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1.
Mol Imaging Biol ; 18(1): 117-26, 2016 Feb.
Article in English | MEDLINE | ID: mdl-26013478

ABSTRACT

PURPOSE: The first biological evaluation of two potent fluorine-18 radiolabelled inhibitors of caspase-3/7 was achieved in a cerebral stroke rat model to visualize apoptosis. PROCEDURES: In vivo characteristics of isatins [(18)F]-2 and [(18)F]-3 were studied and compared by µPET to previously described 1-[4-(2-[(18)F]fluoroethyl)benzyl]-5-(2-methoxymethylpyrrolidin-1-ylsulfonyl)isatin ([(18)F]-1) and to 2-(5-[(18)F]fluoropentyl)-2-methyl-malonic acid ([(18)F]ML-10) used as a reference radiotracer in a rat stroke model. RESULTS: [(18)F]-2 and [(18)F]-3 were radiolabelled with high radiochemical purity and high specific radioactivity. Radioactivity uptakes in ischemic and contralateral brain regions were weak for the three radiolabelled isatins and lower for [(18)F]ML-10. In µPET, time activity curves showed significant uptake differences between both regions of interest for [(18)F]-1 after 45 min. No differences were observed for [(18)F]ML-10. CONCLUSIONS: Radiolabelled isatins are more promising radiotracers to image apoptosis than [(18)F]ML-10 in this stroke animal model without craniectomy. In particular, [(18)F]-1 presented significant uptake in apoptotic area 45 min after administration.


Subject(s)
Apoptosis/drug effects , Caspase 3/metabolism , Caspase 7/metabolism , Caspase Inhibitors/pharmacology , Methylmalonic Acid/analogs & derivatives , Molecular Imaging/methods , Radiopharmaceuticals/pharmacology , Stroke/diagnostic imaging , Animals , Caspase Inhibitors/blood , Caspase Inhibitors/pharmacokinetics , Disease Models, Animal , Isatin/chemistry , Isatin/pharmacology , Male , Methylmalonic Acid/pharmacokinetics , Methylmalonic Acid/pharmacology , Radionuclide Imaging , Radiopharmaceuticals/blood , Radiopharmaceuticals/pharmacokinetics , Rats, Sprague-Dawley , Stroke/pathology , Tissue Distribution/drug effects
2.
J Org Chem ; 80(20): 10086-97, 2015 Oct 16.
Article in English | MEDLINE | ID: mdl-26406157

ABSTRACT

The efficient dehydrofluorination and radiofluorination of N,N-disubstituted-ß-aminoalcohols through an anchimeric-assisted mechanism was developed. An investigation into the influence of N-substituents on the ring opening of the aziridinium intermediate indicated differences in the isomeric ratio and the yields of fluorinated products obtained from N,N-disubstituted-phenylalaninol. This influence was substantial for (18)F-radiofluorination, with yields varying from 0 to 71% at room temperature (RT). Although no significant effects were observed in the fluorine-19 chemistry when the reaction was heated to 90 °C, considerable changes appeared during radiofluorination. In the latter case, the radiochemical yields increased, and degradation of the 2-fluoro-propan-1-amine isomer (b) occurred, leading to a regiospecific reaction in the radiolabeling of [(18)F]-fluorodeprenyl. This method involving nucleophilic radiofluorination at RT was successfully applied to the radiolabeling of [(18)F]-2-fluoroethylamines in which the influence of the N-substituent was also observed.

3.
Mol Imaging Biol ; 15(1): 12-8, 2013 Feb.
Article in English | MEDLINE | ID: mdl-22752653

ABSTRACT

PURPOSE: [(18)F]ML-10 is the most advanced radiopharmaceutical for the clinical imaging of the apoptosis phenomenon by PET. The preparation of this radiopharmaceutical on a commercial radiosynthesis module and the requested quality controls for its release are presented herein. PROCEDURES: ML-10 as reference and its mesyloxy derivative as precursor for labelling with fluorine-18 were prepared. [(18)F]ML-10 was synthesized via a [(18)F]fluorine-de-mesyloxy aliphatic nucleophilic substitution via a GE TRACERLab® FX-FN module. Quality controls were performed. RESULTS: The labelling precursor was obtained in a four step synthesis in 28 % overall yield affording ML-10 in two steps (88 % yield). Pure [(18)F]ML-10 was obtained with a decay corrected yield of 39.8 % ± 8.4 % (n = 7) in 70 min and a specific activity of 235 ± 85 GBq/µmol at the end of synthesis. CONCLUSIONS: [(18)F]ML-10 was prepared on a widely available automated module and passed the quality control. A LC/MS method was developed to measure specific radioactivity.


Subject(s)
Methylmalonic Acid/analogs & derivatives , Positron-Emission Tomography/methods , Radiopharmaceuticals/chemical synthesis , Apoptosis/physiology , Kinetics , Methylmalonic Acid/chemical synthesis , Methylmalonic Acid/chemistry , Molecular Imaging/methods , Radiopharmaceuticals/chemistry
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