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1.
The 2-[(3-carboxy-1-oxopropyl)amino]-2-deoxy-d-glucose (CPADG) was synthesized and radiolabeled with 99mTcO4 to obtain the 99mTc–CPADG complex in high yield. It was stable over 6 h in saline at room temperature and in serum at 37 °C. The partition coefficient and electrophoresis results indicated that the complex was hydrophilic and cationic. In vitro cell studies showed there was an increase in the uptake of 99mTc–CPADG as a function of incubation time and 99mTc–CPADG was possibly transported via the glucose transporters. The biodistribution of 99mTc–CPADG in mice bearing S 180 tumor showed that the complex accumulated in the tumor with high uptake and good retention. The tumor/blood and tumor/muscle ratios increased with time and reached 1.91 and 5.05 at 4 h post-injection. Single photon emission computed tomography (SPECT) image studies showed there was an obvious accumulation in tumor sites, suggesting 99mTc–CPADG would be a promising candidate for tumor imaging.  相似文献   

2.
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   

3.

Abstract  

Auger-emitting radionuclides such as 99mTc have been the focus of recent studies aiming at finding more selective therapeutic approaches. To explore the potential usefulness of 99mTc as an Auger emitter, we have synthesized and biologically evaluated novel multifunctional structures comprising (1) a pyrazolyl-diamine framework bearing a set of donor atoms to stabilize the [M(CO)3]+ (M is Re, 99mTc) core; (2) a DNA intercalating moiety of the acridine orange type to ensure close proximity of the radionuclide to DNA and to follow the internalization and subcellular trafficking of the compounds by confocal fluorescence microscopy; and (3) a bombesin (BBN) analogue of the type X-BBN[7-14] (where X is SGS, GGG) to provide specificity towards cells expressing the gastrin releasing peptide receptor (GRPr). Of the evaluated 99mTc complexes, Tc 3 containing the GGG-BBN[7-14] peptide showed the highest cellular internalization in GRPr-positive PC3 human prostate tumor cells, presenting a remarkably high nuclear uptake in the same cell line. Live-cell confocal imaging microscopy studies with the congener Re complex, Re 3 , showed a considerable accumulation of fluorescence in the nucleus, with kinetics of uptake similar to that exhibited by Tc 3 . Together, these data show that the acridine orange intercalator and the metal fragment are colocalized in the nucleus, which indicates that they remain connected despite the lysosomal degradation of Tc 3 /Re 3 . These compounds are the first examples of 99mTc bioconjugates that combine specific cell targeting with nuclear internalization, a crucial issue to explore use of 99mTc in Auger therapy.  相似文献   

4.
Affibody molecules constitute a novel class of molecular display selected affinity proteins based on non-immunoglobulin scaffold. Preclinical investigations and pilot clinical data have demonstrated that Affibody molecules provide high contrast imaging of tumor-associated molecular targets shortly after injection. The use of cysteine-containing peptide-based chelators at the C-terminus of recombinant Affibody molecules enabled site-specific labeling with the radionuclide 99mTc. Earlier studies have demonstrated that position, composition and the order of amino acids in peptide-based chelators influence labeling stability, cellular processing and biodistribution of Affibody molecules. To investigate the influence of the amino acid order, a series of anti-HER2 Affibody molecules, containing GSGC, GEGC and GKGC chelators have been prepared and characterized. The affinity to HER2, cellular processing of 99mTc-labeled Affibody molecules and their biodistribution were investigated. These properties were compared with that of the previously studied 99mTc-labeled Affibody molecules containing GGSC, GGEC and GGKC chelators. All variants displayed picomolar affinities to HER2. The substitution of a single amino acid in the chelator had an appreciable influence on the cellular processing of 99mTc. The biodistribution of all 99mTc-labeled Affibody molecules was in general comparable, with the main difference in uptake and retention of radioactivity in excretory organs. The hepatic accumulation of radioactivity was higher for the lysine-containing chelators and the renal retention of 99mTc was significantly affected by the amino acid composition of chelators. The order of amino acids influenced renal uptake of some conjugates at 1 h after injection, but the difference decreased at later time points. Such information can be helpful for the development of other scaffold protein-based imaging and therapeutic radiolabeled conjugates.  相似文献   

