The identification of novel orally active mGluR5 antagonist GSK2210875.

The identification of novel orally active mGluR5 antagonist GSK2210875 is described.

1,2,4-triazol-3-yl-thiopropyl-tetrahydrobenzazepines: a series of potent and selective dopamine D(3) receptor antagonists.

The discovery of new highly potent and selective dopamine D3 receptor antagonists has recently permitted characterization of the role of the dopamine D3 receptor in a wide range of preclinical animal models. A novel series of 1,2,4-triazol-3-yl-thiopropyl-tetrahydrobenzazepines demonstrating a high level of D3 affinity and selectivity with an excellent pharmacokinetic profile is reported here. In particular, the pyrazolyl derivative 35 showed good oral bioavailability and brain penetration associated with high potency and selectivity in vitro. In vivo characterization of 35 confirmed that this compound blocks the expression of nicotine- and cocaine-conditioned place preference in the rat, prevents nicotine-triggered reinstatement of nicotine-seeking behavior in the rat, reduces oral operant alcohol self-administration in the mouse, increases extracellular levels of acetylcholine in the rat medial prefrontal cortex, and potentiates the amplitude of the relative cerebral blood volume response to d-amphetamine in a regionally specific manner in the rat brain.

ImmunoPET in Neoplasms of Gastrointestinal Tract, Liver and Pancreas in the XXIst Century: Bridging the Gap Between Diagnosis and Therapy.

Monoclonal antibodies (mAbs) are produced by clones of a unique parent cell which has monovalent affinity and can bind to the same epitope. The chronological breakthrough in mAbs clinical utilization was in 1975, when it becomes possible to produce mAbs to known antigens and immortalize the cell lines. However, the clinical usefulness of mAbs was hampered for many years, basically because of their immunogenicity due to the murine origin. This situation lasted until 1988 when a technique to humanize mAbs was defined. Nuclear Medicine researchers were very quick to gathered the opportunity provided by the development of mAbs. The first papers reporting the preclinical use of radiolabelled mAbs date the early 80's soon followed by the first pivotal use in humans. However, mAbs did not gain a wide clinical use for several reasons connected to the chemistry and biochemistry of radiolabelled mAbs the emergence of clinical 18F-FDG PET. However, the "magic bullet" concept has resisted in the cultural background of Nuclear Medicine physicians for almost twenty years, and has regained importance with the development of engineered mAbs. Herein we present a selected review of preclinical and clinical studies of PET/CT with mAbs in gastrointestinal malignancies.

Selective antagonism at dopamine D3 receptors prevents nicotine-triggered relapse to nicotine-seeking behavior.

Drugs of abuse, including, nicotine have been shown to enhance brain reward functions in the mesocortico-limbic dopamine (DA) system in general, and the nucleus accumbens in particular. The latter occupies a prominent position in the ventral striatum and expresses a high density of DA D(3) receptors. As such, the present study aimed at investigating the effect of the selective D(3) receptor antagonist SB-277011-A on both the stable maintenance of intravenous nicotine self-administration and nicotine-triggered relapse to nicotine-seeking behavior in the rat. SB-277011-A (3-10 mg/kg i.p.) significantly reduced reinstatement of nicotine-seeking behavior without affecting nicotine self-administration per se. These results suggest that DA D(3) receptors are involved in the reinstatement of nicotine-seeking behavior independently of any interaction with the primary reinforcing effects of nicotine itself. These findings point toward the potential use of selective DA D(3) receptor antagonists for the pharmacotherapeutic management of relapse to drug-seeking behaviors.

Antagonism at metabotropic glutamate 5 receptors inhibits nicotine- and cocaine-taking behaviours and prevents nicotine-triggered relapse to nicotine-seeking.

