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1.
Rev Sci Instrum ; 85(3): 033306, 2014 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-24689574

RESUMO

A new algorithm for digital image processing apparatuses is developed to evaluate profiles of high-intensity DC beams from temperature images of irradiated thin foils. Numerical analyses are performed to examine the reliability of the algorithm. To simulate the temperature images acquired by a thermographic camera, temperature distributions are numerically calculated for 20 MeV proton beams with different parameters. Noise in the temperature images which is added by the camera sensor is also simulated to account for its effect. Using the algorithm, beam profiles are evaluated from the simulated temperature images and compared with exact solutions. We find that niobium is an appropriate material for the thin foil used in the diagnostic system. We also confirm that the algorithm is adaptable over a wide beam current range of 0.11-214 µA, even when employing a general-purpose thermographic camera with rather high noise (ΔT(NETD) ≃ 0.3 K; NETD: noise equivalent temperature difference).

2.
Rev Sci Instrum ; 85(2): 02C305, 2014 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-24593642

RESUMO

Solid-state materials suitable for use as proton irradiation targets were investigated for producing high-purity (11)CH4 molecules for heavy-ion cancer therapy. The radioactivity of gas produced by proton irradiation was measured for several target materials. Also, the radioactive molecular species of the produced gas were analyzed by radio gas chromatography. We found that 5 × 10(12) (11)C molecules could be collected by proton irradiation on a NaBH4 target. We also found that the (11)CH4 molecules were produced and collected directly from the irradiated target, owing to the hydrogen atoms bound in the solid-state NaBH4.


Assuntos
Boroidretos , Metano , Aceleradores de Partículas/instrumentação , Radioisótopos de Carbono
3.
Bioorg Med Chem ; 20(1): 305-10, 2012 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-22115838

RESUMO

Dantrolene (1) is a substrate for breast cancer resistant protein, which is widely distributed in the blood-brain-barrier, intestine, gall bladder, and liver. PET study with 1 labeled with a positron emitter can be used to visualize BCRP and to elucidate the effect of BCRP on the pharmacokinetics of drugs. The objective of this study was to label 1 using nitrogen-13 ((13)N, a positron emitter; half-life: 9.9min). Using no-carrier-added [(13)N]NH(3) as the labeling agent, we synthesized [(13)N]dantrolene ([(13)N]1) for the first time. The reaction of carbomyl chloride 2b with [(13)N]NH(3) gave an unsymmetrical urea [(13)N]3, followed by cyclization of [(13)N]3 to afford [(13)N]1. Due to its instability, 2b was prepared in situ by treating amine 5 with triphosgene in a ratio of 4 to 1 and used for subsequent [(13)N]ammonolysis without purification.


Assuntos
Transportadores de Cassetes de Ligação de ATP/química , Amônia/química , Neoplasias da Mama/diagnóstico por imagem , Dantroleno/química , Proteínas de Neoplasias/química , Compostos Radiofarmacêuticos/química , Membro 2 da Subfamília G de Transportadores de Cassetes de Ligação de ATP , Transportadores de Cassetes de Ligação de ATP/metabolismo , Barreira Hematoencefálica , Ciclização , Dantroleno/síntese química , Feminino , Humanos , Marcação por Isótopo , Proteínas de Neoplasias/metabolismo , Radioisótopos de Nitrogênio/química , Fosgênio/análogos & derivados , Fosgênio/química , Tomografia por Emissão de Pósitrons , Compostos Radiofarmacêuticos/síntese química , Ureia/química
4.
Appl Radiat Isot ; 69(7): 1007-13, 2011 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-21420304

RESUMO

The aim of this study was to develop an efficient fully automated synthesis method to achieve a high radiochemical yield of [(18)F]FAZA with a small amount of precursor. A small cartridge containing 25mg of the QMA resin was prepared and evaluated to obtain [(18)F]F(-) in a small quantity of base (K(2)CO(3)), which might allow the use of a small amount of precursor. The labeling and hydrolyzing conditions for [(18)F]FAZA synthesis were also investigated manually. No-carrier-added [(18)F]F(-) was trapped on the small QMA cartridge and eluted with a mixture of Krytofix 222 (2.26 mg, 6.0 µmol) and K(2)CO(3) (0.69 mg, 5.0 µmol) in 70% MeCN (0.4 mL). The automated synthesis of [(18)F]FAZA was optimally performed with a modified NIRS original synthesis system for clinical use, by labeling 2.5mg (5.2 µmol) of the precursor in DMSO (0.4 mL) at 120°C for 10 min, and then by hydrolyzing the (18)F-labeled intermediate with 0.1M NaOH (0.5 mL) at room temperature for 3 min. Using the above condition, the [(18)F]FAZA injection was obtained with a high radiochemical yield of 52.4±5.3% (decay-corrected, n=8) within 50.5±1.5 min.


