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Nieto E.,University of Alcalá | Delgado M.,Complutense University of Madrid | Sobrado M.,Complutense University of Madrid | Sobrado M.,Hospital Universitario La Paz | And 9 more authors.
European Journal of Medicinal Chemistry | Year: 2015

Abstract The synthesis of the new radiotracer precursor 4-Br-NITTP and the radiolabeling of the new tracer 1-(4-bromo-2-nitroimidazol-1-yl)-3-[18F]fluoropropan-2-ol (4-Br-[18F]FMISO) is reported. The cyclic voltammetry behaviour, neuronal cell toxicity, transport through the brain endothelial cell monolayer, in vivo PET imaging and preliminary calculations of the tracer uptake for a rodent model of stroke were studied for the new compound and the results were compared to those obtained with [18F]FMISO, the current gold standard PET hypoxia tracer. The new PET brain hypoxia tracer is more easily reduced, has higher CLogP than [18F]FMISO and it diffuses more rapidly through brain endothelial cells. The new compound is non-toxic to neuronal cells and it allows the in vivo mapping of stroke in mice with higher sensitivity. 4-Br-[18F]FMISO is a good candidate for further development in ischemic stroke. © 2015 Elsevier Masson SAS.


De Cristobal J.,Complutense University of Madrid | De Cristobal J.,Noscira SA | Garcia-Garcia L.,Complutense University of Madrid | Delgado M.,Complutense University of Madrid | And 4 more authors.
Journal of Alzheimer's Disease | Year: 2014

Abnormal levels and hyperphosphorylation of tau protein have been proposed as the underlying cause of a group of neurodegenerative disorders collectively known as 'tauopathies'. The detrimental consequence is the loss of affinity between this protein and the microtubules, increased production of fibrillary aggregates, and the accumulation of insoluble intracellular neurofibrillary tangles. A similar phenotype can be observed in various preclinical models, which have been generated to study the role of tau protein in neurodegenerative disorders. In this study, we have analyzed the brain metabolic activity in an animal model of tauopathy (tauVLW transgenic mice), which has been previously reported to mimic some of the phenotypic features of these disorders. By using a non-invasive technique, positron emission tomography (PET), a longitudinal non-clinical follow up study was carried out during most of the lifespan of these transgenic mice, from the youth to the senescence stages. The results obtained point out to an aging-dependent decrease in 18F-fluoro- deoxyglucose (FDG) uptake in the cerebral areas analyzed, which was already significant at the adult age, i.e., 11 months, and became much more prominent in the oldest animals (19 months old). This observation correlates well with the histopathological observation of neurodegeneration in brain areas where there is overexpression of tau protein. © 2014 - IOS Press and the authors.


Garcia-Garcia L.,Complutense University of Madrid | Shiha A.A.,Complutense University of Madrid | Bascunana P.,Complutense University of Madrid | de Cristobal J.,Complutense University of Madrid | And 4 more authors.
Cellular and Molecular Neurobiology | Year: 2015

It has been reported that fluoxetine, a selective serotonin (5-hydroxytryptamine; 5-HT) reuptake inhibitor, has neuroprotective properties in the lithium–pilocarpine model of status epilepticus (SE) in rats. The aim of the present study was to investigate the effect of 5-HT depletion by short-term administration of p-chlorophenylalanine (PCPA), a specific tryptophan hydroxylase inhibitor, on the brain hypometabolism and neurodegeneration induced in the acute phase of this SE model. Our results show that 5-HT depletion did modify neither the brain basal metabolic activity nor the lithium–pilocarpine-induced hypometabolism when evaluated 3 days after the insult. In addition, hippocampal neurodegeneration and astrogliosis triggered by lithium–pilocarpine were not exacerbated by PCPA treatment. These findings point out that in the early latent phase of epileptogenesis, non-5-HT-mediated actions may contribute, at least in some extent, to the neuroprotective effects of fluoxetine in this model of SE. © 2015 Springer Science+Business Media New York


Shiha A.A.,Complutense University of Madrid | de Cristobal J.,Complutense University of Madrid | Delgado M.,Complutense University of Madrid | Fernandez de la Rosa R.,Complutense University of Madrid | And 4 more authors.
Brain Research Bulletin | Year: 2015

