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Introduction: Mesothelin (MSLN) is overexpressed in a wide variety of cancers with few therapeutic options and has recently emerged as an attractive target for cancer therapy, with a large number of approaches currently under preclinical and clinical investigation. In this respect, developing mesothelin specific tracers as molecular companion tools for predicting patient eligibility, monitoring then response to mesothelin-targeting therapies, and tracking the evolution of the disease or for real-time visualisation of tumours during surgery is of growing importance. Methods: We generated by phage display a nanobody (Nb S1) and used enzymatic approaches were used to site-directed conjugate Nb S1 with either ATTO 647N fluorochrome or NODAGA chelator for fluorescence and positron emission tomography imaging (PET) respectively. Results: We demonstrated that Nb S1 displays a high apparent affinity and specificity for human mesothelin and demonstrated that the binding, although located in the membrane distal domain of mesothelin, is not impeded by the presence of MUC16, the only known ligand of mesothelin, nor by the therapeutic antibody amatuximab. In vivo experiments showed that both ATTO 647N and [68Ga]Ga-NODAGA-S1 rapidly and specifically accumulated in mesothelin positive tumours compared to mesothelin negative tumours or irrelevant Nb with a high tumour/background ratio. The ex vivo biodistribution profile analysis also confirmed a significantly higher uptake of Nb S1 in MSLN-positive tumours than in MSLNlow tumours. Conclusion: We demonstrated for the first time the use of an anti-MSLN nanobody as PET radiotracer for same day imaging of MSLN+ tumours, targeting an epitope compatible with the monitoring of amatuximab-based therapies and current SS1-derived-drug conjugates.
Assuntos
Mesotelina , Neoplasias , Humanos , Distribuição Tecidual , Tomografia por Emissão de Pósitrons , Neoplasias/diagnóstico por imagem , Neoplasias/terapia , Anticorpos BloqueadoresRESUMO
APJ has been extensively described in the pathophysiology of angiogenesis and cell proliferation. The prognostic value of APJ overexpression in many diseases is now established. This study aimed to design a PET radiotracer that specifically binds to APJ. Apelin-F13A-NODAGA (AP747) was synthesized and radiolabeled with gallium-68 ([68Ga]Ga-AP747). Radiolabeling purity was excellent (> 95%) and stable up to 2 h. Affinity constant of [67Ga]Ga-AP747 was measured on APJ-overexpressing colon adenocarcinoma cells and was in nanomolar range. Specificity of [68Ga]Ga-AP747 for APJ was evaluated in vitro by autoradiography and in vivo by small animal PET/CT in both colon adenocarcinoma mouse model and Matrigel plug mouse model. Dynamic of [68Ga]Ga-AP747 PET/CT biodistributions was realized on healthy mice and pigs for two hours, and quantification of signal in organs showed a suitable pharmacokinetic profile for PET imaging, largely excreted by urinary route. Matrigel mice and hindlimb ischemic mice were submitted to a 21-day longitudinal follow-up with [68Ga]Ga-AP747 and [68Ga]Ga-RGD2 small animal PET/CT. [68Ga]Ga-AP747 PET signal in Matrigel was significantly more intense than that of [68Ga]Ga-RGD2. Revascularization of the ischemic hind limb was followed by LASER Doppler. In the hindlimb, [68Ga]Ga-AP747 PET signal was more than twice higher than that of [68Ga]Ga-RGD2 on day 7, and significantly superior over the 21-day follow-up. A significant, positive correlation was found between the [68Ga]Ga-AP747 PET signal on day 7 and late hindlimb perfusion on day 21. We developed a new PET radiotracer that specifically binds to APJ, [68Ga]Ga-AP747 that showed more efficient imaging properties than the most clinically advanced tracer of angiogenesis, [68Ga]Ga-RGD2.