Assuntos
Automação , Hipóxia Celular , Radioisótopos de Flúor , Neoplasias/diagnóstico , Nitroimidazóis , Humanos
5.
J Nucl Med ; 52(4): 592-9, 2011 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-21421722

RESUMO

UNLABELLED: The C2A domain of synaptotagmin I can target apoptotic cells by binding to exposed anionic phospholipids. The goal of this study was to synthesize and develop (18)F-labeled C2A-glutathione-S-transferase (GST) as a molecular imaging probe for the detection of apoptosis and to assess the response of paclitaxel chemotherapy in VX2 rabbit lung cancer. METHODS: (18)F-C2A-GST was prepared by labeling C2A-GST with N-succinimidyl 4-(18)F-fluorobenzoate ((18)F-SFB). (18)F-C2A-GST was confirmed by high-performance liquid chromatography and sodium dodecyl sulfate polyacrylamide gel electrophoresis. The binding of (18)F-C2A-GST toward apoptosis was validated in vitro using camptothecin-induced Jurkat cells. Biodistribution of (18)F-C2A-GST was determined in mice by a dissection method and small-animal PET. Single-dose paclitaxel was used to induce apoptosis in rabbits bearing VX2 tumors (n = 6), and 2 VX2 rabbits without treatment served as control. (18)F-C2A-GST PET was performed before and at 72 h after therapy, and (18)F-FDG PET/CT was also performed before treatment. To confirm the presence of apoptosis, tumor tissue was analyzed and activated caspase-3 was measured. RESULTS: (18)F-C2A-GST was obtained with more than 95% radiochemical purity and was stable for 4 h after formulation. (18)F-C2A-GST bound apoptotic cells specifically. Biodistribution in mice showed that (18)F-C2A-GST mainly excreted from the kidneys and rapidly cleared from blood and nonspecific organs. High focal uptake of (18)F-C2A-GST in the tumor area was determined after therapy, whereas no significant uptake before therapy was found in the tumor with (18)F-FDG-avid foci. The maximum standardized uptake value after therapy was 0.47 ± 0.28, significantly higher than that in the control (0.009 ± 0.001; P < 0.001). The apoptotic index was 79.81% ± 8.73% in the therapy group, significantly higher than that in the control (5.03% ± 0.81%; P < 0.001). Activated caspase-3 after paclitaxel treatment increased to 69.55% ± 16.27% and was significantly higher than that in the control (12.26% ± 5.39%; P < 0.001). CONCLUSION: (18)F-C2A-GST was easily synthesized by conjugation with (18)F-SFB and manifested a favorable biodistribution. Our results demonstrated the feasibility of (18)F-C2A-GST for the early detection of apoptosis after chemotherapy in a VX2 lung cancer model that could imitate the human lung cancer initiation, development, and progress.


Assuntos
Neoplasias Pulmonares/diagnóstico por imagem , Neoplasias Pulmonares/tratamento farmacológico , Compostos Radiofarmacêuticos , Sinaptotagmina I , Animais , Antineoplásicos Fitogênicos/uso terapêutico , Apoptose/efeitos dos fármacos , Caspase 3/metabolismo , Cromatografia Líquida de Alta Pressão , Eletroforese em Gel de Poliacrilamida , Estudos de Viabilidade , Radioisótopos de Flúor , Humanos , Processamento de Imagem Assistida por Computador , Indicadores e Reagentes , Marcação por Isótopo/métodos , Células Jurkat , Masculino , Camundongos , Imagem Molecular , Paclitaxel/uso terapêutico , Tomografia por Emissão de Pósitrons , Coelhos , Compostos Radiofarmacêuticos/química , Compostos Radiofarmacêuticos/farmacocinética , Sinaptotagmina I/química , Sinaptotagmina I/farmacocinética , Distribuição Tecidual
6.
Appl Radiat Isot ; 69(1): 146-57, 2011 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-20933429

RESUMO

A fully automated system for the production of iodine-124, based on techniques of vertical-beam irradiation and dry distillation, was developed. The system, coupled with a capsulated target, was able to irradiate the (124)TeO(2) target up to 29 µA for 1-4h, which yielded iodine-124 with an almost constant yield of 6.9 MBq/µAh at the end of bombardment. All procedures were performed automatically and repeatedly. The newly developed system would be suitable for routine, large-scale productions of iodine-124.


