RESUMO
Tumor diagnosis, especially at the early stages, holds immense significance. Focal adhesion kinase (FAK) is often highly expressed across various types of tumors, making it a promising target for both therapy and diagnosis. In this study, seven novel inhibitors were designed and synthesized. The inhibitory activity of these compounds against FAK was notably potent, with an IC50 range of 1.27-1968 nM. In particular, compounds 7a and 7c, with IC50 values of 5.59 nM and 1.27 nM, respectively, were radiolabeled with F-18 and then evaluated with S-180 tumor-bearing mice. Subsequently, they exhibited moderate-to-high tumor uptake values, with [18F]7a showing 1.39 ± 0.30%ID/g at 60 min post injection and [18F]7c demonstrating 6.58 ± 0.46%ID/g at 30 min post injection. In addition, the results from docking studies revealed the binding specifics of the studied compounds. Overall, these findings hold the potential to offer valuable guidance for enhancing the development of radiotracers and enzyme inhibitors.
Assuntos
Antineoplásicos , Neoplasias , Camundongos , Animais , Proteína-Tirosina Quinases de Adesão Focal , Simulação de Acoplamento Molecular , Neoplasias/diagnóstico por imagem , Neoplasias/tratamento farmacológico , Compostos Radiofarmacêuticos/química , Transporte Biológico , Inibidores de Proteínas Quinases/química , Linhagem Celular Tumoral , Relação Estrutura-Atividade , Antineoplásicos/químicaRESUMO
Focal adhesion kinase (FAK) is considered a promising target for the diagnosis and treatment of cancer. In this work, a series of N,N'-(4-((5-bromo-2-(phenylamino)pyrimidin-4-yl)amino)-1,3-phenylene)diacetamide derivatives were synthesized and evaluated as FAK inhibitors and radiotracers. The studied compounds, possessing the same phenylene-diacetamide chain, exhibited high to moderate enzyme inhibition values (IC50) ranging from 3.7 to 108.0 nM. Compound 13a, which exhibits high FAK enzyme inhibition with an IC50 value of 3.7, could effectively suppress the tumor growth. Furthermore, three compounds were radiolabeled with F-18. Among them, a higher tumor uptake value was observed for [18F]17 (3.73 ± 0.10% ID/g) and [18F]13a (3.66 ± 0.02% ID/g). Compound [18F]18 displayed the highest tumor/blood (35.75) value at 120 min postinjection. In addition, the results from docking studies revealed the binding mechanism of the studied compounds. The findings of this study may provide useful guidance to improve the development of radiotracers and enzyme inhibitors.
Assuntos
Antineoplásicos , Neoplasias , Antineoplásicos/química , Linhagem Celular Tumoral , Proliferação de Células , Desenho de Fármacos , Ensaios de Seleção de Medicamentos Antitumorais , Proteína-Tirosina Quinases de Adesão Focal/metabolismo , Humanos , Simulação de Acoplamento Molecular , Neoplasias/diagnóstico por imagem , Neoplasias/tratamento farmacológico , Inibidores de Proteínas Quinases/química , Inibidores de Proteínas Quinases/farmacologia , Relação Estrutura-AtividadeRESUMO
There are two important topics in the field of cancer research: one is targeted molecular therapy and the other is tumor molecular imaging. Focal adhesion kinase (FAK) is considered as an attractive target for oncologic diagnosis and therapy. A series of 2,4-diaminopyrimidine derivatives were labeled with 18F to study their biological properties and their potential as positron emission tomography tumor imaging agents. They inhibited the activity of FAK with IC50 values in the wide range of 0.6-2164 nM, among which the IC50 of Q6 was 3.2 nM. For the biodistribution in S180-bearing mice, the corresponding [18F]Q6 was relatively good, with the highest uptake of 3.35 ± 0.32 % ID/g at 30 min postinjection, with a tumor/muscle ratio of 2.08 and a tumor/bone ratio of 2.48. Accordingly, [18F]Q6 was considered as a potential PET imaging agent for tumor diagnosis.
