Study of Carbamoyl Fluoride: Synthesis, Properties and Applications.

Carbamoyl fluoride is a fluorinated group that, to this date, remains underexplored, probably due to the lack of data concerning its properties. In this paper, a study of carbamoyl fluoride is presented. Stability studies, in particular under physiological conditions, and lipophilicity measurement were performed. A new easy, safe, inexpensive, and metal-free synthesis method is also described. Finally, a potential use in radiochemistry through a 18 F/19 F isotopic exchange is demonstrated.

A non-human primate model of stroke reproducing endovascular thrombectomy and allowing long-term imaging and neurological read-outs.

Stroke is a devastating disease. Endovascular mechanical thrombectomy is dramatically changing the management of acute ischemic stroke, raising new challenges regarding brain outcome and opening up new avenues for brain protection. In this context, relevant experiment models are required for testing new therapies and addressing important questions about infarct progression despite successful recanalization, reversibility of ischemic lesions, blood-brain barrier disruption and reperfusion damage. Here, we developed a minimally invasive non-human primate model of cerebral ischemia (Macaca fascicularis) based on an endovascular transient occlusion and recanalization of the middle cerebral artery (MCA). We evaluated per-occlusion and post-recanalization impairment on PET-MRI, in addition to acute and chronic neuro-functional assessment. Voxel-based analyses between per-occlusion PET-MRI and day-7 MRI showed two different patterns of lesion evolution: "symptomatic salvaged tissue" (SST) and "asymptomatic infarcted tissue" (AIT). Extended SST was present in all cases. AIT, remote from the area at risk, represented 45% of the final lesion. This model also expresses both worsening of fine motor skills and dysexecutive behavior over the chronic post-stroke period, a result in agreement with cortical-subcortical lesions. We thus fully characterized an original translational model of ischemia-reperfusion damage after stroke, with consistent ischemia time, and thrombus retrieval for effective recanalization.

Preclinical validation of [18F]2FNQ1P as a specific PET radiotracer of 5-HT6 receptors in rat, pig, non-human primate and human brain tissue.

INTRODUCTION: The aim of this study was to perform in-vitro and in-vivo radiopharmacological characterizations of [18F]2FNQ1P, a new PET radiotracer of 5-HT6 receptors, in rat, pig, non-human primate and human tissues. The 5-HT6 receptor is one of the more recently identified serotonin receptors in central nervous system and, because of its role in memory and cognitive processes, is considered as a promising therapeutic target. METHODS: In-vitro autoradiography and saturation binding assays were performed in postmortem brain tissues from rat, pig, non-human primate and human caudate nucleus, completed by serum stability assessment in all species and cerebral radiometabolite and biodistribution studies in rat. RESULTS: In all species, autoradiography data revealed high binding levels of [18F]2FNQ1P in cerebral regions with high 5-HT6 receptor density. Binding was blocked by addition of SB258585 as a specific antagonist. Binding assays provided KD and Bmax values of respectively 1.34 nM and 0.03 pmol·mg-1 in rat, 0.60 nM and 0.04 pmol·mg-1 in pig, 1.38 nM and 0.07 pmol·mg-1 in non-human primate, and 1.39 nM and 0.15 pmol·mg-1 in human caudate nucleus. In rat brain, the proportion of unmetabolized [18F]2FNQ1P was >99% 5 min after iv injection and 89% at 40 min. The biodistribution studies found maximal radioactivity in lungs and kidneys (3.5 ± 1.2% ID/g and 2.0 ± 0.7% ID/g, respectively, 15 min post-injection). CONCLUSION: These radiopharmacological data confirm that [18F]2FNQ1P is a specific radiotracer for molecular imaging of 5-HT6 receptors and suggest that it could be used as a radiopharmaceutical in humans.

Effects of prone position and positive end-expiratory pressure on lung perfusion and ventilation.

OBJECTIVES: Prone positioning is frequently used during acute respiratory distress syndrome. However, mechanisms by which it improves oxygenation are poorly understood, as well as its interaction with positive end-expiratory pressure. This study was conducted to decipher the respective effects of positive end-expiratory pressure and posture during lung injury on regional lung ventilation, perfusion and recruitment assessed by positron emission tomography. DESIGN: Experimental study. SETTING: Research laboratory of a university hospital. SUBJECTS: Six female piglets. INTERVENTIONS: After oleic acid-induced lung injury, all animals were studied in supine and prone position at both positive end-expiratory pressure 0 and positive end-expiratory pressure 10 cm H2O. MEASUREMENTS AND MAIN RESULTS: In each experimental condition, regional lung perfusion and ventilation were assessed with positron emission tomograph using intravenous 15O-labeled water and inhaled nitrogen-13. Nonaerated lung weight was assessed with positron emission tomograph, and alveolar recruitment was defined as the difference of nonaerated lung weight between conditions. Positive end-expiratory pressure was associated with significant alveolar recruitment (130 +/- 85 and 65 +/- 29 g of lung in supine and prone position, respectively [p < 0.05 vs. 0]), whereas recruitment induced by posture was not statistically significant (77 +/- 97 g with positive end-expiratory pressure 0 and 13 +/- 19 g with positive end-expiratory pressure 10 [p > 0.05 vs. 0]). Regardless the posture, positive end-expiratory pressure redistributed both perfusion and ventilation toward dependent regions. Recruitment by positive end-expiratory pressure was restricted to dorsal regions in supine position, but extended diffusely along the ventral-to-dorsal dimension in prone position. Prone position was associated with recruitment in dorsal regions with concomitant derecruitment in ventral regions, magnitude of this being reduced by positive end-expiratory pressure. Prone position redistributed ventilation toward dorsal and ventral regions at positive end-expiratory pressure 0 and positive end-expiratory pressure, respectively. Finally, prone position redistributed perfusion toward ventral regions, to an extent amplified by positive end-expiratory pressure. CONCLUSIONS: Positive end-expiratory pressure and posture act synergistically by redistributing lung regional perfusion toward ventral regions, but have antagonistic effects on regional ventilation.