Previous studies in metabotropic glutamate 5 receptor (mGlu5 receptor) deficient mice have indicated the importance of this receptor in the self-administration of cocaine and locomotor sensitisation to this stimulant. Both ionotropic and metabotropic receptors have been implicated in drug-seeking and drug-taking behaviours, but the specific role of each subtype of metabotropic glutamate receptors (mGlu receptors) is still unknown. In the present series of experiments we further investigated the role of mGlu5 receptors on nicotine, cocaine- and food-taking behaviour. We also investigated the effects of the mGlu5 receptor antagonist MPEP (2-methyl-6-(phenylethynyl)pyridine) on the acute locomotor activating effects of nicotine, the expression of sensitisation to its repeated, intermittent administration, and nicotine-triggered relapse to nicotine-seeking behaviour. The results indicate that MPEP treatment reduced nicotine-induced drug-seeking behaviour in a model of nicotine-triggered relapse to nicotine seeking. Furthermore, MPEP decreased both nicotine and cocaine self-administration without affecting food self-administration under similar schedules of reinforcement. Finally, MPEP reduced both the acute locomotor stimulant effects of nicotine as well as the expression of behavioural sensitisation to its repeated administration. Although the intravenous administration of MPEP at 1 and 10 mg/kg transiently reduced spontaneous locomotor activity during the first 25 min post-administration, we also demonstrated that performance on the accelerating rotarod was not affected when MPEP was given 5 and 30 min prior to the test. Altogether, the present findings strengthen the hypothesis that selective antagonism at mGlu5 receptors may be a new potential pharmacotherapeutic approach for the treatment of drug dependence and addiction.

Deep Inspiration Breath Hold [(18)F]FDG PET-CT on 4-rings scanners in evaluating lung lesions: evidences from a phantom and a clinical study.

OBJECTIVE: To investigate the clinical feasibility of a Deep Inspiration Breath Hold (DIBH) (18)F-FDG PET-CT acquisition in apnea and compare the results obtained between these acts of acquisition in apnea and in Free Breathing in the evaluation of lung lesions. MATERIAL AND METHODS: A pre-clinical phantom study was performed to evaluate the shortest simulated DIBH time according to the minimum detectable lesion that can be detected by our ultrasound scanner. This study was conducted by changing acquisition time and sphere-to-background activity ratio values and by using radioactivity densities similar to those generally found in clinical examinations. In the clinical study, 25 patients with pulmonary lesions underwent a standard whole body (18)F-FDG PET-CT scan in free breathing followed by a 20s single thorax acquisition PET/CT in DIBH acquisition. RESULTS: The phantom study indicated that a 20-s acquisition time provides an accurate evaluation of smallest sphere shaped lesions. In the clinical study, PET-CT scans obtained in DIBH studies showed a significant reduction of misalignment between the PET and CT scan images and an increase of SUVmax compared to free breathing acquisitions. A correlation between the %BH-index and lesion displacement between PET and CT images in FB acquisition was demonstrated, significantly higher for lesions with a displacement>8mm. CONCLUSION: The single 20s acquisition of DIBH PET-CT is a feasible technique for lung lesion detection in the clinical setting. It only requires a minor increase in examination time without special patient training. 20s DIBH scan provided a more precise measurement of SUVmax, especially for lesions in the lower lung lobes which usually show greater displacement between PET and CT scan images in FB acquisition.

Differential effects of glycogen synthase kinase 3 (GSK3) inhibition by lithium or selective inhibitors in the central nervous system.

Glycogen synthase kinase (GSK3) is a constitutively active serine-threonine kinase associated to neurological and psychiatric disorders. GSK3 inhibition is considered a mediator of the efficacy of the mood-stabiliser lithium. This study aimed at comparing the central nervous system effect of lithium with the selective GSK3 inhibitors AZ1080 and compound A in biochemical, cellular, and behavioural tests. Collapsin response mediator protein 2 is a neuron-specific GSK3 substrate. Lithium, AZ1080, and compound A inhibited its phosphorylation in rat primary neurons with different pIC50. After systemic treatments with lithium or GSK3 inhibitors to assess specific functional responses, phosphorylation was unchanged in adult rat brain, while it was strongly inhibited by GSK3 inhibitors in pups, differently from lithium. Lithium may exert neurotrophic effect by increasing brain-derived neurotrophic factor (BDNF) levels: in the present experimental conditions, lithium exerted opposite effects on plasma BDNF levels compared to GSK3 inhibitors, suggesting this effect might not be necessarily mediated by GSK3 inhibition alone. While plasma thyroid-stimulating hormone and luteinising hormone were not affected by lithium, they were decreased by selective inhibitors. GH and prolactin displayed similar responses towards reduction. Follicle-stimulating hormone levels were not altered by treatments, whereas melatonin was specifically increased by AZ1080. Lithium impaired mouse spontaneous locomotion and decreased amphetamine-induced hyper-locomotion. AZ1080 had no effects on locomotion, while compound A reduced spontaneous locomotor activity without effects on amphetamine-induced hyper-locomotion. The present results indicate that a broad correlation between the effects of lithium and selective GSK3 inhibitors could not be devised, suggesting alternative mechanisms, whereas overlapping results could be obtained in specific assays.