Assuntos
Neoplasias/diagnóstico , Tomografia por Emissão de Pósitrons/métodos , Inibidores de Proteínas Quinases/administração & dosagem , Pirimidinas/administração & dosagem , Compostos Radiofarmacêuticos/administração & dosagem , Animais , Linhagem Celular Tumoral , Modelos Animais de Doenças , Desenho de Fármacos , Radioisótopos de Flúor/administração & dosagem , Radioisótopos de Flúor/química , Radioisótopos de Flúor/farmacocinética , Quinase 1 de Adesão Focal/antagonistas & inibidores , Quinase 1 de Adesão Focal/metabolismo , Humanos , Concentração Inibidora 50 , Camundongos , Simulação de Acoplamento Molecular , Neoplasias/patologia , Inibidores de Proteínas Quinases/química , Inibidores de Proteínas Quinases/farmacocinética , Pirimidinas/química , Pirimidinas/farmacocinética , Compostos Radiofarmacêuticos/química , Compostos Radiofarmacêuticos/farmacocinética , Distribuição TecidualRESUMO
As a type of intracellular nonreceptor tyrosine kinase, focal adhesion kinase (FAK) can be highly expressed in most types of tumours and is thus regarded as a promising antitumour target. In this study, a series of novel 2,4-diaminopyrimidine FAK-targeted inhibitors were designed, synthesized and characterized by 1H NMR, 13C HNMR, and HRMS spectra. These compounds, with an IC50 range of 5.0-205.1 nM, showed superior inhibitory activity against FAK. Two compounds, [18F]Q-2 and [18F]Q-4, with respective IC50 values of 5.0 nM and 21.6 nM, were labelled by 18F, accompanied by evaluation of their biodistributions. For [18F]Q-2, at 30 min post-injection, promising target-to-nontarget ratios were observed, associated with tumour/blood, tumour/muscle, and tumour/bone ratios of 1.17, 2.99 and 2.19, respectively. The results indicated that [18F]Q-2 is a potential PET tracer for tumour diagnosis.
Assuntos
Aminopiridinas/farmacologia , Quinase 1 de Adesão Focal/antagonistas & inibidores , Neoplasias/diagnóstico por imagem , Inibidores de Proteínas Quinases/farmacologia , Compostos Radiofarmacêuticos/farmacologia , Aminopiridinas/síntese química , Aminopiridinas/metabolismo , Animais , Desenho de Fármacos , Feminino , Radioisótopos de Flúor/química , Quinase 1 de Adesão Focal/metabolismo , Humanos , Camundongos , Simulação de Acoplamento Molecular , Estrutura Molecular , Ligação Proteica , Inibidores de Proteínas Quinases/síntese química , Inibidores de Proteínas Quinases/metabolismo , Compostos Radiofarmacêuticos/síntese química , Compostos Radiofarmacêuticos/metabolismo , Relação Estrutura-AtividadeRESUMO
The α7-nicotinic acetylcholine receptor (α7-nAChR) subtype, is found to have a connection with the pathogenesis of a variety of psychiatric and neurological disorders. Herein, we report the development of radioiodinated 9-fluorenone derivatives as single-photon emission computed tomography (SPECT) imaging tracers for α7-nAChRs. Among the derivatives, the best member of the series 10 (Kiâ¯=â¯2.23â¯nM) were radiolabeled with 125I for in vitro and in vivo studies. The radiotracer [125I]10 exhibited robust brain uptake and specifically labeled α7-nAChRs with a peak uptake value of 9.49⯱â¯0.87%ID/g in brain. Blocking studies demonstrated that the tracer was highly specific toward α7-nAChR. Furthermore, ex vivo autoradiography and micro-SPECT/CT dynamic imaging in mice confirmed the excellent imaging properties. In addition, molecular docking was also performed to rationalize the potency of the chosen compounds towards α7-nAChRs. To conclude, compound 10 could serve as a promising radiotracer for the α7-nAChRs.