Effect of activated protein C on pulmonary blood flow and cytokine production in experimental acute lung injury.

OBJECTIVE: In acute lung injury (ALI) activated protein C (APC) may reopen occluded lung vessels and minimize lung inflammation. We aimed at assessing the effect of APC on regional lung perfusion, aerated lung volume, cytokine production and oxygenation in experimental ALI. DESIGN AND SETTING: Prospective, controlled study in an imaging facility. PARTICIPANTS: Pigs tracheotomized and mechanically ventilated. INTERVENTION: Pigs were randomly given intravenously APC (n = 8) or saline (n = 8). Thirty minutes later, ALI was induced by injecting oleic acid. MEASUREMENTS AND RESULTS: Lung perfusion and aerated lung volume measured with positron emission tomography, plasma cytokines and arterial blood gas were determined just before ALI and 110 and 290 min thereafter. Lung cytokines were measured at the end of the experiment. PaO2 under F I O2 1 was significantly lower in the APC group before lung injury (473+/-129 vs. 578+/-54 mmHg) and 110 min (342+/-138 vs. 446+/-103 mmHg) and 290 min (303+/-171 vs. 547+/-54 mmHg) thereafter (p < 0.05). Lung perfusion nonsignificantly tended to redistribute towards dorsal lung regions with APC. Total aerated lung volume was not different between APC and control before ALI (10.0+/-1.5 vs. 11.0+/-2.5 ml/kg) (p > 0.05) or thereafter. Plasma IL-6 and IL-8 at 110 min were greater with APC (p < 0.05). CONCLUSIONS: In contrast to studies using other models, pretreatment with APC was associated with worsening oxygenation in the present investigation. This might be due to ventilation-perfusion mismatch, with more perfusion to dependent nonaerated areas.

Alveolar recruitment assessed by positron emission tomography during experimental acute lung injury.

OBJECTIVES: To compare changes in aerated lung volumes measured by positron emission tomography (PET) and inflation volume-pressure curve (V-P) of the respiratory system, and to evaluate the reliability of PET to assess alveolar recruitment. DESIGN AND SETTING: Experimental study in six anesthetized and mechanically ventilated pigs in a PET facility in an experimental university laboratory. INTERVENTIONS: Lung injury was induced by oleic acid. Animals were randomly studied in four conditions: PEEP 0cmH(2)O (ZEEP) in supine position (SP), PEEP 10cmH(2)O in SP, ZEEP in prone position (PP) and PEEP in PP, each applied for 30min. MEASUREMENTS AND RESULTS: With PET aerated lung volume was obtained from pulmonary density analysis using transmission scan (VA(trans)) and from nitrogen-13 kinetics on emission scan (VA(em)). Changes in VA(trans) and VA(em) were computed as the difference in aerated volume between conditions. VA(trans) and VA(em) did not differ between SP and PP, on either ZEEP or PEEP, suggesting no modification in relaxation volume of the respiratory system induced by posture. Changes in VA(trans) or VA(em) were significantly correlated with changes in aerated volume assessed from superimposed V-P curves (R (2)=0.74 and 0.75, respectively). Alveolar recruitment assessed by PET was significantly correlated with both PaO(2) (R (2)=0.61) and PaCO(2) (R (2)=0.40) variations induced by PEEP. CONCLUSIONS: PET is a new reliable tool of scientific interest to image lung volume and alveolar recruitment during acute lung injury.

Quantitative assessment of regional alveolar ventilation and gas volume using 13N-N2 washout and PET.

UNLABELLED: Measurement of alveolar volume (Va) and regional ventilation (a) is crucial to understanding the pathophysiology of acute lung injury and ventilator-induced lung injury. PET has previously been used as a noninvasive, quantitative method to assess a, but formal validation of this technique in experimental lung injury is lacking. This study aims to validate Va and a regional assessment with PET, using inhaled (13)N-N(2) in pigs. METHODS: Two normal and 2 oleic acid-injured pigs were tracheotomized, mechanically ventilated, and studied in 5 different levels of ventilation by changing respiratory rate. In each experimental condition, lungs were washed-in and then washed-out with (13)N-N(2) through an open circuit in the ventilator. Using this method, multiframe images were acquired with a dedicated PET camera. Regions of interest (ROIs) were drawn on each lung. Regional time-activity curves during washout were generated for each ROI and fitted to a mono- and a bicompartmental model. Validation of this method was performed in 2 ways. First, regional values of predicted Va (Va(emission)) were compared with regional volume obtained independently from density analysis on a transmission scan (Va(trans)). Second, regional values of predicted a were summed in each animal during each experimental condition and compared with minute-ventilation values set on the ventilator. RESULTS: The bicompartmental model best fitted the experimental values in normal (94.7% [62.2%-100.0%] (median [interquartile range]) of the ROIs) as well as in injured animals (90.7% [81.6%-97.4%] of the ROIs) (P = 0.49). Va(emission) significantly correlated with Va(trans) (R(2) = 0.89, P < 0.001) but exceeded Va(trans) by 10%. Finally, a strongly and positively correlated with minute-ventilation in both normal (R(2) = 0.96, P < 0.001) and injured (R(2) = 0.96, P < 0.001) animals. CONCLUSION: Measurement of (13)N-N(2) washout using PET is accurate to assess regional alveolar volume and ventilation during experimental acute lung injury.