Assuntos
Adenocarcinoma , Neoplasias do Colo , Animais , Camundongos , Suínos , Apelina , Receptores de Apelina , Radioisótopos de Gálio , Tomografia por Emissão de Pósitrons combinada à Tomografia Computadorizada , Tomografia por Emissão de Pósitrons/métodos , Imagem Molecular/métodos , OligopeptídeosRESUMO
Microvesicles, so-called endothelial large extracellular vesicles (LEVs), are of great interest as biological markers and cell-free biotherapies in cardiovascular and oncologic diseases. However, their therapeutic perspectives remain limited due to the lack of reliable data regarding their systemic biodistribution after intravenous administration. METHODS: Applied to a mouse model of peripheral ischemia, radiolabeled endothelial LEVs were tracked and their in vivo whole-body distribution was quantified by microSPECT/CT imaging. Hindlimb perfusion was followed by LASER Doppler and motility impairment function was evaluated up to day 28 post-ischemia. RESULTS: Early and specific homing of LEVs to ischemic hind limbs was quantified on the day of ischemia and positively correlated with reperfusion intensity at a later stage on day 28 after ischemia, associated with an improved motility function. CONCLUSIONS: This concept is a major asset for investigating the biodistribution of LEVs issued from other cell types, including cancer, thus partly contributing to better knowledge and understanding of their fate after injection.
RESUMO
Succinate influences angiogenesis and neovascularization via a hormonelike effect on G-protein-coupled receptor 91 (GPR91). This effect has been demonstrated in the pathophysiology of diabetic retinopathy and rheumatoid arthritis. To evaluate whether succinate can play a role in acute peripheral ischemia, a preclinical study was conducted with ischemic mice treated with succinate or PBS and evaluated by imaging. Acute ischemia was followed by an increased in GPR91 expression in the ischemic muscle. As assessed with LASER-Doppler, succinate treatment resulted in an earlier and more intense reperfusion of the ischemic hindlimb compared to the control group (* p = 0.0189). A microPET study using a radiolabeled integrin ligand ([68Ga]Ga-RGD2) showed an earlier angiogenic activation in the succinate arm compared to control mice (* p = 0.020) with a prolonged effect. Additionally, clinical recovery following ischemia was better in the succinate group. In conclusion, succinate injection promotes earlier angiogenesis after ischemia, resulting in a more effective revascularization and subsequently a better functional recovery.
Assuntos
Isquemia/diagnóstico por imagem , Isquemia/fisiopatologia , Imagem Multimodal , Neovascularização Fisiológica , Recuperação de Função Fisiológica , Ácido Succínico/administração & dosagem , Doença Aguda , Animais , Células Endoteliais/metabolismo , Feminino , Radioisótopos de Gálio , Membro Posterior/irrigação sanguínea , Membro Posterior/diagnóstico por imagem , Membro Posterior/fisiopatologia , Injeções , Camundongos , Músculos/efeitos dos fármacos , Músculos/metabolismo , Neovascularização Fisiológica/efeitos dos fármacos , Peptídeos Cíclicos/química , Perfusão , Tomografia por Emissão de Pósitrons combinada à Tomografia Computadorizada , Receptores Acoplados a Proteínas G/metabolismo , Recuperação de Função Fisiológica/efeitos dos fármacos , Ácido Succínico/farmacologiaRESUMO
Bioimaging has revolutionized medicine by providing accurate information for disease diagnosis and treatment. Nanotechnology-based bioimaging is expected to further improve imaging sensitivity and specificity. In this context, supramolecular nanosystems based on self-assembly of amphiphilic dendrimers for single photon emission computed tomography (SPECT) bioimaging are developed. These dendrimers bear multiple In3+ radionuclides at their terminals as SPECT reporters. By replacing the macrocyclic 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid cage with the smaller 1,4,7-triazacyclononane-1,4,7-triacetic acid scaffold as the In3+ chelator, the corresponding dendrimer exhibits neutral In3+ -complex terminals in place of negatively charged In3+ -complex terminals. This negative-to-neutral surface charge alteration completely reverses the zeta-potential of the nanosystems from negative to positive. As a consequence, the resulting SPECT nanoprobe generates a highly sought-after biodistribution profile accompanied by a drastically reduced uptake in liver, leading to significantly improved tumor imaging. This finding contrasts with current literature reporting that positively charged nanoparticles have preferential accumulation in the liver. As such, this study provides new perspectives for improving the biodistribution of positively charged nanosystems for biomedical applications.