Assuntos
Fluorenos/síntese química , Simulação de Acoplamento Molecular/métodos , Tomografia Computadorizada de Emissão de Fóton Único/métodos , Receptor Nicotínico de Acetilcolina alfa7/metabolismo , Animais , Fluorenos/química , CamundongosRESUMO
Ent-kaurene diterpenoids are the largest group of known Isodon diterpenoids. Among them, oridonin is accumulated in the leaves, and is the most frequently studied compound because of its antitumor and antibacterial activities. We have identified five copalyl diphosphate synthase (CPS) and six kaurene synthase-like (KSL) genes by transcriptome profiling of Isodon rubescens leaves. An in vitro assay assigns ten of them to five different diterpene biosynthesis pathways, except IrCPS3 that has a mutation in the catalytic motif. The Lamiaceae-specific clade genes (IrCPS1 and IrCPS2) synthesize the intermediate copalyl diphosphate (normal-CPP), while IrCPS4 and IrCPS5 synthesize the intermediate ent-copalyl diphosphate (ent-CPP). IrKSL2, IrKSL4, and IrKSL5 react with ent-CPP to produce an ent-isopimaradiene-like compound, ent-atiserene and ent-kaurene, respectively. Correspondingly, the Lamiaceae-specific clade genes IrKSL1 or IrKSL3 combined with normal-CPP led to the formation of miltiradiene. The compound then underwent aromatization and oxidization with a cytochrome P450 forming two related compounds, abietatriene and ferruginol, which were detected in the root bark. IrKSL6 reacts with normal-CPP to produce isopimaradiene. IrKSL3 and IrKSL6 have the γßα tridomain structure, as these proteins tend to possess the bidomain structure of IrKSL1, highlighting the evolutionary history of KSL gene domain loss and further elucidating chemical diversity evolution from a macroevolutionary stance in Lamiaceae.
Assuntos
Alquil e Aril Transferases/genética , Genes de Plantas , Isodon/enzimologia , Isodon/genética , Alquil e Aril Transferases/química , Sequência de Aminoácidos , Vias Biossintéticas , Diterpenos do Tipo Caurano/química , Diterpenos do Tipo Caurano/metabolismo , Cromatografia Gasosa-Espectrometria de Massas , Regulação da Expressão Gênica de Plantas , Anotação de Sequência Molecular , Filogenia , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Alinhamento de Sequência , Análise de Sequência de RNA , Transcriptoma/genéticaRESUMO
We report a facile and highly efficient method that copper-catalyzed intramolecular annulation to synthesize 3-hydroxy-1-indanones employing simple 2-ethynylbenzaldehyde as starting materials was achieved successfully. This protocol provided a simple synthetic approach to afford 3-hydroxy-1-indanones under mild conditions in good to excellent yields.
RESUMO
Four novel 18 F-labeled quinazoline derivatives with low lipophilicity, [18 F]4-(2-fluoroethoxy)-6,7-dimethoxyquinazoline ([18 F]I), [18 F]4-(3-((4-(2-fluoroethoxy)-7-methoxyquinazolin-6-yl)oxy)propyl)morpholine ([18 F]II), [18 F]4-(2-fluoroethoxy)-7-methoxy-6-(2-methoxyethoxy)quinazoline ([18 F]III), and [18 F]4-(2-fluoroethoxy)-6,7-bis(2-methoxyethoxy)quinazoline ([18 F]IV), were synthesized via a 2-step radiosynthesis procedure with an overall radiochemical yield of 10% to 38% (without decay correction) and radiochemical purities of >98%. The lipophilicity and stability of labeled compounds were tested in vitro. The log P values of the 4 radiotracers ranged from 0.52 to 1.07. We then performed ELISA to measure their affinities to EGFR-TK; ELISA assay results indicated that each inhibitor was specifically bounded to EGFR-TK in a dose-dependent manner. The EGFR-TK autophosphorylation IC50 values of [18 F]I, [18 F]II, [18 F]III, and [18 F]IV were 7.732, 0.4698, 0.1174, and 0.1176 µM, respectively. All labeled compounds were evaluated via cellular uptake and blocking studies in HepG2 cell lines in vitro. Cellular uptake and blocking experiment results indicated that [18 F]I and [18 F]III had excellent cellular uptake at 120-minute postinjection in HepG2 carcinoma cells (51.80 ± 3.42%ID/mg protein and 27.31 ± 1.94%ID/mg protein, respectively). Additionally, biodistribution experiments in S180 tumor-bearing mice in vivo indicated that [18 F]I had a very fast clearance in blood and a relatively high uptake ratio of tumor to blood (4.76) and tumor to muscle (1.82) at 60-minute postinjection. [18 F]III had a quick clearance in plasma, and its highest uptake ratio of tumor to muscle was 2.55 at 15-minute postinjection. These experimental results and experiences were valuable for the further exploration of novel radiotracers of quinazoline derivatives.
