In vivo binding of [11C]tetrabenazine to vesicular monoamine transporters in mouse brain

The time course of regional mouse brain distribution of radioactivity after i.v. injection of a tracer dose of [11C]tetrabenazine ([11C]TBZ) has been determined. Radiotracer uptake into brain is rapid, with 3.2% injected dose in the brain at 2 min. Egress from the brain is also very rapid, with only 0.21% of the injected dose still present in brain at 60 min. Radiotracer washout is slowest from the striatum and hypothalamus, consistent with binding to the higher numbers of vesicular monoamine transporters in those brain regions. The rank order of radioligand binding at 10 min after injection is striatum > hypothalamus > hippocampus > cortex = cerebellum, similar to that found using in vitro assays of the vesicular monoamine transporters. Maximum ratios of striatum/cerebellum and hypothalamus/cerebellum were 2.85 +/- 0.52 and 1.69 +/- 0.25, respectively, at 10 min after injection. Co-injection of unlabeled tetrabenazine (10 mg/kg) or pretreatment with reserpine (1 mg/kg i.p., 24 h prior) was used to demonstrate specific binding of radioligand in striatum, hypothalamus, cortex, hippocampus and cerebellum. Distribution of [11C]TBZ was unaffected by pretreatment with the neuronal dopamine uptake inhibitor GBR 12935 (20 mg/kg i.p., 30 min prior). [11C]Tetrabenazine is thus a promising new radioligand for the in vivo study of monoaminergic neurons using Positron Emission Tomography.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/30357/1/0000759.pd

Synthesis of [11C]tetrabenazine, a vesicular monoamine uptake inhibitor, for PET imaging studies

Tetrabenazine (TBZ), a high affinity and specific inhibitor of the vesicular monoamine transporter, has been labeled with carbon-11 as a potential probe for in vivo positron emission tomographic imaging of monoaminergic neuronal losses in neurodegenerative diseases. [11C]TBZ was synthesized by O-[11C]methylation of the 9-O-desmethylTBZ using [11C]methyl iodide in the presence of tetrabutyl-ammonium hydroxide. The radiochemical yields were 35-55% (decay corrected) and the synthesis time 32-37 min from EOB. [11C]TBZ was obtained with specific activities of 2000-2500 Ci/mmol (EOS) and radiochemical and chemical purities were >95%. [11C]Tetrabenazine is a promising new radioligand for the in vivo study of monoaminergic neurons using PET.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/30889/1/0000558.pd

Chronic AMPK activity dysregulation produces myocardial insulin resistance in the human Arg302Gln-PRKAG2 glycogen storage disease mouse model

BACKGROUND: The cardiac PRKAG2 mutation in the γ2-subunit of adenosine monophosphate activated kinase (AMPK) is characterized by excessive glycogen deposition, hypertrophy, frequent arrhythmias, and progressive conduction system disease. We investigated whether myocardial glucose uptake (MGU) was augmented following insulin stimulation in a mouse model of the PRKAG2 cardiac syndrome. METHODS: Myocardial and skeletal muscle glucose uptake was assessed with 2-[(18)F]fluoro-2-deoxyglucose positron emission tomography imaging in n = 3 transgenic wildtype (TGwt) vs n = 7 PRKAG2 mutant (TGmut) mice at baseline and 1 week later, 30 min following acute insulin. Systolic function, cardiac glycogen stores, phospho-AMPK α, and insulin-receptor expression levels were analyzed to corroborate to the in vivo findings. RESULTS: TGmut Patlak Ki was reduced 56% at baseline compared to TGwt (0.3 ± 0.2 vs 0.7 ± 0.1, t test p = 0.01). MGU was augmented 71% in TGwt mice following acute insulin from baseline (0.7 ± 0.1 to 1.2 ± 0.2, t test p < 0.05). No change was observed in TGmut mice. As expected for this cardiac specific transgene, skeletal muscle was unaffected at baseline with a 33% to 38% increase (standard uptake values) for both genotypes following insulin stimulation. TGmut mice had a 47% reduction in systolic function with a fourfold increase in cardiac glycogen stores correlated with a 29% reduction in phospho-AMPK α levels. There was no difference in cardiac insulin receptor expression between mouse genotypes. CONCLUSIONS: These results demonstrate a correlation between insulin resistance and AMPK activity and provide the basis for the use of this animal model for assessing metabolic therapy in the treatment of affected PRKAG2 patients

Sympathetic nervous dysregulation in the absence of systolic left ventricular dysfunction in a rat model of insulin resistance with hyperglycemia