Assuntos
Radioisótopos do Iodo/química , Tomografia por Emissão de Pósitrons/métodos , Humanos
7.
Neuroimage ; 54(1): 123-30, 2011 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-20705143

RESUMO

The aim of this study was to visualize early infarction in the rat brain after ischemia using a translocator protein (TSPO) (18 kDa) PET ligand [(11)C]DAC with ultra-high specific activity (SA) of 3670-4450 GBq/µmol. An infarction model of rat brain was prepared by ischemic surgery and evaluated 2 days after ischemia using small-animal PET and in vitro autoradiography. Early infarction with a small increase of TSPO expression in the brain was visualized using PET with high SA [(11)C]DAC (average 4060 GBq/µmol), but was not distinguished clearly with usually reported SA [(11)C]DAC (37 GBq/µmol). Infarction in the rat brain 4 days after ischemia was visualized using high and usually reported SAs [(11)C]DAC. Displacement experiments with unlabeled TSPO-selective AC-5216 or PK11195 diminished the difference in radioactivity between ipsilateral and contralateral sides, confirming that the increased uptake on the infracted brain was specific to TSPO. In vitro autoradiography with high SA [(11)C]DAC showed that the TSPO expression increased on early infarction in the rat brain. High SA [(11)C]DAC is a useful and sensitive biomarker for the visualization of early infarction and the characterization of TSPO expression which was slightly elevated in the infarcted brain using PET.


Assuntos
Isquemia Encefálica/complicações , Infarto Cerebral/patologia , Acetamidas , Animais , Autorradiografia/métodos , Barreira Hematoencefálica/fisiologia , Encéfalo/diagnóstico por imagem , Encéfalo/patologia , Radioisótopos de Carbono , Infarto Cerebral/diagnóstico por imagem , Infarto Cerebral/etiologia , Tomografia por Emissão de Pósitrons/métodos , Purinas , Radiografia , Ratos , Verapamil
8.
J Cereb Blood Flow Metab ; 31(1): 124-31, 2011 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-20407462

RESUMO

The catecholamine, dopamine (DA), is synthesized from 3,4-dihydroxy-L-phenylalanine (L-DOPA) by aromatic L-amino acid decarboxylase (AADC). Dopamine metabolism is regulated by monoamine oxidase (MAO) and catechol-O-methyltransferase (COMT). To measure dopaminergic metabolism, we used microdialysis with radiometric detection to monitor L-[ß-(11)C]DOPA metabolites in the extracellular space of the rat striatum. We also evaluated the effects of AADC, MAO, and COMT inhibitors on metabolite profiles. The major early species measured after administration of L-[ß-(11)C]DOPA were [(11)C]3,4-dihydroxyphenylacetic acid ([(11)C]DOPAC) and [(11)C]homovanillic acid ([(11)C]HVA) in a 1:1 ratio, which shifted toward [(11)C]HVA with time. An AADC inhibitor increased the uptake of L-[ß-(11)C]DOPA and L-3-O-methyl-[(11)C]DOPA and delayed the accumulation of [(11)C]DOPAC and [(11)C]HVA. The MAO and COMT inhibitors increased the production of [(11)C]3-methoxytyramine and [(11)C]DOPAC, respectively. These results reflect the L-DOPA metabolic pathway, suggesting that this method may be useful for assessing dopaminergic metabolism.


