Differential behavioural and neurochemical outcomes from chronic paroxetine treatment in adolescent and adult rats: a model of adverse antidepressant effects in human adolescents?

Selective serotonin reuptake inhibitor use is associated with increased risk of suicidal ideation in adolescent humans, yet the neuropharmacological basis of this phenomenon is unknown. Consequently, we examined the behavioural and neurochemical effects of chronic paroxetine (PRX) treatment in adult and adolescent rats. Rats received PRX in their drinking water (target dose 10 mg/kg) for 22 d, during which time they were assessed for depression- and anxiety-like behaviours. Subsequent ex-vivo analyses examined serum PRX concentrations, striatal neurotransmitter content, and regional serotonin and dopamine transporter (SERT, DAT) binding density. After 11–12 d treatment, PRX-treated adolescent rats showed a significant inhibition of social interaction while adults were unaffected. After 19–20 d treatment, adolescents failed to show an antidepressant-like effect of PRX treatment on the forced swim test (FST), while PRX-treated adults showed a typical decrease in immobility and increase in swimming. Two PRX-treated adolescents died unexpectedly after the FST suggesting a compromised response to physical stress. Despite their greater apparent adverse reaction to the drug, adolescents had significantly lower plasma PRX than adults at day 22 of treatment. Chronic PRX treatment had similar effects in adults and adolescents on striatal 5-HT (unchanged relative to controls) and 5-HIAA levels (decreased), while markers of dopaminergic function (DOPAC, HVA, DA turnover) were increased in adults only. SERT density was up-regulated in the amygdala in PRX-treated adolescents only while DAT density in the nucleus accumbens was down-regulated only in PRX-treated adults. These data suggest that the immature rat brain responds differently to PRX and that this might be of use in modelling the atypical response of human adolescents to antidepressants. The age-specific PRX-induced changes in dopaminergic markers and SERT and DAT binding provide clues as to the neural mechanisms underlying adverse PRX effects in adolescent humans. © 2011, Cambridge University Pres

Imaging of tumor hypoxia with [124I]IAZA in comparison with [18F]FMISO and [18F]FAZA – first small animal PET results

PURPOSE: This study was performed to compare the 2-nitroimidazole derivatives [124I]IAZA, [18F]FAZA and well known [18F]FMISO in visualization of tumor hypoxia in a mouse model of human cancer using small animal PET. METHODS: PET imaging of female Balb/c nude mice bearing A431 tumors on a Phillips Mosaic small animal PET scanner was performed 3 h p.i. for all three tracers. Mice injected with [124I]IAZA were scanned again after 24 h and 48 h. In addition to the mice breathing air, in the case of [18F]FAZA and [124I]IAZA a second group of mice for each tracer was kept in an atmosphere of carbogen gas (5% of CO2 + 95 % of O2; from 1 h before to 3 h after injection) to evaluate the oxygenation dependency on uptake (all experiments n = 4). After the final PET scan animals were sacrificed and biodistribution was studied. RESULTS: Mice injected with [18F]FAZA displayed significantly higher tumor-to background (T/B) ratios (5.19 +/- 0.73) compared to those injected with [18F]FMISO (3.98 +/- 0.66; P $lt; 0.05) or [124I]IAZA (2.06 +/- 0.26; P$lt; 0.001) 3 h p.i. Carbogen breathing mice showed lower ratios ([18F]FAZA: 4.06 +/- 0.59; [124I]IAZA: 2.02 +/- 0.36). The T/B ratios increased for [124I]IAZA with time (24 h: 3.83 +/- 0.61; 48 h: 4.20 +/- 0.80), but after these late time points the absolute whole body activity was very low, as could be seen from the biodistribution data (< 0.1 %ID/g for each investigated organ) and ratios were still lower than for [18F]FAZA 3 h p.i. Due to de-iodination uptake in thyroid was high. Biodistribution data were in good agreement with the PET results. CONCLUSIONS: [18F]FAZA showed superior biokinetics compared to [18F]FMISO and [124I]IAZA in this study. Imaging at later time points that are not possible with the short lived 18F labeled tracers resulted in no advantage for [124I]IAZA, i. e. tumor to normal tissue ratios could not be improved. © 1999 Canadian Society for Pharmaceutical Sciences

