR were related to nucleoside transporters. Biodistribution of these complexes in mice bearing tumor showed that they had high tumor uptakes, good tumor/muscle ratios and tumor/blood ratios. Especially for 99mTcO‐3’DTC‐TdR, it exhibited the highest tumor/muscle ratio and tumor/blood ratio at 4 h post‐injection. SPECT/CT imaging studies indicated clear accumulation in tumor, suggesting 99mTcO‐3’DTC‐TdR would be a promising candidate for tumor imaging.  相似文献   

6.
In this study, phenylalanine dithiocarbamate (PHEDTC) ligand was successfully synthesized and then radiolabeled with [99mTcO]3+ core and [99mTc≡N]2+ core to produce 99mTcO–PHEDTC and 99mTcN–PHEDTC, respectively. Both complexes were prepared with high radiochemical purity and had good stability. The partition coefficient results showed they were hydrophilic, while 99mTcN–PHEDTC was more hydrophilic than 99mTcO–PHEDTC. The biodistribution study in mice bearing S 180 tumor showed that 99mTcO–PHEDTC and 99mTcN–PHEDTC had high tumor uptake at 2 h post-injection, 1.91 and 1.21, respectively. The good uptake and retention in tumor together with favorable tumor-to-muscle ratios make them promising candidates for further evaluation as potential tumor imaging agents.  相似文献   

7.
The research in the last decade has been mainly aimed at the development of technetium-99m radiopharmaceuticals, among which are the “3+1”mixed ligand complexes. Two novel [99mTc]“3+1”mixed ligand complexes each carrying the tridentate ligand, the N-(o-Methylthiophenyl)ethylenediamine or the N-(o-Methylthiophenyl)-b-mercaptoacetamide in combination with monothiolate coligand were produced using stannous chloride as reductant and glucoheptonate as transfer ligand. The identification of [99mTc]-6 and [99mTc]-7 was established by thin layer chromatography. The radiochemical purity of two complexes was over 90%. Biodistribution data in mice showed that both [99mTc]-6 and [99mTc]-7 can penetrate the intact blood-brain barrier and exhibited retention in mice brain. The brain uptakes (%ID/g) were 1.76, 1.17, 0.90 and 0.68, 0.38 ,0.37 at 2, 30, and 60 minutes i.v. postinjection for [99mTc]-6 and [99mTc]-7, respectively. Examples in this report comfirm us that it is promising to develop 99mTc complexes as potential brain perfusion agents based on modifying either the tridentate or the monodentate ligands. This revised version was published online in August 2006 with corrections to the Cover Date.  相似文献   

8.
Two peptide ligands conjugated adenine, [9-N-(tritylmercapto acetyl diglycyl aminoethyl) adenine, Tr-MAG2-Ade] and [9-N-(tritylmercapto acetyl triglycyl aminoethyl) adenine, Tr-MAG3-Ade], are synthesized and labeled with 99mTc by directly labeling method. The stability of 99mTc-MAG2-adenine and 99mTc-MAG3-adenine in vitro is measured. The uptake radios of tumor to muscle at 3h post-injection are 5.70 and 4.92, respectively. The biodistribution and scintigraphic imaging studies show that the two complexes have high localization in tumor and high contrasted tumor images can be obtained, which suggest their potential utility as tumor imaging agents. But the high radioactivity of abdomen could prevent the tumor imaging in this area.  相似文献   

9.
[99mTc(I)]+ and [99mTc(I)(CO)3]+ complexes with isocyanide exhibit high stability, which makes them suitable platforms to develop novel 99mTc radiopharmaceuticals. To develop novel 99mTc radiotracers for imaging hypoxia, in this study, a novel L ligand (4-nitroimidazole isocyanide derivative) was synthesized and labelled using [99mTc(I)]+ core and [99mTc(I)(CO)3]+ core to produce [99mTc(L)6]+ and [99mTc(CO)3(L)3]+ with high yields. To verify the structure of the 99mTc complexes, corresponding rhenium analogues were synthesized and characterized. Both of the 99mTc complexes were stable and hydrophilic. in vitro cellular uptake results showed they could exhibit good hypoxic selectivity. The evaluation of biodistribution in mice bearing S180 tumors indicated both of them could accumulate in tumor. Between them, [99mTc(L)6]+ exhibited higher tumor uptake and tumor/non-target ratio than [99mTc(CO)3(L)3]+. Further, single photon emission computed tomography (SPECT) imaging studies of [99mTc(L)6]+ indicated an obvious accumulation in tumor and the value of the region-of-interest (ROI) ratio of the uptake for the tumor site to the corresponding non-tumor region was 5.64 ± 0.52. The above results suggested [99mTc(L)6]+ would be a potential tracer for imaging tumor hypoxia.  相似文献   