Assuntos
Dendrímeros , Nanopartículas , Distribuição Tecidual , Tomografia Computadorizada de Emissão de Fóton Único , Tomografia Computadorizada por Raios XRESUMO
Bioimaging has revolutionized modern medicine, and nanotechnology can offer further specific and sensitive imaging. We report here an amphiphilic dendrimer able to self-assemble into supramolecular nanomicelles for effective tumor detection using SPECT radioimaging. This highlights the promising potential of supramolecular dendrimer platforms for biomedical imaging.
Assuntos
Dendrímeros/química , Nanoestruturas/química , Tensoativos/química , Adenocarcinoma/diagnóstico por imagem , Animais , Linhagem Celular Tumoral , Quelantes/síntese química , Quelantes/química , Dendrímeros/síntese química , Compostos Heterocíclicos com 1 Anel/síntese química , Compostos Heterocíclicos com 1 Anel/química , Humanos , Índio , Radioisótopos de Índio , Camundongos , Micelas , Neoplasias Pancreáticas/diagnóstico por imagem , Radioisótopos , Tensoativos/síntese química , Tomografia Computadorizada de Emissão de Fóton Único/métodosRESUMO
Due to its ideal physical properties, fluorine-18 turns out to be a key radionuclide for positron emission tomography (PET) imaging, for both preclinical and clinical applications. However, usual biomolecules radiofluorination procedures require the formation of covalent bonds with fluorinated prosthetic groups. This drawback makes radiofluorination impractical for routine radiolabeling, gallium-68 appearing to be much more convenient for the labeling of chelator-bearing PET probes. In response to this limitation, a recent expansion of the 18F chemical toolbox gave aluminum [18F]fluoride chemistry a real prominence since the late 2000s. This approach is based on the formation of an [18F][AlF]2+ cation, complexed with a 9-membered cyclic chelator such as NOTA, NODA or their analogs. Allowing a one-step radiofluorination in an aqueous medium, this technique combines fluorine-18 and non-covalent radiolabeling with the advantage of being very easy to implement. Since its first reports, [18F]AlF radiolabeling approach has been applied to a wide variety of potential PET imaging vectors, whether of peptidic, proteic, or small molecule structure. Most of these [18F]AlF-labeled tracers showed promising preclinical results and have reached the clinical evaluation stage for some of them. The aim of this report is to provide a comprehensive overview of [18F]AlF labeling applications through a description of the various [18F]AlF-labeled conjugates, from their radiosynthesis to their evaluation as PET imaging agents.
Assuntos
Alumínio/química , Quelantes , Radioisótopos de Flúor/química , Radioisótopos de Gálio/química , Marcação por Isótopo , Animais , Biomarcadores , Quelantes/química , Compostos de Flúor/química , Humanos , Imagem Molecular/métodos , Estrutura Molecular , Peptídeos/química , Tomografia por Emissão de Pósitrons/métodos , Conformação ProteicaRESUMO
Bioimaging plays an important role in cancer diagnosis and treatment. However, imaging sensitivity and specificity still constitute key challenges. Nanotechnology-based imaging is particularly promising for overcoming these limitations because nanosized imaging agents can specifically home in on tumors via the "enhanced permeation and retention" (EPR) effect, thus resulting in enhanced imaging sensitivity and specificity. Here, we report an original nanosystem for positron emission tomography (PET) imaging based on an amphiphilic dendrimer, which bears multiple PET reporting units at the terminals. This dendrimer is able to self-assemble into small and uniform nanomicelles, which accumulate in tumors for effective PET imaging. Benefiting from the combined dendrimeric multivalence and EPR-mediated passive tumor targeting, this nanosystem demonstrates superior imaging sensitivity and specificity, with up to 14-fold increased PET signal ratios compared with the clinical gold reference 2-fluorodeoxyglucose ([18F]FDG). Most importantly, this dendrimer system can detect imaging-refractory low-glucose-uptake tumors that are otherwise undetectable using [18F]FDG. In addition, it is endowed with an excellent safety profile and favorable pharmacokinetics for PET imaging. Consequently, this dendrimer nanosystem constitutes an effective and promising approach for cancer imaging. Our study also demonstrates that nanotechnology based on self-assembling dendrimers provides a fresh perspective for biomedical imaging and cancer diagnosis.