Strain-specific outcomes of repeated social defeat and chronic fluoxetine treatment in the mouse.

Social stress is a risk factor for affective disorders in vulnerable individuals. Although the biological nature of stress susceptibility/resilience remains to be elucidated, genetic variation is considered amongst the principal contributors to brain disorders. Furthermore, genetic predisposition may be determinant for the therapeutic outcome, as proposed for antidepressant treatments. In the present studies we compared the inherently diverse genetic backgrounds of 2 mouse strains by assessing the efficacy of a chronic antidepressant treatment in a repeated social stress procedure. C57BL/6J and BalbC mice underwent 10-day social defeats followed by 28-day fluoxetine treatment (10 mg/kg/mL, p.o.). In C57BL/6J, most of the social defeat-induced changes were of metabolic nature including persistently altered feed efficiency and decreased abdominal fat stores that were ameliorated by fluoxetine. BalbC mouse behavior was persistently affected by social defeat both in the social avoidance and the forced swim tests, and in either procedure it was restored by chronic fluoxetine, whereas their endocrine parameters were mostly unaffected. The highlighted strain-specific responsivity to the metabolic and behavioral consequences of social defeat and to the chronic antidepressant treatment offers a promising research tool to further explore the underlying neural mechanisms and genetic basis of stress susceptibility and treatment response.

Increased phasic activity of VTA dopamine neurons in mice 3 weeks after repeated social defeat.

Social defeat is an ethologically relevant stress inducing neuroadaptive changes in the mesocorticolimbic dopaminergic system. Three weeks after 10 days of daily defeat salient behaviors and in vivo dopamine (DA) neuron firing were evaluated in mice. Prior defeat induced social avoidance and hyperphagia and increased ventral tegmental area (VTA) DA neuron bursting activity. These data extend previous studies and suggest that increased phasic DA neuron firing in the VTA could be considered amongst the features defining the lasting imprint of social defeat stress.

Different susceptibility to social defeat stress of BalbC and C57BL6/J mice.

Social stress may precipitate psychopathological disorders in susceptible individuals. The present experiments were focused on the biology beyond the differential susceptibility to social stress. Social defeat, an ethologically relevant stressor known to elicit different coping strategies, was used in two mouse strains differing for baseline emotionality, such as C57BL6/J and BalbC. In separate experiments, in both strains a single social defeat decreased home-cage activity without altering social aversion; it diminished body weight only in defeated BalbC mice. In longitudinal experiments, mice experienced repeated social defeats that induced multiple long-term consequences. Defeated C57BL6/J increased their body weight and food intake; defeated BalbC mice diminished their metabolic efficiency. Only defeated BalbC subjects exhibited increased social avoidance levels; no differences from controls were seen on forced swim test response in defeated mice of either strain. No long-term effects of social defeat were detected in peripheral biomarkers of stress, metabolic, and immune responses, although the analysis of selected internal organs revealed decreases in abdominal fat and gonadal organs in all defeated subjects. These results demonstrated a strain-distinctive profile in the susceptibility to social defeat stress, either acutely or chronically, with metabolic consequences more consistently found in C57BL6/J while social aversion induced predominantly in BalbC subjects.

Evidence for the role of dopamine D3 receptors in oral operant alcohol self-administration and reinstatement of alcohol-seeking behavior in mice.