Assuntos
Radioisótopos de Flúor/química , Neoplasias Experimentais/diagnóstico por imagem , Tomografia por Emissão de Pósitrons/métodos , Quinazolinas/química , Compostos Radiofarmacêuticos/síntese química , Animais , Bovinos , Feminino , Células Hep G2 , Humanos , Camundongos , Camundongos Endogâmicos ICR , Compostos Radiofarmacêuticos/farmacocinética , Distribuição TecidualRESUMO
Scutellaria barbata (Lamiaceae) is an important medicinal herb widely used in China, Korea, India, and other Asian countries. Neo-clerodane diterpenoids are the largest known group of Scutellaria diterpenoids and show promising cytotoxic activity against several cancer cell lines. Here, Illumina-based deep transcriptome analysis of flowers, the aerial parts (leaf and stem), and roots of S. barbata was used to explore terpenoid-related genes. In total, 121,958,564 clean RNA-sequence reads were assembled into 88,980 transcripts, with an average length of 1370 nt and N50 length of 2144 nt, indicating high assembly quality. We identified nearly all known terpenoid-related genes (33 genes) involved in biosynthesis of the terpenoid backbone and 14 terpene synthase genes which generate skeletons for different terpenoids. Three full length diterpene synthase genes were functionally identified using an in vitro assay. SbTPS8 and SbTPS9 were identified as normal-CPP and ent-CPP synthase, respectively. SbTPS12 reacts with SbTPS8 to produce miltiradiene. Furthermore, SbTPS12 was proven to be a less promiscuous class I diterpene synthase. These results give a comprehensive understanding of the terpenoid biosynthesis in S. barbata and provide useful information for enhancing the production of bioactive neo-clerodane diterpenoids through genetic engineering.
Assuntos
Alquil e Aril Transferases/genética , Diterpenos/metabolismo , Regulação Enzimológica da Expressão Gênica , Regulação da Expressão Gênica de Plantas , Scutellaria/genética , Scutellaria/metabolismo , Transcriptoma , Alquil e Aril Transferases/metabolismo , Biologia Computacional/métodos , Diterpenos/química , Perfilação da Expressão Gênica , Sequenciamento de Nucleotídeos em Larga Escala , Redes e Vias Metabólicas/genética , Anotação de Sequência Molecular , Filogenia , Scutellaria/classificaçãoRESUMO
Fatty acids are myocardial metabolic agent for detecting myocardial ischemia and infraction. However, no 99m Tc-labeled fatty acids had potential use in clinical practice. In this study, 99m Tc-CpTT-10-oxo-para-PPA (1d), 99m Tc-CpTT-11-oxo-para-PPA (2d), 99m Tc-CpTT-12-oxo-para-PPA (3d), 99m Tc-CpTT-11-oxo-ortho-PPA (4d), and 99m Tc-CpTT-11-oxo-meta-PPA (5d) were synthesized by a double ligand transfer reaction, and their biological behaviors were investigated. Compound 2d achieved good heart to blood ratio (3.39 at 5 min after intravenous), and 2d showed high-heart uptake of 6.20% ID/g at 5 minutes after injection. Compound 3d displayed a prolonged retention in the myocardium (1.43% ID/g at 60 min after injection). Radioactivity accumulation in the lungs, spleen, and blood was eliminated rapidly. In vivo, metabolite analysis presented that compound 6d may be metabolite of 2d through ß-oxidation in tissue. Unfortunately, the biodistribution studies of 1d, 2d, 3d, 4d, and 5d showed fast heart clearance and poor heart to liver ratios, which suggested that the 5 99m Tc-labeled fatty acid analogues cannot be used for diagnosis.
