Gallium : applications for molecular imaging

La tomographie par émission de positons (TEP) est une technique d’imagerie moléculaire avec de meilleures performances que la tomographie par émission monophotonique. Son utilisation contribue à l’amélioration des prises en charge des patients. Dans les centres dépourvus de cyclotrons, le 68Ga disponible à partir d’un générateur constitue une alternative pour le développement de traceurs TEP. Pour pouvoir développer des 68Ga-traceurs, un travail de caractérisation de la qualité des éluats a été effectué. Des méthodes de marquage adaptées ont été mises en place et validées. Nous nous sommes intéressés à trois cibles moléculaires particulièrement intéressantes dans les pathologies cardiovasculaires: les récepteurs de la somatostatine (SSTR) surexprimés dans les tumeurs neuroendocrines (TNE) mais constituant aussi une cible d’intérêt dans les pathologies cardiovasculaires à composante inflammatoire ; la phosphatidylsérine (PS), un marqueur de l’apoptose cellulaire et de l’activation plaquettaire ; la P-sélectine, un marqueur des activations plaquettaire et endothéliale. Les traceurs suivants ont été développés: 1) Analogues de la somatostatine ciblant les SSTR: a)68Ga-DOTANOC validé pour l’imagerie des TNE-Gastroentéropancréatiques dans le cadre d’un essai clinique multicentrique. b) 68Ga-NODAGANOC testé in vitro sur des cellules d’adénocarcinome pancréatique. Cette validation initiale dans l’application la plus fréquente(oncologie) a pour objectif de faciliter le passage vers des applications cardiovasculaires futures (athérosclérose, myocardite...) ; 2) Un peptide ciblant la PS : le 68Ga-P04087 ; 3) Un polysaccharide ciblant la P-sélectine: 68Ga-NODAGA-Asphy. Les deux derniers traceurs ont été testés sur un modèle d’endocardite infectieuse chez le rat.The Positron emission tomography (PET) is a molecular imaging technique with usually better performances than Single-Photon Emission Computed Tomography. Consequently, the use of PET and appropriate tracers could enable clinicians to make a better therapeutic decision, thus improving the management of patients. In centers without cyclotrons, 68Ga available from a generator is an alternative for the development of PET tracers. In order to develop 68Ga labeled-molecules, a characterization of the quality of the eluates was performed. Radiolabeling techniques adapted to the quality of the starting material were developed and validated. In this thesis we focused on three particularly interesting molecular targets in cardiovascular pathologies: somatostatin receptors (SSTR), overexpressed in neuroendocrine tumors (NETs) but also constituting a target of interest in cardiovascular diseases with an inflammatory component; phosphatidylserine (PS), a marker of cell apoptosis and platelet activation; P-selectin, a marker of platelet and endothelial activation.The following tracers have been developed: 1) Somatostatin analogues which target SSTR: a) 68Ga-DOTANOC validated for Gastroenteropancreatic-NETs imaging and used in a multicenter clinical trial. b) 68Ga-NODAGANOC tested in vitro on pancreatic adenocarcinoma cells. This initial validation in the most common application (oncology) aims to facilitate the transition to future cardiovascular applications (atherosclerosis, myocarditis ...) 2) A peptide for PS targeting: 68Ga-P04087; 3) A polysaccharide for P-selectin targeting: 68Ga-NODAGA-Asphy. The last two radiolabeled molecules were tested in a rat model of infective endocarditis

Décret du 15 juin 1888, premier décret réglementant l'exercice de la pharmacie en Tunisie, et évolution de la législation pharmaceutique avant et après l'indépendance