The present study examined the effects of the acute intraperitoneal (i.p.) administration of the selective dopamine (DA) D(3) receptor antagonist SB-277011A (10, 20 or 30 mg/kg i.p.) on the oral operant self-administration of alcohol in male C57BL/6N mice. These effects were compared with those of naltrexone (0.5, 1 and 2 mg/kg i.p.) and acamprosate (100, 200 and 400 mg/kg i.p.). Compared with vehicle, the acute administration of SB-277011A (10 or 20 mg/kg) did not significantly alter the operant self-administration of alcohol, whereas the 30 mg/kg dose significantly reduced alcohol intake (g/kg), the number of reinforcers, and the number of active lever presses. The oral self-administration of alcohol was not significantly altered by the acute administration of either naltrexone or acamprosate, compared with vehicle-treated mice. SB-277011A, naltrexone and acamprosate were also tested in a model of drug/cue-triggered reinstatement of alcohol-seeking behavior. In this model, neither naltrexone (2 mg/kg) nor acamprosate (400 mg/kg) prevented relapse to alcohol-seeking behavior. In contrast, SB-277011A significantly reduced reinstatement of alcohol seeking in a dose-dependent manner. Provided these results can be extrapolated to humans, they suggest that selective DA D(3) receptor antagonists may be useful in the pharmacotherapeutic management of alcohol intake and prevention of relapse to alcohol-seeking behavior.

Evidence that lacidipine at nonsustained antihypertensive doses activates nitrogen monoxide system in the endothelium of salt-loaded Dahl-S rats.

Lacidipine is a clinically active, antihypertensive calcium antagonist of the 1,4 dihydropyridine (DHP) class. It is also capable of vascular protection when administered (prophylactically and therapeutically) at nonsustained antihypertensive doses to salt-sensitive Dahl-S rats: useful animal models for studying the vasoprotective effect of calcium antagonists. In our previous work using voltammetry with selective biosensors, we observed that lacidipine implements endothelial nitrogen monoxide (NO) in normal rats. These experiments, performed in aortic rings obtained from Dahl-S rats analyzed with voltammetry and specific biosensors, further demonstrate that lacidipine, given at doses that do not control the development of hypertension (1 mg/kg), enhance endothelial NO activity. Taken together with the observation that 1 mg/kg lacidipine, and not its vehicle, is able to prevent vascular damage and concomitant increases in mortality (accelerated by a salt diet), this voltametric data suggest that NO acts as a component of positive influence of this DHP on vascular structure and function.

Role of dopamine D3 receptors in the addictive properties of ethanol.

After the cloning of the dopamine D(1) and D(2) receptors (1-3), several additional dopamine receptors were identified. These new subtypes included the D(3) and D(4) receptors, which are similar to D(2), and the D(5) receptor, which is similar to D(1) (4-6). Although most studies have focused on the role of dopamine D(1) and D(2) receptors in mediating the addictive liability of drugs, the lack of selective pharmacological tools has significantly hampered this particular field of research. In contrast, recent studies using selective competitive antagonists have shown that the dopamine D(3) receptor is involved in drug-seeking behavior. The present review is intended to highlight a new, promising area in alcohol research that focuses on the role of the dopamine D(3) receptor in the addictive properties of ethanol.

Involvement of the nitric oxide system in the anti-atherosclerotic potential of lacidipine in the ApoE-deficient mouse: a morphological, functional, and electrochemical study.

The present study investigated the anti-atherosclerotic activity of lacidipine, a calcium antagonist with antioxidant properties in apoE-deficient mice. These mice show widespread vascular lesions which closely resemble the inflammatory-fibrous plaques seen in humans in atherosclerosis. Mice were fed a Western-type diet (WTD), and treated for 8 weeks with either vehicle or lacidipine at 3 or 10 mg/kg/day. In parallel with histological studies of atherosclerotic lesions in the aorta, functional studies on vascular acetylcholine (ACh) reactivity and analysis of voltammetric levels of nitric oxide (NO) were performed. Recent work has suggested that dihydropyridines (DHPs) modulate vascular relaxation via an increase in the release of NO. Lacidipine treatment had no effect on the plasma lipid profile. However, a significant (p < 0.01) dose-related reduction of 36.4% and 43.3% of the aortic lesion area in respect to methocel-treated mice was observed. Moreover, the aortic ring from control apoE-deficient mice fed a WTD for 8 weeks showed a lower relaxation in response to ACh in comparison to wild-type C57BL/6J mice; on the contrary, lacidipine-treated apoE-deficient mice lacidipine-treated displayed a response similar to that of wildtype C57BL/6J mice. Voltammetric analyses demonstrated a significant decrease of NO release in apoE-deficient mice, while lacidipine-treated mice showed enhanced activity of the NO system. We conclude that lacidipine reduced the extent of atherosclerotic area in hypercholesterolemic apoE-deficient mice, and this reduction may be associated with the capacity of the drug to maintain endothelial NO levels at concentrations useful to protect against vascular damage.