Assuntos
Ácidos Graxos/química , Coração/diagnóstico por imagem , Tecnécio/química , Tomografia Computadorizada de Emissão de Fóton Único/métodos , Animais , Estabilidade de Medicamentos , Ácidos Graxos/síntese química , Ácidos Graxos/farmacocinética , Camundongos , Traçadores Radioativos , Radioquímica , Distribuição TecidualRESUMO
This study reports the synthesis and evaluation studies of 6'-cyclopentadienyl tricarbonyl technetium-99m 6'-oxo-11-(hexanamide)undecanoic acid (1). 1 was prepared with 26.5 ± 4.3% of radiochemical yield and more than 98% of radiochemical purity. Tissue distribution in mice showed that high radioactivity accumulated in the heart with moderate clearance. However, unfortunately, similar to those of other technetium-labeled fatty acid analogs, the biodistribution studies of 1 in mice showed poor heart-to-blood ratios, which suggested that 1 cannot be used as myocardial imaging agent, and it may provide a theoretical basis or a lab experience for corresponding fatty acid tracers studies.
Assuntos
Compostos de Organotecnécio/síntese química , Compostos Radiofarmacêuticos/síntese química , Animais , Feminino , Camundongos , Imagem de Perfusão do Miocárdio , Compostos de Organotecnécio/farmacocinética , Compostos Radiofarmacêuticos/farmacocinética , Ratos , Distribuição TecidualRESUMO
PURPOSE: The (131)I-tRRL small peptide probe has been identified in our previous study as a robust tumor molecular radiopharmaceutical that specifically binds to tumor-derived endothelial cells. In this study we developed a smaller structure cyclic tRRL (g2) radiolabeled with (99m)Tc as a novel and optimized peptide probe on tumor angiogenesis molecular imaging. METHODS: Both tRRL (g2) and control peptide GGG (g2), as well as FITC-RRL (g2) and FITC-GGG (g2) peptide chains were synthesized and characterized by high performance liquid chromatography (HPLC) and electrospray ionization mass spectrometry (EMI-MS) analysis. After synthesis and purification, the peptides were radiolabeled with (99m)Tc by a one-step method for quantitative cell-binding assay and biodistribution experiments. A cell adhesion assay was performed to image tumor-derived endothelial cells-binding specificity with the novel RRL (g2) peptide probe in vitro. The biodistribution experiment was performed to show the tumor uptake of (99m)Tc-RRL (g2) compared with other tissues in human glioblastoma-bearing nude mice in vivo. RESULTS: FITC-RRL (g2) had significantly higher tumor-derived endothelial cell-binding affinity and specificity than the control FITC-GGG (g2). (99m)Tc-RRL (g2) had higher tumor uptake (2,578 ± 0.293 at 30 min postinjection) and longer tumor retention than (99m)Tc-GGG (g2) in the tumor models tested. The tumor specificity of (99m)Tc-RRL (g2) was also confirmed by successful quantitative cell binding experiments. CONCLUSION: (99m)Tc-RRL (g2) has more good characteristics such as higher tumor uptake ratio and short half life time compared with (131I)-tRRL. The information obtained here may guide the future development of RRL peptide-based tumor angiogenesis molecular imaging and internal radiotherapeutic agents targeting tumor neovascularity.