The decree of June 15th, 1888, the first text that legislates the pharmacy practice in Tunisia and the progress of the pharmaceutical legislation before and after the independence - In 1881, the French protectorate is established in Tunisia whose independence will not be officially declared before March 20th, 1956. This article presents the content of the decree of June 15th, 1888, the first text that legislates pharmacy practice in Tunisia. The publication of this decree, a real fundamental text, did not put an end to the illegal practice of pharmacy in the Regency, which could be explained by the few shortcomings of the text, the legislator's inability to implement the law, the ignorance and the inadvertency of the diplomats, and also the "regime of the surrenders" (le régime des capitulations) which, by preventing the pharmaceutical inspection, gave free rein to all the offenders. This situation led in the course of time to the promulgation of a number of laws which progressively allowed a better organization of the pharmaceutical profession in the Regency. The progress made by the pharmaceutical legislation throughout the French protectorate continued after the independence of Tunisia as is attested by the law number 73-55 of August 3rd, 1973 which is still in use at present.En 1881, le Protectorat français est établi sur la Tunisie dont l'indépendance ne sera officiellement déclarée que le 20 mars 1956. Dans cet article, nous décrivons le contenu du décret du 15 juin 1888, premier texte légiférant l'exercice de la pharmacie en Tunisie. L'institution de ce décret, véritable texte fondateur, n'a cependant pas mis fin à l'exercice illégal de la profession dans la Régence. Ceci pourrait s'expliquer par les quelques insuffisances du texte, l'incapacité du législateur à appliquer la loi, l'ignorance et l'inadvertance des diplomates ou encore le « régime des capitulations » qui, en bloquant l'inspection pharmaceutique, donnait libre cours à tous les contrevenants. Une telle situation a conduit à la promulgation, au fil des années, d'un ensemble de textes de lois qui ont permis progressivement une meilleure organisation de la profession pharmaceutique dans la Régence. Le progrès ainsi connu par la législation pharmaceutique tout au long du Protectorat français s'est poursuivi après l'indépendance de la Tunisie. En témoigne la loi 73-55 du 3 août 1973 actuellement en vigueur.Ben Azzouna Rana, Hamdane Ridha. Décret du 15 juin 1888, premier décret réglementant l'exercice de la pharmacie en Tunisie, et évolution de la législation pharmaceutique avant et après l'indépendance. In: Revue d'histoire de la pharmacie, 94ᵉ année, n°352, 2006. pp. 479-496

Exposure duration to mutated TTR is a key parameter determining diphosphonates cardiac uptake in FAP

International audienc

Early angiogenesis detected by PET imaging with 64Cu-NODAGA-RGD is predictive of bone critical defect repair

International audienc

Detection of Apoptotic Cells in a Rabbit Model with Atherosclerosis-Like Lesions Using the Positron Emission Tomography Radiotracer [ 18

[ 18 F]ML-10 (2-(5-fluoro-pentyl)-2-methylmalonic acid) is a positron emission tomography (PET) radiotracer that accumulates in cells presenting apoptosis-specific membrane alterations. The aim of this study was to test whether [ 18 F]ML-10 allows for the detection of apoptotic cells located in atherosclerotic plaques in rabbits. Atherosclerotic plaques were induced in the aortas of five rabbits, and five additional rabbits were used as controls. Activity in the aortas was quantified in vivo and ex vivo. The localization of [ 18 F]ML-10 to the aortic wall was identified by autoradiography. Average target to background ratios measured in vivo by PET were higher in the aortas of atherosclerotic rabbits compared with those of control rabbits (2.00 ± 0.52 vs 1.22 ± 0.30; p < .05). Differences in [ 18 F]ML-10 uptake between atherosclerotic and control aortas were confirmed ex vivo by PET and gamma counting (23.9 ± 11.2 vs 1.1 ± 2.4 counts/pixel; p <.05; 3.6 ± 2.0 vs 0.05 ± 0.05 % of injected activity/g; p < .05, respectively). Strong correlation was observed between the accumulation of [ 18 F]ML-10 in aortic segments as detected by autoradiography and the number of apoptotic cells on corresponding histologic sections ( r 2 = .75; p < .05). In this study, we found that atherosclerotic plaques rich in apoptotic cells can be detected with [ 18 F]ML-10 and PET