Assuntos
Neoplasias do Colo/diagnóstico por imagem , Complexos de Coordenação/farmacocinética , Radioisótopos de Gálio/farmacocinética , Glioblastoma/diagnóstico por imagem , Neoplasias Pancreáticas/diagnóstico por imagem , Tomografia por Emissão de Pósitrons/métodos , Neoplasias da Próstata/diagnóstico por imagem , Animais , Linhagem Celular Tumoral , Neoplasias do Colo/patologia , Meios de Contraste/química , Meios de Contraste/farmacocinética , Complexos de Coordenação/sangue , Complexos de Coordenação/química , Dendrímeros/química , Fluordesoxiglucose F18/química , Radioisótopos de Gálio/sangue , Radioisótopos de Gálio/química , Glioblastoma/patologia , Compostos Heterocíclicos/química , Compostos Heterocíclicos com 1 Anel , Xenoenxertos , Humanos , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Neoplasias Pancreáticas/patologia , Neoplasias da Próstata/patologiaRESUMO
AIM: Zinc has proved its efficacy in many models of ischemia reperfusion (I/R) injury. In this study, we used zinc acexamate (ZAC) as an exogenous source of zinc against renal I/R injury and we investigated whether its protective effects are mediated by the decrease of oxidative stress, inflammation, and mitochondria induced-apoptosis. METHODS: Rats were orally pretreated with vehicle or ZAC (10 or 100â¯mg/kg) 24â¯h and 30â¯min prior to 1â¯h of bilateral renal warm ischemia and 2â¯h of reperfusion. RESULTS: Our data showed that 10â¯mg/kg of ZAC, but not 100â¯mg/kg, improved renal architecture and function. Also, the low dose of ZAC up-regulated antioxidant enzymes activities and glutathione level and decreased lipids and proteins oxidation. Interestingly, the use of ZAC resulted in a significant reduce of pro-inflammatory cytokines (IL-1ß, IL-6 and MCP-1), enhanced mitochondria integrity and decreased expression of the pro-apoptotic protein caspase-9. CONCLUSION: We conclude that renal I/R induced oxidative stress, inflammation and apoptosis and that the use of ZAC at 10â¯mg/kg, but not 100â¯mg/kg, protects rat kidneys from I/R injury by down-regulating these processes.
Assuntos
Aminocaproatos/uso terapêutico , Antioxidantes/uso terapêutico , Apoptose/efeitos dos fármacos , Rim/efeitos dos fármacos , Mitocôndrias/efeitos dos fármacos , Estresse Oxidativo/efeitos dos fármacos , Traumatismo por Reperfusão/prevenção & controle , Aminocaproatos/administração & dosagem , Animais , Antioxidantes/administração & dosagem , Citocinas/imunologia , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Rim/irrigação sanguínea , Masculino , Ratos Wistar , Isquemia QuenteRESUMO
Ischaemia reperfusion (I/R) is associated with liver injury and impaired regeneration during partial hepatectomy (PH). The aim of this study was to investigate the effect of thymoquinone (TQ), the active compound of essential oil obtained from Nigella sativa seeds, on rat liver after PH. Male Wistar rats were divided equally into four groups (n = 6) receiving an oral administration of either vehicle solution (sham and PH groups) or TQ at 30 mg/kg (TQ and TQ + PH groups) for 10 consecutive days. Then, rats underwent PH (70%) with 60 minutes of ischaemia followed by 24 hours of reperfusion (PH and TQ + PH groups). Alanine aminotransferase (ALT) activity and histopathological damage were determined. Also, antioxidant parameters, liver regeneration index, hepatic adenosine triphosphate (ATP) content, endoplasmic reticulum (ER) stress and apoptosis were assessed. In response to PH under I/R, liver damage was significantly alleviated by TQ treatment as evidenced by the decrease in ALT activity (P < .01) and histological findings (P < .001). In parallel, TQ preconditioning increased hepatic antioxidant capacities. Moreover, TQ improved mitochondrial function (ATP, P < .05), attenuated ER stress parameters and repressed the expression of apoptotic effectors. Taken together, our results suggest that TQ preconditioning could be an effective strategy to reduce liver injury after PH under I/R. The protective effects were mediated by the increase of antioxidant capacities and the decrease of ER stress and apoptosis.