10.
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   

11.
Recently, prostate-specific membrane antigen (PSMA) has gained momentum in tumor nuclear molecular imaging as an excellent target for both the diagnosis and therapy of prostate cancer. Since 2008, after years of preclinical research efforts, a plentitude of radiolabeled compounds mainly based on low molecular weight PSMA inhibitors (PSMA-i) have been described for imaging and theranostic applications, and some of them have been transferred to the clinic. Most of these compounds include radiometals (e.g., 68Ga, 64Cu, 177Lu) for positron emission tomography (PET) imaging or endoradiotherapy. Nowadays, although the development of new PET tracers has caused a significant drop in single-photon emission tomography (SPECT) research programs and the development of new technetium-99m (99mTc) tracers is rare, this radionuclide remains the best atom for SPECT imaging owing to its ideal physical decay properties, convenient availability, and rich and versatile coordination chemistry. Indeed, 99mTc still plays a relevant role in diagnostic nuclear medicine, as the number of clinical examinations based on 99mTc outscores that of PET agents and 99mTc-PSMA SPECT/CT may be a cost-effective alternative for 68Ga-PSMA PET/CT. This review aims to give an overview of the specific features of the developed [99mTc]Tc-tagged PSMA agents with particular attention to [99mTc]Tc-PSMA-i. The chemical and pharmacological properties of the latter will be compared and discussed, highlighting the pros and cons with respect to [68Ga]Ga-PSMA11.  相似文献   

12.
Two novel diamine dioxime ligands, 4,7‐diaza‐3,8‐diethyldecane‐2,9‐dione bis oxime (3) and 4,9‐diaza‐3,10‐diethyldodecane‐2,11‐dione bis oxime (5), were synthesized in order to develop new brain perfusion imaging agents, based on 99mTc(V)‐complexes. The synthesis involved condensation of 2‐hydroxyimino‐3‐pentanone with appropriate diamine in protic solvent which afforded the bis imine adducts. Subsequent reduction of imine functional groups yielded a diastereoisomeric mixture of 3 and 5. UV–visible, IR, 1H NMR, 13C NMR and elemental analysis were used to characterize the structures of the synthesized compounds. 99mTc‐complexes of both diamine dioximes were prepared and radiolabeling conditions optimized to give the maximum yield. Physicochemical parameters of the labeled complexes as well as and their biodistribution in rats were investigated. Both compounds (3 and 5) formed 99mTc‐complexes with a net charge of zero, determined by electrophoresis. The resultant lipophilic 99mTc‐complexes of 3 and 5 were readily formed at pH ~9.0 within 10 min at room temperature with yields of 90% and 95%, respectively. The 99mTc‐3 complex was found to be stable within 1 h, while 99mTc‐5 was stable for a few hours. A significant brain uptake of 99mTc‐3 (2.1% injected dose) and 99mTc‐5 (1.8% injected dose) complexes, 2 min after injection, is in accordance with their lipophilicity. The present study suggests that both ligands are promising candidates as new 99mTc‐based brain‐imaging agents. Copyright © 2012 John Wiley & Sons, Ltd.  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 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.  相似文献   

15.
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   

16.
The radiosynthesis of [99mTc]-phenformin ([99mTc]-1-phenethylbiguanide) complex and its suitability as precursor of the radiopharmaceuticals for the tumor imaging was assessed. Radiochemical purity of the [99mTc]-complex was determined using radio-TLC and was studied by the HPLC with radiochemical detection, while its stability in challenge experiments. The results show, that due to the sufficient stability and lipophilicity of the complex, it fulfills our expectations for promising radiopharmaceutical precursor not only for the diagnostic agent, but also for the drug suitable for the oncological Auger electron therapy.  相似文献   

17.
11C, 18F and 123I fatty acids are used for myocardial imaging, and 99mTc‐labeled fatty acids are more desirable substitutes than other radiolabeled fatty acids. In the work reported, [99mTc]‐CpTT‐10‐oxo‐FPA ( 1c ), [99mTc]‐CpTT‐12‐oxo‐FPA ( 2c ), [99mTc]‐CpTT‐14‐oxo‐FPA ( 3c ) and [99mTc]‐CpTT‐16‐oxo‐FPA ( 4c ) were prepared with 60.76–70.92% of radiochemical yield and purity of more than 95%. These radiotracers ( 1c , 2c , 3c , 4c ) were chemically stable when incubated in Sprague Dawley rat serum for 3 h at 37 °C. Tissue distribution studies in female mice indicated that 2c had high initial heart uptake (8.84%ID g?1 at 1 min post‐injection) and 4c had long retention in the heart (1.45%ID g?1 at 30 min post‐injection). Metabolite analysis showed 4c could be metabolized to 5c via β‐oxidation with loss of two ? CH2? in the myocardium, the radiometabolite being excreted via urine. However, low heart uptake suggested that 4c cannot be used as a diagnostic imaging agent. Copyright © 2016 John Wiley & Sons, Ltd.  相似文献   

18.
In order to seek novel technetium-99m bacterial infection imaging agents, a ciprofloxacin xanthate (CPF2XT) was synthesized and radiolabeled with [99mTcN]2+ core to obtain the 99mTcN-CPF2XT complex, which exhibited high radiochemical purity, hydrophilicity, and good stability in vitro. The bacteria binding assay indicated that 99mTcN-CPF2XT had specificity to bacteria. A study of biodistribution in mice showed that 99mTcN-CPF2XT had a higher uptake in bacterial infection tissues than in turpentine-induced abscesses, indicating that it could distinguish bacterial infection from sterile inflammation. Compared to 99mTcN-CPFXDTC, the abscess/blood and abscess/muscle ratios of 99mTcN-CPF2XT were higher and the uptakes of 99mTcN-CPF2XT in the liver and lung were obviously decreased. The results suggested that 99mTcN-CPF2XT would be a potential bacterial infection imaging agent.  相似文献   

19.
The favorable nuclear properties in combination with the rich coordination chemistry make technetium-99m the radioisotope of choice for the development of myocardial perfusion tracers. In the early 1980s, [99mTc]Tc-Sestamibi, [99mTc]Tc-Tetrofosmin, and [99mTc]Tc-Teboroxime were approved as commercial radiopharmaceuticals for myocardial perfusion imaging in nuclear cardiology. Despite its peculiar properties, the clinical use of [99mTc]Tc-Teboroxime was quickly abandoned due to its rapid myocardial washout. Despite their widespread clinical applications, both [99mTc]Tc-Sestamibi and [99mTc]Tc-Tetrofosmin do not meet the requirements of an ideal perfusion imaging agent due to their relatively low first-pass extraction fraction and high liver absorption. An ideal radiotracer for myocardial perfusion imaging should have a high myocardial uptake; a high and stable target-to-background ratio with low uptake in the lungs, liver, stomach during the image acquisition period; a high first-pass myocardial extraction fraction and very rapid blood clearance; and a linear relationship between radiotracer myocardial uptake and coronary blood flow. Although it is difficult to reconcile all these properties in a single tracer, scientific research in the field has always channeled its efforts in the development of molecules that are able to meet the characteristics of ideality as much as possible. This short review summarizes the developments in 99mTc myocardial perfusion tracers, which are able to fulfill hitherto unmet medical needs and serve a large population of patients with heart disease, and underlines their strengths and weaknesses, the lost and found opportunities thanks to the developments of the new ultrafast SPECT technologies.  相似文献   

20.
The labeling of (bio)molecules with metallic radionuclides such as 99mTc demands conjugated, multidentate chelators. However, this is not always necessary since phenyl rings can directly serve as integrated, organometallic ligands. Bis-arene sandwich complexes are generally prepared by the Fischer–Hafner reaction. In extension of this, we show that [99mTc(η6-C6R6)2]+-type complexes are directly accessible from water and [99mTcO4], even using arenes incompatible with Fischer–Hafner conditions. To unambiguously confirm the nature of these unprecedented 99mTc complexes, their rhenium homologous have been prepared by substituting naphthalene ligands in [Re(η6-C10H8)2]+ with the corresponding phenyl groups. The ease with which highly stable [99mTc(η6-C6R6)2]+ complexes are formed under standard labeling conditions enables a multitude of new potential imaging agents based on commercial pharmaceuticals or lead structures.  相似文献   

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