Assuntos
Inibidores das Descarboxilases de Aminoácidos Aromáticos , Inibidores de Catecol O-Metiltransferase , Dopamina/metabolismo , Inibidores Enzimáticos/farmacologia , Levodopa , Inibidores da Monoaminoxidase/farmacologia , Neostriado/metabolismo , Compostos Radiofarmacêuticos , Ácido 3,4-Di-Hidroxifenilacético/metabolismo , Animais , Benserazida/farmacologia , Biotransformação , Catecóis/farmacologia , Cromatografia Líquida de Alta Pressão , Dopaminérgicos/farmacologia , Líquido Extracelular/metabolismo , Ácido Homovanílico/metabolismo , Masculino , Microdiálise , Neostriado/efeitos dos fármacos , Neostriado/enzimologia , Pargilina/farmacologia , Ratos , Ratos Sprague-Dawley , Espectrofotometria Ultravioleta
9.
Nucl Med Biol ; 37(7): 831-5, 2010 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-20870158

RESUMO

INTRODUCTION: High specific radioactivity is preferable in the measurement of neuroreceptor bindings with positron emission tomography (PET) because receptor occupancy by mixed cold ligand hampers the accurate estimation of receptor binding. Recently, we succeeded in synthesizing [(11)C]raclopride, a dopamine D(2) receptor ligand, with ultra-high specific radioactivity, i.e., several thousand GBq/µmol. In the present study, we compared the [(11)C]raclopride bindings to dopamine D(2) receptors between radioligands with ultra-high specific radioactivity and ordinary high specific radioactivity in healthy human subjects. METHODS: Two PET studies using [(11)C]raclopride with ultra-high specific radioactivity (4302-7222 GBq/µmol) or ordinary high specific radioactivity (133-280 GBq/µmol) were performed on different days in 14 healthy men. Binding potential (BP) was calculated by the simplified reference tissue method, peak equilibrium method, and area-under-the-curve method for each region-of-interest using time-activity data in the cerebellum as a reference brain region. RESULTS: BP values for radioligands with ultra-high specific radioactivity and ordinary high specific radioactivity calculated by the simplified reference tissue method were 4.06 ± 0.29 and 4.10 ± 0.25 in the putamen, 0.44 ± 0.07 and 0.47 ± 0.07 in the thalamus and 0.37 ± 0.06 and 0.38 ± 0.06 in the temporal cortex, respectively (mean ± S.D.). No significant difference in BP was observed between ultra-high specific radioactivity and ordinary high specific radioactivity in any of the brain regions. CONCLUSION: BP values of [(11)C]raclopride with ultra-high specific radioactivity did not differ from those with ordinary high specific radioactivity in the measured brain regions, including striatal and extrastriatal regions.


Assuntos
Química Encefálica , Radioisótopos de Carbono , Antagonistas de Dopamina , Racloprida , Receptores de Dopamina D2/análise , Adulto , Humanos , Ligantes , Imageamento por Ressonância Magnética , Masculino , Tomografia por Emissão de Pósitrons , Adulto Jovem
10.
Ann Nucl Med ; 24(4): 249-60, 2010 May.
Artigo em Inglês | MEDLINE | ID: mdl-20364374

RESUMO

OBJECTIVE: Dopamine transporter (DAT) is a reuptake carrier of dopamine at presynapse that regulates dopaminergic neural transmission. [(11)C]PE2I is a cocaine analog developed as a potent positron emission tomography (PET) ligand for DAT with high selectivity. The aim of this study was to evaluate the applicability of quantification methods using reference tissue models for [(11)C]PE2I. METHODS: Dynamic PET scans were performed in 6 young healthy male volunteers after an intravenous bolus injection of [(11)C]PE2I. Metabolite-corrected arterial plasma-input functions were obtained. Compartment model analysis and plasma-input Logan analysis were performed to determine the kinetic parameters and distribution volume (V (T)). The distribution volume ratio (DVR) was calculated as the ratio of V (T) in the cerebral region to that in the cerebellum. DVRs were also determined by the original multilinear reference tissue model method (MRTMo) and the simplified reference tissue model method (SRTM), comparing the results with those obtained from graphical analysis using arterial input function. To estimate errors in DVR calculated using the reference tissue model, a simulation study that focused on cerebellar kinetics and scan duration was performed. RESULTS: The highest [(11)C]PE2I binding was observed in the striatum, followed by the midbrain and thalamus. The 2-tissue model was preferable to the 1-tissue model for describing the [(11)C]PE2I kinetics in the cerebellum. Both the measured and 90-min simulated data showed that reference tissue models caused an underestimation of DVR in the striatum. The simulation showed that 90-min scan duration was insufficient when cerebellar kinetics was described as a 1-tissue model. Nevertheless, DVR values determined by MRTMo and SRTM were in good agreement with those by the graphical approach in other lower binding regions. CONCLUSION: Due to the [(11)C]PE2I kinetics in the cerebellum and limited scan duration for (11)C, MRTMo and SRTM underestimated the striatal DVR. Despite this limitation, the present study demonstrated the applicability of reference tissue models. Since DAT in the midbrain and thalamus is of interest in the pathophysiology of neuropsychiatric disease, this noninvasive quantitative analysis will be useful for clinical investigations.