RESUMO
Oxidative stress is a major factor involved in the pathogenesis of renal ischemia/reperfusion (I/R). Exogenous zinc (Zn) was suggested as a potent antioxidant; however, the mechanism by which it strengthens the organ resistance against the effects of reactive oxygen species (ROS) is not yet investigated. The present study aims to determine whether acute zinc chloride (ZnCl2 ) administration could attenuate endoplasmic reticulum (ER) stress, autophagy, and inflammation after renal I/R. Rats were subjected to either sham operation (Sham group, n = 6), or 1 hr of bilateral ischemia followed by 2 hr of reperfusion (I/R groups, n = 6), or they received ZnCl2 orally 24 hr and 30 min before ischemia (ZnCl2 group, n = 6). Rats were subjected to 1 hr of bilateral renal ischemia followed by 2 hr of reperfusion (I/R group, n = 6). Our results showed that ZnCl2 enhances renal function and reduces cytolysis (p < 0,05). In addition, it increased significantly the activities of antioxidant enzymes (SOD, CAT, and GPX) and the level of GSH in comparison to I/R (p < 0,05). Interestingly, ZnCl2 treatment resulted in significant decreased ER stress, as reflected by GRP78, ATF-6,p-eIF-2α, XPB-1, and CHOP downregulaion. Rats undergoing ZnCl2 treatment demonstrated a low expression of autophagy parameters (Beclin-1 and LAMP-2), which was correlated with low induction of apoptosis (caspase-9, caspase-3, and p-JNK), and reduction of inflammation (IL-1ß, IL-6, and MCP-1) (p < 0,05). In conclusion, we demonstrated the potential effect of Zn supplementation to modulate ER pathway and autophagic process after I/R.
Assuntos
Injúria Renal Aguda/tratamento farmacológico , Cloretos/administração & dosagem , Estresse Oxidativo/efeitos dos fármacos , Traumatismo por Reperfusão/tratamento farmacológico , Compostos de Zinco/administração & dosagem , Injúria Renal Aguda/genética , Injúria Renal Aguda/fisiopatologia , Animais , Antioxidantes/administração & dosagem , Apoptose/efeitos dos fármacos , Autofagia/genética , Chaperona BiP do Retículo Endoplasmático , Estresse do Retículo Endoplasmático/genética , Humanos , Rim/metabolismo , Rim/patologia , Masculino , Ratos , Espécies Reativas de Oxigênio/metabolismo , Traumatismo por Reperfusão/genética , Traumatismo por Reperfusão/metabolismo , Traumatismo por Reperfusão/patologiaRESUMO
This study was undertaken to evaluate the protective effect of thymoquinone (TQ), the bioactive compound of Nigella sativa seeds, against warm ischemia-reperfusion (I/R) injury in liver. Rats were given an oral administration of a vehicle solution (sham group) or TQ at the appropriate dose (10, 20, 30 and 40mg/kg) for ten days consecutively. Following, they were subjected to 60min of partial hepatic ischemia followed by 24h of reperfusion. .Transaminase activities, histopathological changes, TNFα and antioxidant parameters were evaluated. Also, endoplasmic reticulum (ER) stress, mitochondrial damage and apoptosis were studied. In addition, ERK and P38 phosphorylation was determined by Western blot technique. We found that TQ at 30mg/kg is the effective dose to protect rat liver against I/R injury. Moreover, 30mg/kg of TQ prevented histological damages, inflammation and oxidative stress. Interestingly, it decreased the expression of ER stress parameters including GRP78, CHOP and caspase-12. In parallel, it improved mitochondrial function and attenuated the expression of apoptotic parameters. Furthermore, TQ significantly enhanced ERK and P38 phosphorylation. In conclusion, we demonstrated the potential of TQ to protect the rat liver against I/R injury through the prevention of ER stress and mitochondrial dysfunction. These effects implicate the prevention of oxidative stress.