Radiopharmaceuticals for PET imaging of neuroinflammation - Les radiopharmaceutiques pour l’imagerie TEP de la neuroinflammation

Abstract Recently, accumulating evidence has revealed that neuroinflammation appears to be the cornerstone of many neurological diseases including stroke, multiple sclerosis, Alzheimer's disease or Parkinson's disease. Neuroinflammation causes neuronal damages by activation of numerous cells and molecular mediators in diseases involving the inflammatory process. In this article, we focus on noninvasive molecular imaging of radioligands that target inflammatory cells and molecules involved in neuroinflammation. PET is in fact one of the most promising imaging techniques to visualize and quantify neuroinflammation in vivo. We have also summarized the potential neuroinflammation imaging targets and corresponding PET radioligands. Résumé Des données scientifiques récentes et de plus en plus nombreuses ont mis en évidence le rôle central joué par le processus de neuroinflammation dans la physiopathologie de nombreuses maladies neurologiques, telles que l’accident vasculaire cérébral, la sclérose en plaques, la maladie d’Alzheimer ou encore la maladie de Parkinson. Dans ces maladies impliquant le processus inflammatoire, la neuro-inflammation cause en effet des dommages neuronaux par activation de nombreuses cellules et médiateurs moléculaires. L’imagerie par tomographie par émission de positons (TEP) apparaît comme une approche prometteuse pour visualiser et quantifier in vivo la neuro-inflammation de façon non invasive, grâce en particulier au développement de radioligands ciblant spécifiquement diverses molécules impliquées dans cette réaction inflammatoire cérébrale. Dans cette revue sont présentés les cibles moléculaires potentielles pour l’imagerie TEP de la neuro-inflammation ainsi que les médicaments radiopharmaceutiques correspondants

Octadentate zirconium(IV)-loaded macrocycles with varied stoichiometry assembled from hydroxamic acid monomers using metal-templated synthesis

Published: February 28, 2017The reaction between Zr(IV) and the forward endo-hydroxamic acid monomer 4-[(5-aminopentyl)(hydroxy)amino]-4-oxobutanoic acid (for-PBH) in a 1:4 stoichiometry in the presence of diphenylphosphoryl azide and triethylamine gave the octadentate Zr(IV)-loaded tetrameric hydroxamic acid macrocycle for-[Zr(DFOT₁)] ([M + H]⁺ calc 887.3, obs 887.2). In this metal-templated synthesis (MTS) approach, the coordination preferences of Zr(IV) directed the preorganization of four oxygen-rich bidentate for-PBH ligands about the metal ion prior to ring closure under peptide coupling conditions. The replacement of for-PBH with 5-[(5-aminopentyl) (hydroxy)amino]-5-oxopentanoic acid (for-PPH), which contained an additional methylene group in the dicarboxylic acid region of the monomer, gave the analogous Zr(IV)-loaded macrocycle for-[Zr(PPDFOT₁)] ([M + H]⁺ calc 943.4, obs 943.1). A second, well-resolved peak in the liquid chromatogram from the for-PPH MTS system also characterized as a species with [M + H]⁺ 943.3, and was identified as the octadentate complex between Zr(IV) and two dimeric tetradentate hydroxamic acid macrocycles for-[Zr(PPDFOT1D)₂]. Treatment of for-[Zr(PPDFOT₁)] or for-[Zr(PPDFOT1D)₂] with EDTA at pH 4.0 gave the respective hydroxamic acid macrocycles as free ligands: octadentate PPDFOT₁ or two equivalents of tetradentate PPDFOT1D (homobisucaberin, HBC). At pH values closer to physiological, EDTA treatment of for-[Zr(DFOT₁)], for-[Zr(PPDFOT₁)], or Zr(IV) complexes with related linear tri- or tetrameric hydroxamic acid ligands showed the macrocycles were more resistant to the release of Zr(IV), which has implications for the design of ligands optimized for the use of Zr(IV)-89 in positron emission tomography (PET) imaging of cancer.William Tieu, Tulip Lifa, Andrew Katsifis, and Rachel Cod

In Vivo Measurement of Hippocampal GABAA/cBZR Density with [18F]-Flumazenil PET for the Study of Disease Progression in an Animal Model of Temporal Lobe Epilepsy