Assuntos
Neoplasias Encefálicas/diagnóstico por imagem , Glioblastoma/diagnóstico por imagem , Imagem Molecular/métodos , Neovascularização Patológica , Oligopeptídeos , Compostos de Organotecnécio , Compostos Radiofarmacêuticos , Animais , Neoplasias Encefálicas/metabolismo , Neoplasias Encefálicas/patologia , Linhagem Celular Tumoral , Desenho Assistido por Computador , Células Endoteliais/diagnóstico por imagem , Células Endoteliais/metabolismo , Glioblastoma/metabolismo , Glioblastoma/patologia , Meia-Vida , Humanos , Camundongos , Camundongos Nus , Simulação de Acoplamento Molecular , Oligopeptídeos/síntese química , Oligopeptídeos/farmacocinética , Compostos de Organotecnécio/síntese química , Compostos de Organotecnécio/farmacocinética , Cintilografia , Compostos Radiofarmacêuticos/síntese química , Compostos Radiofarmacêuticos/farmacocinética , Distribuição Tecidual , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/metabolismoRESUMO
For over 40 years, none of the previous 99mTc-labeled fatty acids for myocardial imaging has potential clinical use. 99mTc-(C10-6-thia-CO2H)(MIBI)5 is the first 99mTc-labeled fatty acid to exhibit good myocardial uptake (2.06 ± 0.06%ID/g) at 60 min post injection, high heart-to-liver ratio (6.43 ± 1.85 and 9.68 ± 0.76), high heart-to-lung ratio (9.48 ± 1.39 and 11.02 ± 0.89), and high heart-to-blood ratio (164.01 ± 43.51 and 197.36 ± 32.29) at 60 and 120 min in Sprague-Dawley (SD) rats, respectively. It also demonstrated excellent myocardial imaging quality. The above target-to-nontarget ratios exceeded those of [123I]BMIPP and were higher than or close to those of 99mTc-MIBI at 60 and 120 min. Most of 99mTc-(C10-6-thia-CO2H)(MIBI)5 was partially ß-oxidized to protein-bound metabolites in myocardium. Administration of trimetazidine dihydrochloride (TMZ, a fatty acid ß-oxidation inhibitor) to rats caused 51% reduction in the myocardial uptake of 99mTc-(C10-6-thia-CO2H)(MIBI)5 and 61% reduction in the distribution of 99mTc-radioactivity in a residual tissue pellet at 60 min, indicating its considerable sensitivity to myocardial fatty acid ß-oxidation.
Assuntos
Coração , Miocárdio , Ratos , Animais , Ratos Sprague-Dawley , Coração/diagnóstico por imagem , Miocárdio/metabolismo , Tomografia Computadorizada de Emissão de Fóton Único/métodos , Ácidos Graxos/metabolismo , Compostos de Organotecnécio/metabolismoRESUMO
Background: It has been confirmed that the α7-nicotinic acetylcholine receptor (α7nAChR) is an important target for identifying vulnerable atherosclerotic plaques. Previously, we successfully designed and synthesized a series of 18F-labeled PET molecular probes targeting α7nAChR, which are mainly used in the diagnosis of Alzheimer's disease. Based on the characteristics of α7nAChR in blood vessels, we have firstly screened for a suitable novel 18F-labeled PET molecular probe ([18F]YLF-DW), with high selectivity for α7nAChR over α4ß2nAChR and a good effect for the imaging of atherosclerotic animal models, to effectively identify vulnerable atherosclerotic plaques at an early stage. Meanwhile, we compared it with the "gold standard" pathological examination of atherosclerosis, to verify the reliability of [18F]YLF-DW in early diagnosis of atherosclerosis. Methods: The vulnerable atherosclerotic plaques model of ApoE-/-mice were successfully established. Then based on the methods of 3D-QSAR and molecular docking, we designed oxazolo[4,5-b] pyridines and fluorenone compounds, which are targeted at α7nAChR. Through further screening, a novel alpha7 nicotinic acetylcholine receptor radioligand ([18F]YLF-DW) was synthesized and automatically 18F-labeled using a Stynthra RNplus module. Subsequently, we employed [18F]YLF-DW for the targeting of α7nAChR in atherosclerotic plaques and control group, using a micro-PET/CT respectively. After imaging, the mice were sacrificed by air embolism and the carotid arteries taken out for making circular sections. The paraffin embedded specimens were sectioned with 5 µm thickness and stained with oil red. After staining, immunohistochemistry experiment was carried out to verify the effect of micro-PET/CT imaging. Results: The micro-PET/CT imaging successfully identified the vulnerable atherosclerotic plaques in the carotid arteries of ApoE-/-mice; whereas, no signal was observed in normal control mice. In addition, compared with the traditional imaging agent [18F]FDG, [18F]YLF-DW had a significant effect on the early plaques imaging of carotid atherosclerosis. The results of oil red staining and immunohistochemistry also showed early formations of carotid plaques in ApoE-/-mice and provided pathological bases for the evaluation of imaging effect. Conclusion: We innovated to apply the novel molecular probe ([18F]YLF-DW) to the identification of vulnerable atherosclerotic plaques in carotid arteries, to detect atherosclerosis early inflammatory response and provide powerful input for the early diagnosis of atherosclerotic lesions, which may play an early warning role in cardiovascular acute events.