Assuntos
Apoptose/efeitos dos fármacos , Benzoquinonas/farmacologia , Estresse do Retículo Endoplasmático/efeitos dos fármacos , Isquemia/tratamento farmacológico , Fígado/efeitos dos fármacos , Mitocôndrias/efeitos dos fármacos , Traumatismo por Reperfusão/tratamento farmacológico , Animais , Antioxidantes/metabolismo , Isquemia/metabolismo , Fígado/metabolismo , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Masculino , Mitocôndrias/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Fosforilação/efeitos dos fármacos , Substâncias Protetoras/farmacologia , Ratos , Ratos Wistar , Reperfusão/métodos , Traumatismo por Reperfusão/metabolismo , Fator de Necrose Tumoral alfa/metabolismo , Isquemia Quente/métodos , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismoRESUMO
INTRODUCTION: Nitrite has been found to protect liver graft from cold preservation injury. However, the cell signaling pathway involved in this protection remains unclear. Here, we attempt to clarify if the NOS pathway by using the NOS inhibitor, L-NAME (L-NG-Nitroarginine methyl ester). ANIMALS AND METHODS: Rat livers were conserved for 24 h at 4°C in (IGL-1) solution enriched or not with nitrite at 50 nM. In a third group, rats were pretreated with 50 mg/kg of L-NAME before their liver procurement and preservation in IGL-1 supplemented with nitrite (50 nM) and L-NAME (1 mM). After 24 h of cold storage, rat livers were ex-vivo perfused at 37°C during 2 h. Control livers were perfused without cold storage. RESULTS: Nitrite effectively protected the rat liver grafts from the onset of cold I/R injury. L-NAME treatment did not abolish the beneficial effects of nitrite. Liver damage, protein oxidation and lipid peroxidation remained at low levels in both nitrite-treated groups when compared to IGL-1 group. Antioxidant enzyme activities and functional parameters were unchanged after NOS inhibition. CONCLUSION: Despite NOS inhibition by L-NAME, nitrite can still provide hepatic protection during cold I/R preservation. This suggests that nitrite acts through a NOS-independent pathway.
Assuntos
Fígado/efeitos dos fármacos , NG-Nitroarginina Metil Éster/farmacologia , Nitritos/farmacologia , Traumatismo por Reperfusão/prevenção & controle , Animais , Criopreservação , Peroxidação de Lipídeos/efeitos dos fármacos , Fígado/metabolismo , Óxido Nítrico Sintase/antagonistas & inibidores , Ratos , Transdução de Sinais/efeitos dos fármacosRESUMO
Two [(18)F]fluoroalkyl substituted amino acids differing only by the presence or absence of a methyl group on the α-carbon, (S)-2-amino-7-[(18)F]fluoro-2-methylheptanoic acid ((S)-[(18)F]FAMHep, (S)-[(18)F]14) and (S)-2-amino-7-[(18)F]fluoroheptanoic acid ((S)-[(18)F]FAHep, (S)-[(18)F]15), were developed for brain tumor imaging and compared to the well-established system L amino acid tracer, O-(2-[(18)F]fluoroethyl)-l-tyrosine ([(18)F]FET), in the delayed brain tumor (DBT) mouse model of high-grade glioma. Cell uptake, biodistribution, and PET/CT imaging studies showed differences in amino acid transport of these tracer by DBT cells. Recognition of (S)-[(18)F]15 but not (S)-[(18)F]14 by system L amino acid transporters led to approximately 8-10-fold higher uptake of the α-hydrogen substituted analogue (S)-[(18)F]15 in normal brain. (S)-[(18)F]15 had imaging properties similar to those of (S)-[(18)F]FET in the DBT tumor model while (S)-[(18)F]14 afforded higher tumor to brain ratios due to much lower uptake by normal brain. These results have important implications for the future development of α-alkyl and α,α-dialkyl substituted amino acids for brain tumor imaging.