PURPOSE: Imbalance of inhibitory GABAergic neurotransmission has been proposed to play a role in the pathogenesis of temporal lobe epilepsy (TLE). This study aimed to investigate whether [(18)F]-flumazenil ([(18)F]-FMZ) PET could be used to non-invasively characterise GABA(A)/central benzodiazepine receptor (GABA(A)/cBZR) density and affinity in vivo in the post-kainic acid status epilepticus (SE) model of TLE. METHODS: Dynamic [(18)F]-FMZ -PET scans using a multi-injection protocol were acquired in four male wistar rats for validation of the partial saturation model (PSM). SE was induced in eight male Wistar rats (10 weeks of age) by i.p. injection of kainic acid (7.5–25 mg/kg), while control rats (n = 7) received saline injections. Five weeks post-SE, an anatomic MRI scan was acquired and the following week an [(18)F]-FMZ PET scan (3.6–4.6 nmol). The PET data was co-registered to the MRI and regions of interest drawn on the MRI for selected structures. A PSM was used to derive receptor density and apparent affinity from the [(18)F]-FMZ PET data. KEY FINDINGS: The PSM was found to adequately model [(18)F]-FMZ binding in vivo. There was a significant decrease in hippocampal receptor density in the SE group (p<0.01), accompanied by an increase in apparent affinity (p<0.05) compared to controls. No change in cortical receptor binding was observed. Hippocampal volume reduction and cell loss was only seen in a subset of animals. Histological assessment of hippocampal cell loss was significantly correlated with hippocampal volume measured by MRI (p<0.05), but did not correlate with [(18)F]-FMZ binding. SIGNIFICANCE: Alterations to hippocampal GABA(A)/cBZR density and affinity in the post-kainic acid SE model of TLE are detectable in vivo with [(18)F]-FMZ PET and a PSM. These changes are independent from hippocampal cell and volume loss. [(18)F]-FMZ PET is useful for investigating the role that changes GABA(A)/cBZR density and binding affinity play in the pathogenesis of TLE

PET imaging of brain inflammation during early epileptogenesis in a rat model of temporal lobe epilepsy.

Background Recently, inflammatory cascades have been suggested as a target for epilepsy therapy. Positron emission tomography (PET) imaging offers the unique possibility to evaluate brain inflammation longitudinally in a non-invasive translational manner. This study investigated brain inflammation during early epileptogenesis in the post-kainic acid-induced status epilepticus (KASE) model with post-mortem histology and in vivo with [18F]-PBR111 PET. Methods Status epilepticus (SE) was induced (N = 13) by low-dose injections of KA, while controls (N = 9) received saline. Translocator protein (TSPO) expression and microglia activation were assessed with [125I]-CLINDE autoradiography and OX-42 immunohistochemistry, respectively, 7 days post-SE. In a subgroup of rats, [18F]-PBR111 PET imaging with metabolite-corrected input function was performed before post-mortem evaluation. [18F]-PBR111 volume of distribution (V t) in volume of interests (VOIs) was quantified by means of kinetic modelling and a VOI/metabolite-corrected plasma activity ratio. Results Animals with substantial SE showed huge overexpression of TSPO in vitro in relevant brain regions such as the hippocampus and amygdala (P < 0.001), while animals with mild symptoms displayed a smaller increase in TSPO in amygdala only (P < 0.001). TSPO expression was associated with OX-42 signal but without obvious cell loss. Similar in vivo [18F]-PBR111 increases in V t and the simplified ratio were found in key regions such as the hippocampus (P < 0.05) and amygdala (P < 0.01). Conclusion Both post-mortem and in vivo methods substantiate that the brain regions important in seizure generation display significant brain inflammation during epileptogenesis in the KASE model. This work enables future longitudinal investigation of the role of brain inflammation during epileptogenesis and evaluation of anti-inflammatory treatments. © 2012, Springer

Synthesis and biological characterisation of 18F-SIG343 and 18F-SIG353, novel and high selectivity σ2 radiotracers, for tumour imaging properties

Sigma2 (σ2) receptors are highly expressed in cancer cell lines and in tumours. Two novel selective 18F-phthalimido σ2 ligands, 18F-SIG343 and 18F-SIG353, were prepared and characterised for their potential tumour imaging properties. © 2013 Nguyen et al.; licensee Springer.© Nguyen et al.; licensee Springer. 2013 This article is published under license to BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited