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.

BACKGROUND: 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); specificity was equally high with both imaging techniques (93% vs. 94%, 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.

Synthesis, gallium labelling and characterization of P04087, a functionalized phosphatidylserine-binding peptide.

BACKGROUND: Radiolabeled phosphatidylserine (PS)-binding peptides represent an innovative strategy for molecular imaging of apoptosis and thrombus. The hexapeptide PGDLSR was described as a selective and high affinity ligand for PS. In this work, we synthesized and evaluated a gallium labelled-PGDLSR peptide as a potential and selective radiopharmaceutical for nuclear imaging. PGDLSR-ß-alanine-NODAGA (P04087) was prepared using Fmoc-based synthesis and then chelated with cold gallium, 68Ga and 67Ga. The affinity of Ga-P04087 for PS was evaluated by a competitive binding assay using biotinylated AnnexinV. The in vitro stability of the radiotracer was checked at room temperature and after incubation in human serum at 37 °C with and without a metalloprotease inhibitor. The in vivo binding of 67Ga-P04087 to phosphatidylserine was evaluated in a rat model of infective endocarditis. RESULTS: PGDLSR was successfully prepared with a yield of 31%. P04087 was obtained with a yield of 28% and in high chemical purity (>95%). The radiochemical purities of 67Ga-P04087 and 68Ga-P04087 exceeded 98% in all cases. IC50 of P04087 and Ga-P04087 were in the same order of magnitude (10-7M). The radiolabelled product was stable for 24 h at room temperature, but was very rapidly degraded in human serum in the absence of a protease inhibitor, which had a stabilizing effect. No focal uptake could be detected visually in the cardiac area on SPECT images. On autoradiography however, a focal uptake of 67Ga-P04087 in the valve area was present and histological slices demonstrated localization of peptide binding at the peripheral layer of vegetations. CONCLUSION: In spite of the preservation of the peptide affinity to the PS after its conjugation to the NODAGA chelator, and of the presence of 67Ga-P04087 uptake on autoradiography, the absence of detectable foci in vivo in the valve area may be attributed to both the low intensity of the signal and the presence of background activity originating from blood pool and surrounding tissues in the living animals. Further modifications are necessary to design a radiolabeled peptide with higher binding potencies to PS while possessing enhanced metabolic stability in vivo.

68Ga 'vacuum elution approach' for direct radiolabelling of DOTA-conjugated and NODAGA-conjugated peptides.

BACKGROUND/OBJECTIVES: The Ge/Ga generator is of increasing interest for clinical PET. The arrival on the market of the pharmaceutical-grade generator, which provides an eluate with chemical and radiochemical purities in conformity with the European Pharmacopeia specifications, makes the direct labelling of vectors possible. The kit formulation strategies using single vial productions can improve the access of hospitals and imaging centres that are not equipped with costly automated synthesis modules to the Ga-radiopharmaceutical production. The manual radiosynthesis of Ga requires handling of a relatively high amount of radioactivity, resulting in a high radiation dose to the hand. Moreover, the elution of the Ga/Ge generator with 5 ml of HCl as recommended by the manufacturer leads to a low Ga concentration, which can decrease the efficiency of the labelling procedure. The aim of our approach is to circumvent these disadvantages and to offer an alternative to the hand elution and labelling for a routine production of Ga-radiopharmaceuticals. METHODS: A mixture of buffer and peptide was first transferred to an evacuated collection vial. Fixed volume of HCl was adapted to the inlet line of the generator. The elution was then performed by the action of vacuum and the labeling occurs at RT or 95°C. RESULTS AND CONCLUSION: The 'vacuum elution approach' developed in this work enables the elution of 95% of the available generator activity with 2.5 ml of eluent, the direct labelling of DOTA-conjugated and NODAGA-conjugated peptides with high radiochemical (>97% for all cases) and radionuclidic (100%) purities without exposure of the hand to radiation during the preparation steps.

Detection of Apoptotic Cells in a Rabbit Model with Atherosclerosis-Like Lesions Using the Positron Emission Tomography Radiotracer [18F]ML-10.

[18F]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 [18F]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 [18F]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 [18F]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 [18F]ML-10 in aortic segments as detected by autoradiography and the number of apoptotic cells on corresponding histologic sections (r2 = .75; p < .05). In this study, we found that atherosclerotic plaques rich in apoptotic cells can be detected with [18F]ML-10 and PET.

A new (68)Ga anionic concentration and purification method for automated synthesis of [(68)Ga]-DOTA or NODAGA conjugated peptides in high radiochemical purity.

The (68)Ge/(68)Ga generator is of increasing interest for clinical PET. For successful labelling, the eluate has to be purified. The aim of our approach is to improve the existing anionic methods which have a number of advantages compared to other methods but which use high concentrated HCl, and require an additional anionizing step. A new (68)Ga-eluate anionic purification method that enables rapid and high efficiency labelling of DOTA and NODAGA conjugated peptides in high radiochemical purity is described. The new method uses NaCl as an alternative Cl(-) source to the corrosive HCl and combines the three standard steps in a single step. The recovery yield was ≥90%, and the (68)Ge breakthrough was in conformity with the European Pharmacopeia limit. An automated labelling of DOTA and NODAGA-conjugated peptides was performed with the new method, using acetate sodium buffer, with a total duration of 13 min and a radiochemical yield >85%. The labelled peptides have a radiochemical purity exceeding 99% and can be used directly without any further purification step and without the quality control by gas chromatography. Furthermore, the new method has an economic advantage: it offers the possibility to use generator until 20 months after the calibration date.

[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]. / 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 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.