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Aging and diseases generally result from tissue inability to maintain homeostasis through adaptation. The adult heart is particularly vulnerable to disequilibrium in homeostasis because its regenerative abilities are limited. Here, we report that MLIP (muscle enriched A-type lamin-interacting protein), a unique protein of unknown function, is required for proper cardiac adaptation. Mlip(-/-) mice exhibited normal cardiac function despite myocardial metabolic abnormalities and cardiac-specific overactivation of Akt/mTOR pathways. Cardiac-specific MLIP overexpression led to an inhibition of Akt/mTOR, providing evidence of a direct impact of MLIP on these key signaling pathways. Mlip(-/-) hearts showed an impaired capacity to adapt to stress (isoproterenol-induced hypertrophy), likely because of deregulated Akt/mTOR activity. Genome-wide association studies showed a genetic association between Mlip and early response to cardiac stress, supporting the role of MLIP in cardiac adaptation. Together, these results revealed that MLIP is required for normal myocardial adaptation to stress through integrated regulation of the Akt/mTOR pathways.

[13N]Ammonia is one of the most commonly used Positron Emission Tomography (PET) radiotracers in humans to assess myocardial perfusion and measure myocardial blood flow. Here, we report a reliable semi-automated process to manufacture large quantities of [13N]ammonia in high purity by proton-irradiation of a 10 mM aqueous ethanol solution using an in-target process under aseptic conditions. Our simplified production system is based on two syringe driver units and an in-line anion-exchange purification for up to three consecutive productions of ~30 GBq (~800 mCi) (radiochemical yield = 69 ± 3% n.d.c) per day. The total manufacturing time, including purification, sterile filtration, reformulation, and quality control (QC) analyses performed before batch release, is approximately 11 min from the End of Bombardment (EOB). The drug product complies with FDA/USP specifications and is supplied in a multidose vial allowing for two doses per patient, two patients per batch (4 doses/batch) on two separate PET scanners simultaneously. After four years of use, this production system has proved to be easy to operate and maintain at low costs. Over the last four years, more than 1000 patients have been imaged using this simplified procedure, demonstrating its reliability for the routine production of large quantities of current Good Manufacturing Practices (cGMP)-compliant [13N]ammonia for human use. [ABSTRACT FROM AUTHOR]

Angiotensin II type 1 receptors (AT1R) blocker losartan is used in patients with renal and cardiovascular diseases. [18F]fluoropyridine‐losartan has shown favorable binding profile for quantitative renal PET imaging of AT1R with selective binding in rats and pigs, low interference of radiometabolites and appropriate dosimetry for clinical translation. A new approach was developed to produce [18F]fluoropyridine‐losartan in very high molar activity. Automated radiosynthesis was performed in a three‐step, two‐pot, and two‐HPLC‐purification procedure within 2 h. Pure [18F]FPyKYNE was obtained by radiofluorination of NO2PyKYNE and silica‐gel‐HPLC purification (40 ± 9%), preventing the formation of nitropyridine‐losartan in the second step. Conjugation with trityl‐losartan azide via click chemistry, followed by acid hydrolysis, C18‐HPLC purification and reformulation provided [18F]fluoropyridine‐losartan in 11 ± 2% (decay‐corrected from [18F]fluoride, EOB). Using tris[(1‐(3‐hydroxypropyl)‐1H‐1,2,3‐triazol‐4‐yl)methyl]‐amine (THPTA) as a Cu(I)‐stabilizing agent for coupling [18F]FPyKYNE to the unprotected losartan azide afforded [18F]fluoropyridine‐losartan in similar yields (11 ± 3%, decay‐corrected from [18F]fluoride, EOB). Reverse‐phase HPLC was optimized by reducing the pH of the mobile phase to achieve complete purification and high molar activities (467 ± 60 GBq/μmol). The use of radioprotectants prevented tracer radiolysis for 10 h (RCP > 99%). The product passed the quality control testing. This reproducible automated radiosynthesis process will allow in vivo PET imaging of AT1R expression in several diseases. [ABSTRACT FROM AUTHOR]

Altered sympathetic nervous activity has been linked to the development and persistence of obesity, partly relating to overfeeding. Binding of the selective, positron-emitting phosphodiesterase-4 (PDE4) inhibitor (R)-[[sup.11]C]rolipram provides a direct index of the CAMP-hydrolyzing enzyme PDE4. This study examines progressive alterations in PDE4 in a high-fat-fed obese animal model. (R)-[[sup.11]C]Rolipram was injected into diet-induced obese (DIO) and diet-resistant (DR) rats; the animals were killed after 45 min, tissues were extracted, and radioactivity was quantified. Responsiveness of PDE4 to acute noradrenaline (NA) stimulation was determined by 3 h pretreatment with the NA reuptake inhibitor desipramine. There was minimal variance in caloric intake, weight gain, fasting glucose, insulin, and energy expenditure (indirect calorimetry) measures. Basal (R)-[[sup.11]C]rolipram binding was comparable between DIO and DR rats at 2 or 8 weeks of feeding. The normal increase of PDE4 levels in response to elevated NA by desipramine pretreatment was ablated in PDE4-rich tissues, including brain, heart, and skeletal muscle, of DIO animals after 8 weeks of high-fat diet. Lean DR rats maintained PDE4 responsiveness indicative of a normal NA signal transduction. Key words: diet-induced thermogenesis, sympathetic nervous system, noradrenergic signaling, (R)-[[sup.11]C]rolipram, positron emission tomography, high-fat diet, obesity. Une modification de l'activite nerveuse sympathique a ete liee au developpement et au maintien de l'obesite, decoulant en partie d'une suralimentation. La fixation de l'inhibiteur selectif de la phosphodiesterase-4 (PDE4) emetteur de positons, (R)-[[sup.11]C]rolipram, fournit un indice direct de l'enzyme PDE4 hydrolysant l'AMPc. La presente etude examine les modifications progressives de la PDE4 dans un modele animal obese soumis a une diete hyperlipidique. On a injecte le (R)-[[sup.11]C]rolipram a des rats rendus obeses par la diete (OD) et a des rats resistants a la diete (RD), sacrifie les animaux apres 45 min, extrait les tissus et quantifie la radioactivite. On a determine la reactivite de la PDE4 a une stimulation aigue induite par la noradrenaline (NA), 3 h apres un pretraitement avec l'inhibiteur de recapture de NA, desipramine. On a observe une variance minimale dans les mesures de l'apport calorique, de gain corporel, de glucose a jeun, d'insuline et de depense energetique (calorimetrie indirecte). La retention basale de (R)-[[sup.11]C]rolipram a ete comparable chez les rats OD et RD apres 2 ou 8 semaines de diete. L'augmentation normale des taux de PDE4 en reponse a l'augmentation de NA par le pretraitement a la desipramine a ete supprimee dans les tissus riches en PDE4, dont le cerveau, le coeur et le muscle squelettique, des animaux OD apres 8 semaines de diete hyperlipidique. Les rats RD maigres ont maintenu une reactivite de la PDE4 indiquant une transduction de signal normale par la NA. Mots-cles : thermogenese induite par la diete, systeme nerveux sympathique, signalisation noradrenergique, (R)-[[sup.11]C]rolipram, tomographie d'emission de positons, diete hyperlipidique, obesite. [Traduit par la Redaction], Introduction Obesity confers elevated risk for several comorbidities, including type 2 diabetes mellitus, hypertension, and cardiovascular disease (Kannel et al. 1967; Poirier et al. 2006). The sympathetic nervous system (SNS) [...]