Assuntos
Encéfalo/metabolismo , Proteínas da Membrana Plasmática de Transporte de Dopamina/metabolismo , Modelos Biológicos , Nortropanos/metabolismo , Tomografia por Emissão de Pósitrons , Adulto , Artérias/fisiologia , Encéfalo/irrigação sanguínea , Encéfalo/fisiologia , Dopamina/metabolismo , Humanos , Masculino , Valores de Referência , Reprodutibilidade dos Testes , Sinapses/fisiologia , Transmissão Sináptica , Fatores de Tempo , Adulto Jovem
11.
Nucl Med Biol ; 37(1): 67-72, 2010 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-20122670

RESUMO

An ultrafast and efficient high-performance liquid chromatographic (LC) method was developed to purify positron emission tomography (PET) radiopharmaceuticals as well as for metabolite analysis of the plasma sample. Chromatographic separation was achieved on a short (60 mm length) semipreparative (10 mm I.D.) column packed with 2.5-mum particles using a mixture of acetonitrile and sodium phosphate buffer as the mobile phase at a flow rate of 8-10 ml/min. Under the optimum conditions, excellent separation of the target PET probe was obtained from chemical/radiochemical impurities or radioactive metabolites with a very short run time of 2 min. This characteristic enabled significant shortening of the purification and evaporation processes in the production of short-lived radiopharmaceuticals and highly sensitive radiometric analysis with good temporal resolution during the metabolism study.


Assuntos
Cromatografia Líquida/métodos , Compostos Radiofarmacêuticos/isolamento & purificação , Compostos Radiofarmacêuticos/metabolismo , Radioisótopos de Carbono/química , Cromatografia de Fase Reversa , Humanos , Tomografia por Emissão de Pósitrons , Purinas/sangue , Purinas/química , Purinas/metabolismo , Compostos Radiofarmacêuticos/análise , Fatores de Tempo
13.
Mol Imaging Biol ; 12(2): 181-91, 2010 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-19784702

RESUMO

OBJECTIVE: Gefitinib (N-(3-chloro-4-fluorophenyl)-7-methoxy-6-[3-(morpholin-4-yl)propoxy]quinazolin-4-amine, Iressa) is an approved anticancer drug. In this study, we labeled gefitinib with carbon-11 and evaluated [(11)C]gefitinib to explore its specific binding in intact fibrosarcoma (NFSa)-bearing mice. METHODS: [(11)C]Gefitinib was synthesized by the reaction of desmethyl precursor (1) with [(11)C]CH(3)I. In vitro uptake of [(11)C]gefitinib into NFSa, human-A431 epidermoid carcinoma, and Jurkat T cells was determined. Positron emission tomography (PET) imaging using [(11)C]gefitinib was performed for NFSa-bearing mice. RESULTS: [(11)C]Gefitinib accumulated into NFSa cells with 2.1 uptake ratio (UR)/mg protein in cells. Addition of nonradioactive gefitinib decreased uptake in a concentration-dependent manner. [(11)C]Gefitinib also had high uptake (2.6 UR/mg protein) into epidermal growth factor receptor/tyrosine kinase (EGFR/TK)-rich A431 cells but low uptake (0.2 UR/mg protein) into EGFR/TK-poor Jurkat cells. In vivo distribution study on NFSa-bearing mice by the dissection method revealed that [(11)C]gefitinib specifically accumulated into the tumor. The ratio of radioactivity in tumors to that in blood and muscle as two comparative regions increased from 0.4 to 6.0 and from 0.6 to 5.0 during this experiment (0-60 min), respectively. PET for NFSa-bearing mice produced a clear tumor image, although high radioactivity was distributed throughout the body. Treatment with nonradioactive gefitinib (100 mg/kg) decreased uptake in the tumor. In vivo metabolite analysis demonstrated that [(11)C]gefitinib was stable in the tumor, liver, kidney, and blood. CONCLUSION: These results demonstrated the promising potential of [(11)C]gefitinib to serve as a PET ligand for in vivo imaging of NFSa-bearing mice.