The role of serotonin (5-hydroxytryptamine; 5-HT) in epileptogenesis still remains controversial. In this regard, it has been reported that serotonergic drugs can alter epileptogenesis in opposite ways. The main objective of this work was to investigate the effect of the selective 5-HT selective reuptake inhibitor (SSRI) fluoxetine administered subacutely (10mg/kg/day×7 days) on the eventual metabolic impairment induced by the lithium-pilocarpine model of epilepsy in rats. In vivo 2-deoxy-2-[18F]fluoro-d-glucose ([18F] FDG) positron emission tomography (PET) was performed to assess the brain glucose metabolic activity on days 3 and 30 after the insult. In addition, at the end of the experiment (day 33), several histochemical and neurochemical assessments were performed for checking the neuronal functioning and integrity.Three days after the insult, a marked reduction of [18F] FDG uptake (about 30% according to the brain region) was found in all brain areas studied. When evaluated on day 30, although a hypometabolism tendency was observed, no statistically significant reduction was present in any region analyzed. In addition, lithium-pilocarpine administration was associated with medium-term hippocampal and cortical damage, since it induced neurodegeneration, glial activation and augmented caspase-9 expression. Regarding the effect of fluoxetine, subacute treatment with this SSRI did not significantly reduce the mortality rate observed after pilocarpine-induced seizures. However, fluoxetine did prevent not only the short-term metabolic impairment, but also the aforementioned signs of neuronal damage in surviving animals to lithium-pilocarpine protocol. Finally, fluoxetine increased the density of GABAA receptor both at the level of the dentate gyrus and CA1-CA2 regions in pilocarpine-treated animals. Overall, our data suggest a protective role for fluoxetine against pilocarpine-induced brain damage. Moreover, this action may be associated with an increase of GABAA receptor expression in hippocampus. © 2014 Elsevier Inc.


Nieto E.,University of Alcalá | Alajarin R.,University of Alcalá | Alvarez-Builla J.,University of Alcalá | Larranaga I.,Instituto Tecnologico PET | And 2 more authors.
Synthesis | Year: 2010

A new synthetic approach to the precursor of the hypoxia marker [ 18F]-FMISO has been developed. Three different tosylation methods were studied for the preparation of the key intermediate. The overall yield is markedly higher than the yields reported for previous syntheses. The precursor was used to prepare [18F]-FMISO and the results were comparable to those obtained when a commercial precursor was used. © 2010 Georg Thieme Verlag Stuttgart New York.


Bascunana P.,Complutense University of Madrid | Bascunana P.,Hannover Medical School | Javela J.,Complutense University of Madrid | Javela J.,Antonio Nariño University | And 6 more authors.
Molecular Imaging and Biology | Year: 2016

Purpose: Epileptogenesis, i.e., development of epilepsy, involves a number of processes that alter the brain function in the way that triggers spontaneous seizures. Kindling is one of the most used animal models of temporal lobe epilepsy (TLE) and epileptogenesis, although chemical kindling suffers from high inter-assay success unpredictability. This study was aimed to analyze the eventual regional brain metabolic changes during epileptogenesis in the pentylenetetrazole (PTZ) kindling model in order to obtain a predictive kindling outcome parameter. Procedures: In vivo longitudinal positron emission tomography (PET) scans with 2-deoxy-2-[18F]fluoro-D-glucose ([18F]FDG) along the PTZ kindling protocol (35 mg/kg intraperitoneally (i.p.), 18 sessions) in adult male rats were performed in order to evaluate the regional brain metabolism. Results: The half of the PTZ-injected rats reached the kindled state. In addition, a significant decrease of [18F]FDG uptake at the end of the protocol in most of the brain structures of kindled animals was found, reflecting the characteristic epilepsy-associated hypometabolism. However, PTZ-injected animals but not reaching the kindled state did not show this widespread brain hypometabolism. Retrospective analysis of the data revealed that hippocampal [18F]FDG uptake normalized to pons turned out to be a predictive index of the kindling outcome. Thus, a 19.06 % reduction (p = 0.008) of the above parameter was found in positively kindled rats compared to non-kindled ones just after the fifth PTZ session. Conclusion: Non-invasive PET neuroimaging was a useful tool for discerning epileptogenesis progression in this animal model. Particularly, the [18F]FDG uptake of the hippocampus proved to be an early predictive parameter to differentiate resistant and non-resistant animals to the PTZ kindling. © 2016 World Molecular Imaging Society


Garcia G.,University of Alcalá | Abet V.,University of Alcalá | Alajarin R.,University of Alcalá | Alvarez-Builla J.,University of Alcalá | And 7 more authors.
European Journal of Medicinal Chemistry | Year: 2014

N-(4-[18F]-Fluoropyridin-2-yl)-N-{2-[4-(2-methoxyphenyl) piperazin-1-yl]ethyl}-carboxamides were prepared by labeling their 4-nitropyridin-2-yl precursors through nitro substitution by the 18F anion. In vitro and in vivo tests showed that the cyclohexanecarboxamide derivative is a reversible, selective and high affinity 5-HT1A receptor antagonist (IC50 = 0.29 nM, ki = 0.18 nM) with high brain uptake, slow brain clearance and stability to defluorination when compared with conventional standards. This PET radioligand is a promising candidate for an improved in vivo quantification of 5-HT1A receptors in neuropsychiatric disorders. © 2014 Published by Elsevier Masson SAS.