<p>Abstract</p> <p>Background</p> <p>Diabetes mellitus is strongly associated with cardiovascular dysfunction, derived in part from impairment of sympathetic nervous system signaling. Glucose, insulin, and non-esterified fatty acids are potent stimulants of sympathetic activity and norepinephrine (NE) release. We hypothesized that sustained hyperglycemia in the high fat diet-fed streptozotocin (STZ) rat model of sustained hyperglycemia with insulin resistance would exhibit progressive sympathetic nervous dysfunction in parallel with deteriorating myocardial systolic and/or diastolic function.</p> <p>Methods</p> <p>Cardiac sympathetic nervous integrity was investigated <it>in vivo </it>via biodistribution of the positron emission tomography radiotracer and NE analogue [¹¹C]<it>meta-</it>hydroxyephedrine ([¹¹C]HED). Cardiac systolic and diastolic function was evaluated by echocardiography. Plasma and cardiac NE levels and NE reuptake transporter (NET) expression were evaluated as correlative measurements.</p> <p>Results</p> <p>The animal model displays insulin resistance, sustained hyperglycemia, and progressive hypoinsulinemia. After 8 weeks of persistent hyperglycemia, there was a significant 13-25% reduction in [¹¹C]HED retention in myocardium of STZ-treated hyperglycemic but not euglycemic rats as compared to controls. There was a parallel 17% reduction in immunoblot density for NE reuptake transporter, a 1.2 fold and 2.5 fold elevation of cardiac and plasma NE respectively, and no change in sympathetic nerve density. No change in ejection fraction or fractional area change was detected by echocardiography. Reduced heart rate, prolonged mitral valve deceleration time, and elevated transmitral early to atrial flow velocity ratio measured by pulse-wave Doppler in hyperglycemic rats suggest diastolic impairment of the left ventricle.</p> <p>Conclusions</p> <p>Taken together, these data suggest that sustained hyperglycemia is associated with elevated myocardial NE content and dysregulation of sympathetic nervous system signaling in the absence of systolic impairment.</p

Newly Identified Nematodes from Mono Lake Exhibit Extreme Arsenic Resistance

Extremophiles have much to reveal about the biology of resilience, yet their study is limited by sampling and culturing difficulties [1, 2, 3]. The broad success and small size of nematodes make them advantageous for tackling these problems [4, 5, 6]. We investigated the arsenic-rich, alkaline, and hypersaline Mono Lake (CA, US) [7, 8, 9] for extremophile nematodes. Though Mono Lake has previously been described to contain only two animal species (brine shrimp and alkali flies) in its water and sediments [10], we report the discovery of eight nematode species from the lake, including microbe grazers, parasites, and predators. Thus, nematodes are the dominant animals of Mono Lake in species richness. Phylogenetic analysis suggests that the nematodes originated from multiple colonization events, which is striking, given the young history of extreme conditions at Mono Lake [7, 11]. One species, Auanema sp., is new, culturable, and survives 500 times the human lethal dose of arsenic. Comparisons to two non-extremophile sister species [12] reveal that arsenic resistance is a common feature of the genus and a preadaptive trait that likely allowed Auanema to inhabit Mono Lake. This preadaptation may be partly explained by a variant in the gene dbt-1 shared with some Caenorhabditis elegans natural populations and known to confer arsenic resistance [13]. Our findings expand Mono Lake’s ecosystem from two known animal species to ten, and they provide a new system for studying arsenic resistance. The dominance of nematodes in Mono Lake and other extreme environments and our findings of preadaptation to arsenic raise the intriguing possibility that nematodes are widely pre-adapted to be extremophiles

Etude d'un dissipateur thermique à mini-canaux destiné au conditionnement du faIsceau sur le synchrotron

Le présent travail représente une étude numérique du transfert thermique dans un prototype de dissipateur de chaleur à mini-canaux destiné au refroidissement de l'absorbeur de lumière sur la ligne PSICHE du synchrotron soleil. Ce dernier est un accélérateur de particules qui produit des lumières de forte puissance sur un large spectre de longueur d'ondes. Un refroidissement efficace de l'absorbeur permet d'une part d'améliorer la qualité du faisceau sur l'anneau du stockage et sur les lignes de lumière et d'autre part d'augmenter la puissance de la lumière produite pour les applications de re

SPECT and PET imaging of adrenomedullin receptors: a promising strategy for studying pulmonary vascular diseases

Circulating adrenomedullin (AM) levels are elevated in several cardiovascular diseases, including pulmonary vascular diseases causing pulmonary hypertension. To date the perfusion agent (99m)Tc-albumin macroaggregates (MAA) is the only approved radiopharmaceutical used for imaging of pulmonary circulation. Unlike (99m)Tc-MAA, imaging the AM receptors involves a molecular process dependent on the density of the receptors and the affinity of specific radioligands. The AM receptors are abundantly distributed in lung capillaries and its integrity provides protection in the development of pulmonary vascular diseases. This review summarizes the development and characterization of radioligands for in vivo imaging of AM receptors as an early predictor of the onset of a pulmonary vascular disease.</p

Highlight selection of radiochemistry and radiopharmacy developments by editorial board (January-June 2020)

BackgroundThe Editorial Board of EJNMMI Radiopharmacy and Chemistry releases a biyearly highlight commentary to describe trends in the field.ResultsThis commentary of highlights has resulted in 19 different topics selected by each member of the Editorial Board addressing a variety of aspects ranging from novel radiochemistry to first in man application of novel radiopharmaceuticals.ConclusionTrends in radiochemistry and radiopharmacy are highlighted demonstrating the progress in the research field being the scope of EJNMMI Radiopharmacy and Chemistry

Highlight selection of radiochemistry and radiopharmacy developments by editorial board

BackgroundThe Editorial Board of EJNMMI Radiopharmacy and Chemistry releases a biyearly highlight commentary to update the readership on trends in the field of radiopharmaceutical development.ResultsThis commentary of highlights has resulted in 23 different topics selected by each member of the Editorial Board addressing a variety of aspects ranging from novel radiochemistry to first in man application of novel radiopharmaceuticals.ConclusionTrends in radiochemistry and radiopharmacy are highlighted demonstrating the progress in the research field being the scope of EJNMMI Radiopharmacy and Chemistry