Assuntos
Fibrossarcoma/diagnóstico por imagem , Imagem Molecular/métodos , Quinazolinas/síntese química , Animais , Radioisótopos de Carbono , Linhagem Celular Tumoral , Gefitinibe , Humanos , Masculino , Camundongos , Tomografia por Emissão de Pósitrons , Quinazolinas/química , Quinazolinas/farmacocinética , Distribuição Tecidual
14.
Biomed Chromatogr ; 24(2): 202-8, 2010 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-19630073

RESUMO

A highly sensitive reversed-phase liquid chromatographic (HPLC) method was investigated to analyze a range of positron emission tomography (PET) radiopharmaceuticals using electrogenerated chemiluminescence (ECL) detection. ECL is based on the reaction of PET molecules with tris(2,2'-bipyridyl)ruthenium(III) [Ru(bpy)(3)(3+)], which is generated through the on-line electro-oxidation of Ru(bpy)(3)(2+). In 21 different radiopharmaceuticals studied, 18 compounds could be detected with detection limits (signal-to-noise ratio = 3) of 0.12-72 ng/mL per 20 microL injection. Sufficient reproducibility and linearity were obtained for the quantitative determination of PET molecules in pharmaceutical fluid. This method could be successfully applied to quality control tests of PET radiopharmaceuticals with ultra-high specific radioactivity.


Assuntos
2,2'-Dipiridil/análogos & derivados , Tomografia por Emissão de Pósitrons/normas , Compostos Radiofarmacêuticos/análise , 2,2'-Dipiridil/química , 2,2'-Dipiridil/normas , Radioisótopos de Carbono/análise , Cromatografia Líquida de Alta Pressão , Complexos de Coordenação , Eletroquímica , Concentração de Íons de Hidrogênio , Indicadores e Reagentes , Luminescência , Pirrolidinas/química , Controle de Qualidade , Compostos Radiofarmacêuticos/normas , Reprodutibilidade dos Testes , Salicilamidas/química , Soluções
15.
Bioorg Med Chem Lett ; 19(21): 6222-4, 2009 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-19783141

RESUMO

The synthesis of (R,S)-[4-11C]baclofen, the first 11C-labeled GABAB agonist, was demonstrated via Michael addition of nitro[11C]methane as a key step. A tetrabutylammonium fluoride promoted Michael addition of nitro[11C]methane to methyl p-chlorocinnamate, followed by the nitro-group reduction in the presence of NiCl2 and NaBH4 in aqueous MeOH and alkaline hydrolysis yielded (R,S)-[4-11C]baclofen in 36.4+/-1.8% radiochemical conversion in three steps within 20 min.


Assuntos
Baclofeno/síntese química , Metano/análogos & derivados , Nitroparafinas/química , Compostos Radiofarmacêuticos/síntese química , Baclofeno/química , Baclofeno/farmacologia , Radioisótopos de Carbono , Agonistas GABAérgicos , Agonistas dos Receptores de GABA-B , Metano/química , Tomografia por Emissão de Pósitrons , Compostos Radiofarmacêuticos/química , Receptores de GABA-B/metabolismo
16.
Nucl Med Biol ; 36(7): 801-9, 2009 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-19720292

RESUMO

INTRODUCTION: The aim of this study was to evaluate N-benzyl-N-[(11)C]methyl-2-(7-methyl-8-oxo-2-phenyl-7,8-dihydro-9H-purin-9-yl)acetamide ([(11)C]DAC) as a novel peripheral-type benzodiazepine receptor (PBR) ligand for tumor imaging. METHODS: [(11)C]DAC was synthesized by the reaction of a desmethyl precursor with [(11)C]CH(3)I. In vitro uptake of [(11)C]DAC was examined in PBR-expressing C6 glioma and intact murine fibrosarcoma (NFSa) cells. In vivo distribution of [(11)C]DAC was determined using NFSa-bearing mice and small-animal positron emission tomography (PET). RESULTS: [(11)C]DAC showed specific binding to PBR in C6 glioma cells, a standard cell line with high PBR expression. Specific binding of [(11)C]DAC was also confirmed in NFSa cells, a target tumor cell line in this study. Results of PET experiments using NFSa-bearing mice, showed that [(11)C]DAC was taken up specifically into the tumor, and pretreatment with PK11195 abolished the uptake. CONCLUSIONS: [(11)C]DAC was taken up into PBR-expressing NFSa. [(11)C]DAC is a promising PET ligand that can be used for imaging PBR in tumor-bearing mice.