RESUMO
Classical (99m)Tc(CO)(3)(+) and novel (99m)Tc(CO)(2)(NO)(2+) cores complexed with flavonol derivatives were prepared. Autoradiography of postmortem AD transgenic mice (Tg C57, APP, PS1 12-month-old) brain section confirmed the binding property of [(99m)Tc(CO)(3)(+)-3-OH-flavone](0) to Abeta((1-40)) aggregates, while the novel (99m)Tc(CO)(2)(NO)(2+) labeled compounds showed no binding sites in AD transgenic mice sections. Intravenous administration of [(99m)Tc(CO)(3)(+)-3-OH-flavone](0) resulted in moderate brain uptake (0.48+/-0.05%ID/g) at 5 min post-injection and slow clearance from the brain issues in 2h post-injection (120 min: 0.39+/-0.08%ID/g). Then an Abeta((1-40))-receptor-targeted Re(CO)(3)(+)-3-OH-flavone, was prepared to identify the structure of the technetium complex. UV-vis absorption and fluorescence emission properties have been studied at room temperature in order to determine the natures of the lowest electronically excited states of Re(CO)(3)(+)-3-OH-flavone and the ligand. The fluorescent rhenium complex Re(CO)(3)(+)-3-OH-flavone showed high affinity for Abeta((1-40)) aggregates in vitro by fluorescence spectra (dissociation constant (K(d))=11.16 nM). In conclusion, the results suggested that (99m)Tc(CO)(3)(+)-3-OH-flavone should be a suitable candidate as Abeta plaque SPECT imaging agent for AD.
Assuntos
Peptídeos beta-Amiloides/metabolismo , Flavonóis/química , Compostos de Organotecnécio/química , Fragmentos de Peptídeos/metabolismo , Rênio/química , Animais , Cromatografia Líquida de Alta Pressão , Flavonóis/metabolismo , Camundongos , Camundongos Transgênicos , Compostos de Organotecnécio/metabolismo , Rênio/metabolismo , Espectrometria de Fluorescência , Espectrofotometria UltravioletaRESUMO
In this work, methods for predicting the distribution of compounds between blood and tissue were investigated using nonlinear regression analysis. For the tissue/blood partition coefficient, 282 compounds and 810 activity data for seven tissues were selected. Twenty-four parameters were studied for each state of the compound. A study set with the most compounds and activity data in similar studies was established, and a model with good prediction ability was obtained. A total of 773 data points were randomly divided into two data sets: the training set contained 623 data points (n = 623, r = 0.822, s = 0.438, F = 142.2, and Q = 0.814) and the test set contained 150 data points (n = 150, r = 0.814, and s = 0.334). Furthermore, individual tissue/blood distribution coefficients were also studied in depth to obtain separate models for predicting the distribution coefficient of a drug between blood and a tissue. By applying these models, not only can the tissue/blood distribution coefficient or single tissue/blood distribution coefficient of the seven tissues and organs of the human body be predicted, but the distribution of the drug molecules in different states (neutral, cation, and anion) in the three tissue components can also be predicted.