Assuntos
Aminoácidos Neutros/farmacocinética , Aminoácidos/farmacocinética , Neoplasias Encefálicas/diagnóstico por imagem , Encéfalo/diagnóstico por imagem , Glioma/diagnóstico por imagem , Hidrogênio/química , Tomografia por Emissão de Pósitrons/métodos , Compostos Radiofarmacêuticos/farmacocinética , Substituição de Aminoácidos , Aminoácidos/química , Aminoácidos/metabolismo , Aminoácidos Neutros/química , Aminoácidos Neutros/metabolismo , Animais , Transporte Biológico , Encéfalo/metabolismo , Neoplasias Encefálicas/metabolismo , Radioisótopos de Flúor/química , Radioisótopos de Flúor/metabolismo , Radioisótopos de Flúor/farmacocinética , Glioma/metabolismo , Masculino , Metilação , Camundongos , Camundongos Endogâmicos BALB C , Compostos Radiofarmacêuticos/química , Compostos Radiofarmacêuticos/metabolismo , Distribuição Tecidual , Tirosina/análogos & derivadosRESUMO
A novel (18)F-labeled α,α-disubstituted amino acid-based tracer, 2-amino-5-[(18)F]fluoro-2-methylpentanoic acid ([(18)F]FAMPe), has been developed for brain tumor imaging with a longer alkyl side chain than previously reported compounds to increase brain availability via system L amino acid transport. Both enantiomers of [(18)F]FAMPe were obtained in good radiochemical yield (24-52% n = 8) and high radiochemical purity (>99%). In vitro uptake assays in mouse DBT gliomas cells revealed that (S)-[(18)F]FAMPe enters cells partly via sodium-independent system L transporters and also via other nonsystem A transport systems including transporters that recognize glutamine. Biodistribution and small animal PET/CT studies in the mouse DBT model of glioblastoma showed that both (R)- and (S)-[(18)F]FAMPe have good tumor imaging properties with the (S)-enantiomer providing higher tumor uptake and tumor to brain ratios. Comparison of the SUVs showed that (S)-[(18)F]FAMPe had higher tumor to brain ratios compared to (S)-[(18)F]FET, a well-established system L substrate.
Assuntos
Aminoácidos de Cadeia Ramificada/química , Aminoácidos Neutros/química , Neoplasias Encefálicas/diagnóstico por imagem , Glioma/diagnóstico por imagem , Ácidos Pentanoicos/química , Compostos Radiofarmacêuticos/química , Sistemas de Transporte de Aminoácidos Neutros/metabolismo , Aminoácidos de Cadeia Ramificada/síntese química , Aminoácidos de Cadeia Ramificada/farmacologia , Aminoácidos Neutros/síntese química , Aminoácidos Neutros/farmacologia , Animais , Encéfalo/diagnóstico por imagem , Encéfalo/metabolismo , Neoplasias Encefálicas/metabolismo , Radioisótopos de Flúor , Glioma/metabolismo , Masculino , Camundongos Endogâmicos BALB C , Ácidos Pentanoicos/síntese química , Ácidos Pentanoicos/farmacocinética , Tomografia por Emissão de Pósitrons , Compostos Radiofarmacêuticos/síntese química , Compostos Radiofarmacêuticos/farmacocinética , Estereoisomerismo , Distribuição TecidualRESUMO
Following the promising antileishmanial results previously obtained in monoamidoxime series, a new series of derivatives was synthesized using manganese(III) acetate, Wittig reactions and Suzuki-Miyaura cross coupling reactions. Pharmacomodulation in R(1), R(2) or R(3) substituents on the amidoxime structure is shown to influence antiprotozoan activity in vitro: a monosubstituted phenyl group in R1 (32-35) led to an activity against Leishmania donovani promastigotes (32, IC50 = 9.16 µM), whereas a polysubstituted group (36-37) led to an activity against Plasmodium falciparum (36, IC50 = 2.76 µM). Modulating chemical substituents in R(2) and R(3) only influenced the antiplasmodial activity in vitro. This suggests that the amidoxime scaffold has properties that could make it a promising new antiparasitic pharmacophore.