Preclinical Validation of Tc–Annexin A5–128 in Experimental Autoimmune Myocarditis and Infective Endocarditis: Comparison with Tc–HYNIC–Annexin A5

Hydrazinonicotinamide–annexin A5 (HYNIC-Anx), a 99m technetium ( 99m Tc)-labeled agent targeting phosphatidylserine, proved to be sensitive for the detection of apoptosis and thrombosis but is no longer available for clinical use. A mutant of human annexin designed for direct 99m Tc labeling (referred to as Anx A5–128) showed improved binding affinity to phosphatidylserine and is expected to be used in humans. We compared both radiotracers with regard to pharmacokinetics and diagnostic ability in animal models. Biodistribution studies were performed in normal rats. Radiolabeled Anx A5–128 and HYNIC-Anx were compared in cardiovascular settings involving phosphatidylserine expression: experimental autoimmune myocarditis and infective endocarditis. Initial blood clearance was faster for Anx A5–128 than for HYNIC-Anx, and tissue biodistribution was similar overall for both tracers. The diagnostic sensitivity of Anx A5–128 was excellent and comparable to that of HYNIC-Anx. Anx A5–128 showed biodistribution and diagnostic ability similar to those of the HYNIC-Anx derivative, supporting its translation to clinical use

Head-to-head comparison of the diagnostic performances of Rubidium-PET and SPECT with CZT camera for the detection of myocardial ischemia in a population of women and overweight individuals

International audienceBackground: The aim of this study was to compare the diagnostic performances for the detection of myocardial ischemia of 82-Rb-PET-MPS and 99m-Tc-SPECT-MPS in overweight individuals and women.Methods and results: Men with BMI ≥ 25 and women referred for MPS were considered for inclusion. All individuals underwent 99m-Tc-SPECT-MPS with CZT cameras and 82-Rb-PET-MPS in 3D-mode. Individuals with at least one positive MPS were referred for coronary angiography (CA) with FFR measurements. A criterion for positivity was a composite endpoint including significant stenosis on CA or, in the absence of CA, the occurrence of acute coronary event during the following year. 313 patients (46% women) with mean BMI of 31.8 ± 6.5 were included. Sensitivity for the detection of myocardial ischemia was higher with 82-Rb-PET-MPS compared with 99m-Tc-SPECT-MPS (85% vs. 57%, P .05). 82-Rb-PET allowed for a more accurate detection of patients with a high-risk coronary artery disease (HR-CAD) than 99m-Tc-SPECT-MPS (AUC = 0.86 vs. 0.75, respectively; P = .04).Conclusions: In women and overweight individuals, 82-Rb-PET-MPS provides higher sensitivity for the detection of myocardial ischemia than 99m-Tc-SPECT-MPS thanks to a better image quality and an improved detection of HR-CAD

Preclinical Validation of 99m

Hydrazinonicotinamide–annexin A5 (HYNIC-Anx), a 99m technetium ( 99m Tc)-labeled agent targeting phosphatidylserine, proved to be sensitive for the detection of apoptosis and thrombosis but is no longer available for clinical use. A mutant of human annexin designed for direct 99m Tc labeling (referred to as Anx A5–128) showed improved binding affinity to phosphatidylserine and is expected to be used in humans. We compared both radiotracers with regard to pharmacokinetics and diagnostic ability in animal models. Biodistribution studies were performed in normal rats. Radiolabeled Anx A5–128 and HYNIC-Anx were compared in cardiovascular settings involving phosphatidylserine expression: experimental autoimmune myocarditis and infective endocarditis. Initial blood clearance was faster for Anx A5–128 than for HYNIC-Anx, and tissue biodistribution was similar overall for both tracers. The diagnostic sensitivity of Anx A5–128 was excellent and comparable to that of HYNIC-Anx. Anx A5–128 showed biodistribution and diagnostic ability similar to those of the HYNIC-Anx derivative, supporting its translation to clinical use