Assuntos
Modelos Biológicos , Farmacocinética , Distribuição Tecidual , Ânions , Cátions , HumanosRESUMO
In the title compound, C(14)H(27)NO(5), the hydr-oxy group and one of the acetate carbonyl O atoms are linked by an intra-molecular O-Hâ¯O hydrogen bond, forming an eight-membered ring. This inter-action gives rise to an asymmetric mol-ecular conformation.
RESUMO
A neutral compound Re(CO)(3)(L) (L: 2-((2-(2,6-diethylphenylamino)-2-oxoethyl)(2-ethoxy-2-oxoethyl)amino)acetic acid, an IDA analogue) has been synthesized and evaluated for in vitro imaging probes of beta-amyloid (Abeta) aggregates. Results of X-ray measurement of Re(CO)(3)(L) demonstrated that the coordination mode of Re(CO)(3)(L) was different from that of classical Re/Tc(I) (tricarbonyl)-IDA analogues; the structure of Re(CO)(3)(L) was confirmed by means of infrared spectrum, HPLC-UV, TOF MS, and X-ray measurements (Cambridge Crystallographic Data Centre number is 732731): monoclinic P2(1)/c, a = 15.6636 (12) A, b = 10.9360 (8) A, c = 27.756 (2) A, alpha = 90.000 (0) degrees , beta = 90.783 (5) degrees , gamma = 90.000 (0) degrees , and Z = 8. The binding affinity for beta-amyloid plaques was assessed by in vitro binding assay using preformed synthetic Abeta((1-40)) aggregates. The neutral compound Re(CO)(3)(L) showed binding affinity to Abeta aggregates at micromolar level by fluorescence spectroscopy, and this work will encourage for further exploration of imaging agents labeled by (99m)Tc(CO)(3) (+) center as probes for beta-amyloid plaques in vivo.
RESUMO
A series of 9H-fluoren-9-one substituents were synthesized and evaluated for imaging cerebral α7-nAChRs. Meta-iodine substituted 9-fluorenone 5 with high binding affinity (K i = 9.3 nM) and selectivity was radiolabeled with 125I. Fully in vitro and in vivo studies of [125I]5 have been performed. [125I]5 exhibited well brain uptake with a peak concentration of 7.5 ± 0.9% ID/g in mice brains. Moreover, ex vivo autoradiography studies and micro single-photon emission computed tomography (micro-SPECT/CT) dynamic imaging in mice confirmed its in vivo imaging properties. Besides, molecular docking and MD studies were also performed to interpret the binding mechanisms of the two series of ligands towards α7-nAChRs. To conclude, the meta-iodine substituted 9-fluorenone [125I]5 could be a promising tracer for imaging α7-nAChRs.
RESUMO
Infection caused by hepatitis C virus (HCV) is a significant world health problem for which novel therapies are in urgent demand. Nonstructural (NS5B) viral proteins have emerged as an attractive target for drug discovery efforts toward antiviral for hepatitis C virus. Toward this target several series of NS5B inhibitors that showed activity in the replicon assay have been reported. In this article, we gave a report of the NS5B allosteric sites and the corresponding non-nucleoside inhibitors, which belong to different chemical classes. Then using comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA) methods, 3-dimension quantitative structure-activity relationships (3D-QSAR) models have been built with more than two hundred benzimidazole/indole derivative inhibitors. These studies indicated that the QSAR models were statistically significant and had high predictabilities (CoMFA: q(2)=0.823, r(2)=0.942; CoMSIA: q(2)=0.817, r(2)=0.935). The flexible docking method, which was performed by the DOCK6.0 software, positioned all of the inhibitors into the allosteric site to determine the probable binding conformation. The CoMFA and CoMSIA models based on the docking conformations also yielded statistically significant and high predictive QSAR models (CoMFA: q(2)=0.509, r(2)=0.768; CoMSIA: q(2)=0.582, r(2)=0.854). Our models would offer help to better comprehend the structure-activity relationships existent for this class of compounds and also facilitate the design of new inhibitors with good chemical diversity.