Assuntos
Acetamidas/farmacocinética , Proteínas de Transporte/metabolismo , Neoplasias/diagnóstico por imagem , Neoplasias/metabolismo , Purinas/farmacocinética , Receptores de GABA-A/metabolismo , Receptores de GABA/metabolismo , Acetamidas/química , Animais , Transporte Biológico , Imuno-Histoquímica , Isoquinolinas/farmacologia , Masculino , Camundongos , Neoplasias/patologia , Tomografia por Emissão de Pósitrons , Ligação Proteica/efeitos dos fármacos , Purinas/química , Radioquímica , Ratos , Distribuição Tecidual
17.
J Neurosci Methods ; 184(1): 37-41, 2009 Oct 30.
Artigo em Inglês | MEDLINE | ID: mdl-19619585

RESUMO

Glutamine synthetase (GS) is selectively localized in astrocytes and has important roles in the central nervous system (CNS). Cerebral extracellular excess ammonia and glutamate are taken up by astrocytes and converted to glutamine via GS to protect the CNS against neurotoxicity. In this study, we monitored cerebral extracellular 13N-glutamine derived from 13N-ammonia as a potential marker for astroglial metabolism using in vivo microdialysis combined with ultra performance liquid chromatography-radiometric detection. This method allowed rapid and highly sensitive radiometric analysis of 13N-ammonia and its metabolite, 13N-glutamine, in striatal extracellular fluid with good time resolution. Inhibition of GS with methionine sulfoximine resulted in a decrease of extracellular 13N-glutamine accompanied by an increase of 13N-ammonia as compared with control. Fluorocitrate, a selective inhibitor of glial metabolism, also decreased 13N-glutamine production and increased unmetabolized 13N-ammonia. In contrast, 13N-glutamine was increased with 5 mmol/kg of ammonium acetate without significant changes in 13N-ammonia as compared with control. These results suggest that the concentration of extracellular 13N-glutamine strongly reflects the biological changes in the metabolic activity of astroglial cells.


Assuntos
Amônia/metabolismo , Cromatografia Líquida/métodos , Corpo Estriado/metabolismo , Espaço Extracelular/metabolismo , Microdiálise/métodos , Radiometria/métodos , Acetatos/farmacologia , Amônia/sangue , Animais , Astrócitos/efeitos dos fármacos , Astrócitos/metabolismo , Citratos/farmacologia , Corpo Estriado/efeitos dos fármacos , Glutamato-Amônia Ligase/antagonistas & inibidores , Glutamina/metabolismo , Masculino , Metionina Sulfoximina/farmacologia , Radioisótopos de Nitrogênio/sangue , Radioisótopos de Nitrogênio/metabolismo , Ratos , Ratos Sprague-Dawley , Fatores de Tempo
18.
Synapse ; 63(11): 961-71, 2009 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-19593823

RESUMO

The aim of this study was to evaluate N-benzyl-N-[11C]methyl-2-(7-methyl-8-oxo-2-phenyl-7,8-dihydro-9H-purin-9-yl)acetamide ([11C]DAC) as a new translocator protein (18 kDa) [TSPO, formerly known as the peripheral-type benzodiazepine receptor (PBR)] positron emission tomography (PET) ligand in normal mice and unilateral kainic acid (KA)-lesioned rats. DAC is a derivative of AC-5216, which is a potent and selective PET ligand for the clinical investigation of TSPO. The binding affinity and selectivity of DAC for TSPO were similar to those of AC-5216, and DAC was less lipophilic than AC-5216. The distribution pattern of [11C]DAC was in agreement with TSPO distribution in rodents. No radioactive metabolite of [11C]DAC was found in the mouse brain, although it was metabolized rapidly in mouse plasma. Using small-animal PET, we examined the in vivo binding of [11C]DAC for TSPO in KA-lesioned rats. [11C]DAC and [11C]AC-5216 exhibited similar brain uptake in the lesioned and nonlesioned striatum, respectively. The binding of [11C]DAC to TSPO was increased significantly in the lesioned striatum, and [(11)C]DAC showed good contrast between the lesioned and nonlesioned striatum (the maximum ratio was about threefold). In displacement experiments, the uptake of [11C]DAC in the lesioned striatum was eventually blocked using an excess of either unlabeled DAC or PK11195 injected. [11C]DAC had high in vivo specific binding to TSPO in the injured rat brain. Therefore, [11C]DAC is a useful PET ligand for TSPO imaging, and its specific binding to TSPO is suitable as a new biomarker for brain injury.


Assuntos
Lesões Encefálicas/diagnóstico por imagem , Purinas/metabolismo , Purinas/farmacologia , Compostos Radiofarmacêuticos/metabolismo , Compostos Radiofarmacêuticos/farmacologia , Receptores de GABA/metabolismo , Animais , Radioisótopos de Carbono/química , Radioisótopos de Carbono/metabolismo , Radioisótopos de Carbono/farmacologia , Cromatografia Líquida de Alta Pressão , Agonistas de Aminoácidos Excitatórios/toxicidade , Ácido Caínico/toxicidade , Ligantes , Masculino , Camundongos , Tomografia por Emissão de Pósitrons , Purinas/química , Ensaio Radioligante , Compostos Radiofarmacêuticos/química , Ratos , Ratos Sprague-Dawley , Receptores de GABA/química , Distribuição Tecidual
19.
Bioorg Med Chem ; 17(15): 5665-75, 2009 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-19586774

RESUMO

In this study, we synthesized and evaluated several amino 4-hydroxy-2(1H)-quinolone (4HQ) derivatives as new PET radioligand candidates for the glycine site of the NMDA receptors. Among these ligands, we discovered that 7-chloro-4-hydroxy-3-{3-(4-methylaminobenzyl) phenyl}-2-(1H)-quinolone (12) and 5-ethyl-7-chloro-4-hydroxy-3-(3-methylaminophenyl)-2(1H)-quinolone (32) have high affinity for the glycine site (K(i) values; 11.7 nM for 12 and 11.8 nM for 32). In vitro autoradiography experiments indicated that [(11)C]12 and [(11)C]32 showed high specific binding in the brain slices, which were strongly inhibited by both glycine agonists and antagonists. In vivo brain uptake of these (11)C-labeled 4HQs were examined in normal mice. Cerebellum to blood ratio of accumulation, of both [(11)C]12 and [(11)C]32 at 30 min were 0.058, which were slightly higher than those of cerebrum to blood ratio (0.043 and 0.042, respectively). These results indicated that [(11)C]12 and [(11)C]32 have poor blood brain barrier permeability. Although the plasma protein-binding ratio of [(11)C]32 was much lower than methoxy analogs (71% vs 94-98%, respectively), [(11)C]32 still binds with plasma protein strongly. It is conjectured that still acidic moiety and high affinity with plasma protein of [(11)C]32 may prevent in vivo brain uptake. In conclusion, [(11)C]12 and [(11)C]32 are unsuitable for imaging cerebral NMDA receptors.


Assuntos
Tomografia por Emissão de Pósitrons/métodos , Quinolonas/química , Quinolonas/metabolismo , Compostos Radiofarmacêuticos/química , Compostos Radiofarmacêuticos/metabolismo , Receptores de N-Metil-D-Aspartato/análise , Animais , Autorradiografia , Sítios de Ligação , Encéfalo/metabolismo , Glicina/metabolismo , Camundongos , Estrutura Molecular , Ligação Proteica , Quinolonas/sangue , Quinolonas/farmacocinética , Radioquímica , Compostos Radiofarmacêuticos/sangue , Compostos Radiofarmacêuticos/farmacocinética , Receptores de N-Metil-D-Aspartato/metabolismo , Relação Estrutura-Atividade
20.
Bioorg Med Chem Lett ; 19(13): 3439-41, 2009 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-19481934

RESUMO

The nitroaldol reaction of nitro[(11)C]methane and formaldehyde using EtOH and EtONa efficiently provided 2-nitro[(11)C]ethanol in 3min. The nitro group reduction in the presence of NiCl(2) and NaBH(4) in MeOH followed by purification using semi-preparative HPLC using 10% EtOH aqueous solution as an eluent proved to be a practical and accessible method for the synthesis of 2-amino[2-(11)C]ethanol.


Assuntos
Etanolaminas/síntese química , Metano/análogos & derivados , Nitroparafinas/química , Compostos Radiofarmacêuticos/síntese química , Isótopos de Carbono/química , Etanolaminas/química , Metano/síntese química , Metano/química , Nitroparafinas/síntese química , Compostos Radiofarmacêuticos/química , Fatores de Tempo
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