Assuntos
Antiparasitários/química , Antiparasitários/farmacologia , Oximas/química , Oximas/farmacologia , Espectroscopia de Ressonância Magnética Nuclear de Carbono-13 , Concentração Inibidora 50 , Espectrometria de Massas por Ionização por ElectrosprayRESUMO
A convenient microwave irradiation protocol was utilized for the synthesis of b-ketosulfones 1-5 in good yields. These sulfones reacted with alkenes through a radical oxidative cyclization mediated by Mn(OAc)3. Dihydrofurans 6-10 were obtained in moderate to good yields starting from 1,1-disubstituted alkenes. Dihydrofurans 11-15 were synthesized in moderate yields and unexpected cyclopropanes 16-19 were obtained in low yields starting from 1,2-disubstituted alkenes. This protocol offers access to various dihydrofurans which could be tested for their antiparasitic potential.
Assuntos
Acetatos/química , Compostos Organometálicos/química , Oxirredução , Estirenos/química , Alcenos/química , Antiparasitários/síntese química , Antiparasitários/química , Ciclização , Ciclopropanos/síntese química , Furanos/síntese química , Furanos/química , Estilbenos/química , Raios XRESUMO
A three step synthesis of various thiobarbiturate derivatives 17-24 was established. The first step is mediated by Mn(OAc)3, in order to generate a carbon-carbon bond between a terminal alkene and malonate. Derivatives 1-8 were obtained in moderate to good yields under mild conditions. This key step allows synthesis of a wide variety of lipophilic thiobarbiturates, which could be tested for their anticonvulsive or anesthesic potential.
Assuntos
Acetatos/química , Técnicas de Química Sintética/métodos , Compostos Organometálicos/química , Tiobarbitúricos/síntese químicaRESUMO
A new series of monoamidoxime derivatives was synthesized using manganese(III) acetate by microwave irradiation. Several amidoximes (27-31, 33, 38) showed valuable in vitro activities toward Leishmania donovani promastigotes, exhibiting IC(50) values between 5.21 and 7.89 µM. In parallel, the cytotoxicity of these compounds was evaluated on murine J774A.1 cells, revealing the corresponding selectivity index (SI). Among the 13 tested compounds, 4 monoamidoximes (27-30) exhibited an SI more than 20 times better than pentamidine. Moreover, monoamidoxime 28 (4-[5-Benzyl-3-(4-fluorophenylsulfonyl)-5-methyl-4,5-dihydrofuran-2-yl]-N'-hydroxybenzimidamide) is 40 times more selective than pentamidine, and 1.6 times more than amphotericin B, used as reference drug compounds.
Assuntos
Antiprotozoários/síntese química , Leishmania donovani/efeitos dos fármacos , Estágios do Ciclo de Vida/efeitos dos fármacos , Oximas/síntese química , Acetatos/química , Anfotericina B/farmacologia , Animais , Antiprotozoários/farmacologia , Linhagem Celular , Concentração Inibidora 50 , Leishmania donovani/crescimento & desenvolvimento , Macrófagos/efeitos dos fármacos , Macrófagos/parasitologia , Camundongos , Micro-Ondas , Compostos Organometálicos/química , Oximas/farmacologia , Pentamidina/farmacologia , Relação Estrutura-AtividadeRESUMO
An original series of amidoxime derivatives was synthesized using manganese(III) acetate, Buchwald-Hartwig and Heck reactions. Two amidoximes (39 and 52) showed interesting in vitro activities toward Leishmania donovani promastigotes, exhibiting 8.3 and 8.8 µM IC(50) values. Moreover, the cytotoxicity of these compounds was evaluated on human THP1 cells, giving access to the corresponding selectivity index. Among the 25 tested compounds, amidoximes 38 and 39 and diamidoximes 50 and 52 exhibited a better selectivity index than pentamidine used as a drug compound reference.