Deep Inspiration Breath Hold [18F]FDG PET-CT on 4-rings scanners in evaluating lung lesions: Evidences from a phantom and a clinical study / [18F]FDG PET/TC en ausencia de respiración utilizando escáneres de 4 anillos en la valoración de lesiones pulmonares: evidencias de un estudio clínico y con maniquí

Objective: To investigate the clinical feasibility of a Deep Inspiration Breath Hold (DIBH) 18F-FDG PET-CT acquisition in apnea and compare the results obtained between these acts of acquisition in apnea and in Free Breathing in the evaluation of lung lesions. Material and methods: A pre-clinical phantom study was performed to evaluate the shortest simulated DIBH time according to the minimum detectable lesion that can be detected by our ultrasound scanner. This study was conducted by changing acquisition time and sphere-to-background activity ratio values and by using radioactivity densities similar to those generally found in clinical examinations. In the clinical study, 25 patients with pulmonary lesions underwent a standard whole body 18F-FDG PET-CT scan in free breathing followed by a 20 s single thorax acquisition PET/CT in DIBH acquisition. Results: The phantom study indicated that a 20-s acquisition time provides an accurate evaluation of smallest sphere shaped lesions. In the clinical study, PET-CT scans obtained in DIBH studies showed a significant reduction of misalignment between the PET and CT scan images and an increase of SUVmax compared to free breathing acquisitions. A correlation between the %BH-index and lesion displacement between PET and CT images in FB acquisition was demonstrated, significantly higher for lesions with a displacement > 8 mm. Conclusion: The single 20 s acquisition of DIBH PET-CT is a feasible technique for lung lesion detection in the clinical setting. It only requires a minor increase in examination time without special patient training. 20 s DIBH scan provided a more precise measurement of SUVmax, especially for lesions in the lower lung lobes which usually show greater displacement between PET and CT scan images in FB acquisition (AU)

Objetivo: Estudiar la viabilidad clínica de la adquisición 18F-FDG PET-TC en apnea y comparar los resultados obtenidos entre las adquisiciones en apnea y en respiración libre en la valoración de lesiones pulmonares. Material y métodos: Se ha realizado un estudio preclínico en maniquí con objeto de establecer el tiempo mínimo de adquisición en apnea en función de la más pequeña lesión evidenciable con nuestro tomógrafo. Este estudio se obtuvo modificando los tiempos de adquisición y la relación de actividad entre esfera y fondo utilizando actividades parecidas a las encontradas en la práctica clínica. En el estudio clínico, 25 pacientes con lesiones pulmonares fueron evaluados mediante PET-TC con 18F-FDG en respiración libre y posteriormente en apnea de 20 segundos. Resultados: El estudio en maniquí indicó que una adquisición de 20 segundos es adecuada para la valoración de las esferas más pequeñas. En el estudio clínico, las adquisiciones PET-TC obtenidas en apnea mostraron una significativa reducción de la desalineación entre la imagen PET y la imagen TC y un incremento en el valor del SUVmax respecto a las adquisiciones en respiración libre. Hemos demostrado la existencia de correlación entre el %BH-index y la desalineación en respiración libre, significativamente mayor en las lesiones con desalineación superior a 8 mm. Conclusiones: La adquisición PET-TC de 20 segundos en apnea es una técnica viable para la detección de la lesión pulmonar en el entorno clínico y requiere solo un pequeño aumento en el tiempo de examen sin requerir especial entrenamiento del paciente. La adquisición en apnea aporta una medida más precisa del SUVmax, especialmente en las lesiones de los lóbulos inferiores que normalmente presentan una marcada desalineación entre las imágenes PET y TC (AU)