5.
Aiming to develop new bone-seeking radiotracers based on the organometallic core fac-[99mTc(CO)3]+ with improved radiochemical and biological properties, we have prepared new conjugates with phosphonate pendant groups. The conjugates comprise a chelating unit for metal coordination, which corresponds to a pyrazolyl-containing backbone (pz) with a N,N,N donor-atom set, and a pendant diethyl phosphonate (pz-MPOEt), phosphonic acid (pz-MPOH) or a bisphosphonic acid (pz-BPOH) group for bone targeting. Reactions of the conjugates with the precursor [99mTc(H2O)3(CO)3]+ yielded (mote than 95%) the single and well-defined radioactive species [99mTc(CO)33-pz-MPOEt)]+ (1a), [99mTc(CO)33-pz-MPOH]+ (2a) and [99mTc(CO)33-pz-BPOH)]+ (3a), which were characterized by reversed-phase high-performance liquid chromatography . The corresponding Re surrogates (13), characterized by the usual analytical techniques, including X-ray diffraction analysis in the case of 1, allowed for macroscopic identification of the radioactive conjugates. These radioactive complexes revealed high stability both in vitro (phosphate-buffered saline solution and human plasma) and in vivo, without any measurable decomposition. Biodistribution studies of the complexes in mice indicated a fast rate of blood clearance and high rate of total radioactivity excretion, occurring primarily through the renal–urinary pathway in the case of complex 3a. Despite presenting moderate bone uptake (3.04 ± 0.47% injected dose per gram of organ, 4 h after injection), the high stability presented by 3a and its adequate in vivo pharmacokinetics encourages the search for new ligands with the same chelating unit and different bisphosphonic acid pendant arms.  相似文献   

6.
The deoxyglucose dithiocarbamate (DGDTC) was successfully labeled with the 99mTc(CO)3 core to provide the corresponding 99mTc(CO)3–DGDTC complex in good yields. The radiochemical purity of the 99mTc(CO)3–DGDTC complex was over 90%, as measured by high performance liquid chromatography (HPLC). The complex possessed good stability in saline at room temperature and in mouse plasma at 37 °C. Its partition coefficient result indicated that it was a hydrophilic complex. The electrophoresis results showed the complex was neutral. The biodistribution of 99mTc(CO)3–DGDTC in mice bearing S 180 tumor showed that the complex clearly accumulated in tumor, exhibiting high tumor/blood and tumor/muscle ratios and good tumor retention. Single photon emission computed tomography (SPECT) image studies showed there was a visible uptake in tumor sites, suggesting 99mTc(CO)3–DGDTC could be considered as a potential tumor imaging agent.  相似文献   

7.
Two somatostatin analogues, [99mTc]Demotide and [99mTc]Demotate 4, were compared with [99mTc]Demotate 1, a previously reported somatostatin receptor subtype 2 (sst2) targeting tracer. Conjugates were prepared by coupling an open‐chain tetraamine chelator to D ‐Phe1 of [Tyr3]‐octreotide or [Tyr3]‐octreotate, respectively, via a p‐benzylaminodiglycolic acid spacer adopting solid‐phase peptide synthesis techniques. Peptide conjugates were collected in a highly pure form after chromatographic purification. Eventually, [99mTc]Demotide and [99mTc]Demotate 4 were obtained in ~1 Ci/µmol specific activity and >96% purity after labeling under alkaline conditions. Demotide and Demotate 4 exhibited similar high binding affinities for the sst2 expressed in AR4‐2J cells with IC50 values 0.16 and 0.10 nM, respectively. The (radio)metallated analogues [99mTc]Demotide and [99mTc]Demotate 4 showed equally high affinities to the sst2 during saturation binding assays in AR4‐2J cell membranes (Kds 0.08 and 0.07 nM, respectively). During incubation at 37 °C with AR4‐2J cells, the radiopeptides internalized effectively via a receptor‐mediated process, with [99mTc]Demotate 4 exhibiting a faster internalization rate than [99mTc]Demotide. After injection in athymic mice bearing sst2‐expressing AR4‐2J tumors, the radiotracers showed high and specific uptake in the tumor (>25%ID/g at 1 h) and in the sst2–positive organs. However, both [99mTc]Demotide and [99mTc]Demotate 4 showed unfavorably higher background activity, especially in the abdomen, in comparison to [99mTc]Demotate 1 and are, therefore, less suited than [99mTc]Demotate 1 for sst2‐targeted tumor imaging in man. Copyright © 2005 European Peptide Society and John Wiley & Sons, Ltd.  相似文献   