Garcia-Garcia L.,Complutense University of Madrid | Delgado M.,Complutense University of Madrid | Al-Sayed A.A.,Complutense University of Madrid | Bascunana P.,Complutense University of Madrid | And 5 more authors.
Molecular Imaging and Biology | Year: 2015

Purpose: p-Chloroamphetamine (PCA) is a neurotoxin that selectively degenerates the serotonin (5-HT) axon terminals. In order to study the brain metabolic consequences induced by serotonergic denervation, a single dose of PCA (2.5 or 10 mg/kg i.p.) was administered to male adult rats.Procedures: In vivo regional brain metabolism was evaluated 3 and 21 days after PCA (2.5 or 10 mg/kg; i.p.) injection by 2-deoxy-2-[18F] fluoro-d-glucose ([18F] FDG) positron emission tomography (PET). At day 22, the following markers of neurotoxicity were determined: (a) 5-HT axon terminal lesion by 5-HT transporter (SERT) autoradiography, (b) reactive gliosis by glial fibrillary acidic protein immunohistochemistry, and (c) eventual neurodegeneration by DAPI/Fluoro-Jade C labeling.Results: An average of 20 % reduction of [18F] FDG uptake in most brain areas was observed at day 21 under 10 mg/kg PCA treatment. Instead, 2.5 mg/kg PCA only reduced metabolic activity in neocortex. Likewise, the high dose of PCA exerted a strong decrease (>30 %) in SERT density in several 5-HT innervated regions, but no effect was found in midbrain raphe nuclei, the main source of serotonergic neurons. Although PCA induced astroglial activation both in hippocampus and cortex in response to axotomy, no signs of neuronal death in these areas were detected.Conclusions: Overall, [18F] FDG PET revealed that the reduction of the brain metabolic activity induced by PCA is related to 5-HT axon terminal lesion, with no apparent affectation of neuronal viability. © 2014, World Molecular Imaging Society.


de Cristobal J.,Noscira SA | de Cristobal J.,Complutense University of Madrid | Garcia-Garcia L.,Complutense University of Madrid | Delgado M.,Complutense University of Madrid | And 4 more authors.
Current Alzheimer Research | Year: 2014

Increased Glycogen synthase kinase-3 (GSK-3) activity is believed to contribute to the etiology of chronic disorders such as Alzheimer's disease, one of the earliest diseases linked to GSK-3 dysfunction. Numerous mouse models with modified GSK-3 have been generated in order to study the physiology of GSK-3, its implication in diverse pathologies and the potential effect of GSK-3 inhibitors. In this study we have characterised and evaluated the brain metabolic changes induced by GSK-3β overexpression in transgenic mice throughout their lifespan. The conditional Tet/GSK-3β transgenic line used in this study has been previously extensively characterized at the pathological, biochemical and cognitive levels. Now we have investigated the effect GSK-3β overexpression on the 18F-fluoro-deoxyglucose (FDG) uptake by positron emission tomography (PET), taking advantage from this non-invasive technique which has allowed us to track individually the same animals throughout their lives. The results obtained during the longitudinal analysis showed a reduction of metabolic activity in several brain regions, such as cortex, striatum and hippocampus, consistent with the areas where the transgene is being expressed. The reduction of the metabolic activity in these mice is observed from the first time point, performed at the age of 3 months, and maintained throughout the whole study, until the oldest age tested (19 months). This effect seems to be reverted in a satellite group of 3-month transgenic animals treated with the classical GSK-3 inhibitor lithium, as they show higher FDG uptake values compared with untreated age-matched transgenic animals. © 2014 Bentham Science Publishers.


PubMed | Complutense University of Madrid, Instituto Tecnologico PET and University of Alcalá
Type: | Journal: European journal of medicinal chemistry | Year: 2014

N-(4-[(18)F]-Fluoropyridin-2-yl)-N-{2-[4-(2-methoxyphenyl)piperazin-1-yl]ethyl}-carboxamides were prepared by labeling their 4-nitropyridin-2-yl precursors through nitro substitution by the (18)F anion. Invitro and invivo tests showed that the cyclohexanecarboxamide derivative is a reversible, selective and high affinity 5-HT1A receptor antagonist (IC50=0.29nM, ki=0.18nM) with high brain uptake, slow brain clearance and stability to defluorination when compared with conventional standards. This PET radioligand is a promising candidate for an improved invivo quantification of 5-HT1A receptors in neuropsychiatric disorders.

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