8.
The chlorambucil l-histidine conjugate was synthesized and radiolabeled with [99mTc(CO)3]+ core to form the 99mTc(CO)3(His–CB) complex. The radiochemical purity of the complex was over 90%. It had good hydrophilicity and was stable at room temperature. The high initial tumor uptake with certain retention, fast clearance from background, good tumor/non-tumor ratios and satisfactory scintigraphic images highlighted the potential of 99mTc(CO)3(His–CB) as a tumor imaging agent.  相似文献   

9.
We have designed (S)-(5-(azetidin-2-ylmethoxy)pyridine-3-yl)methyl cyclopentadienyltricarbonyl technetium carboxylate ([99mTc]CPTT–A–E) with high affinity for nicotinic acetylcholine receptors (nAChRs) using (2(S)-azetidinylmethoxy)-pyridine (A-85380) as the lead compound to develop a Tc-99m-cyclopentadienyltricarbonyl-technetium (99mTc)-labeled nAChR imaging probe. Because technetium does not contain a stable isotope, cyclopentadienyltricarbonyl rhenium (CPTR) was synthesized by coordinating rhenium, which is a homologous element having the same coordination structure as technetium. Further, the binding affinity to nAChR was evaluated. CPTR–A–E exhibited a high binding affinity to nAChR (Ki = 0.55 nM). Through the radiosynthesis of [99mTc]CPTT–A–E, an objective compound could be obtained with a radiochemical yield of 33% and a radiochemical purity of greater than 97%. In vitro autoradiographic study of the brain exhibited that the local nAChR density strongly correlated with the amount of [99mTc]CPTT–A–E that was accumulated in each region of interest. Further, the in vivo evaluation of biodistribution revealed a higher accumulation of [99mTc]CPTT–A–E in the thalamus (characterized by the high nAChR density) when compared with that in the cerebellum (characterized by the low nAChR density). Although additional studies will be necessary to improve the uptake of [99mTc]CPTT–A–E to the brain, [99mTc]CPTT–A–E met the basic requirements for nAChR imaging.  相似文献   

10.
It is essential in any method for radiolabeling antibody with99mTc that the labeling procedure is rapid and reliable, producing a highly stable99mTc-antibody complex with minimal effect on the immunoreactivity of the antibody. In the present study, analysis of the stability and homogeneity of radiolabeled (99mTc and125I) antibodies (HMFG1 and PR1A3) was carried out by fast protein liquid chromatography (FPLC) using superose-6 and S-200 columns, and by polyacrylamide gel electrophoresis (PAGE) followed by autoradiography. Superose 6 and S-200 gel filtration analysis showed the radiolabel (99mTc or125I) eluting with a retention time identical to that of native antibody. No peaks of relative molecular size (Mr) corresponding to possible antibody fragments were seen in either the UV or the radioactive FPLC elution profiles. PAGE analysis of99mTc labeled antibody, however, revealed the presence of a number of radiolabeled antibody fragments (Mr<IgG) that were not detected by the same analysis of125I labeled antibody. The stability of the radiolabeled antibodies in serum in vitro was also studied. FPLC (superose-6) analysis after 45 h incubation in normal serum in vitro revealed 3.3% (HMFG1), and 20% (PR1A3) of the99mTc on a molecule or aggregate with a Mr greater than that of IgG. There is also the appearance of small amounts of99mTc-labeled material with a Mr<IgG in the later fractions (2.2% for HMFG1 and 4.9% for PR1A3). Similar results were obtained using radioiodinated antibody, although the small amount of low molecular size material detected as a single peak with a longer retention time than the99mTc equivalent corresponds to free iodide.  相似文献   

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