Radiosynthesis and radiopharmacological evaluation of [N-methyl-11C]Org 34850 as a glucocorticoid receptor (GR)-binding radiotracer |
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| Affiliation: | 1. Institut für Radiopharmazie, Forschungszentrum Dresden-Rossendorf e.V., POB 51 01 19, D-01314 Dresden, Germany;2. Department of Oncologic Imaging, Cross Cancer Institute, University of Alberta, Edmonton, Alberta, Canada T6G 1Z2;3. Schering-Plough, PO Box 20, 5340 BH Oss, The Netherlands;1. Dipartimento NEUROFARBA-Sezione di Farmaceutica e Nutraceutica, Università di Firenze, Via Ugo Schiff 6, 50019 Sesto Fiorentino, FI, Italy;2. Dipartimento di Scienze della Salute, Università di Firenze, Viale Pieraccini 6, 50139 Firenze, Italy;3. Université Paris 13, Sorbonne Paris Cité, Laboratoire CSPBAT, CNRS (UMR 7244), UFR-SMBH, 74 Rue Marcel Cachin, 93017 Bobigny, France;1. Department of Chemical Engineering, Qilu University of Technology (Shandong Academy of Sciences), Jinan 250353, China;2. The University of Nottingham Malaysia Campus, Semenyih, Selangor Darul Ehsan, Malaysia;1. Institut für Pharmazeutische und Medizinische Chemie der Universität Münster, Corrensstraße 48, D-48149 Münster, Germany;2. Helmholtz-Zentrum Dresden-Rossendorf, Institut für Radiopharmazeutische Krebsforschung Forschungsstelle Leipzig, Abteilung Neuroradiopharmaka, Permoserstraße 15, D-04318 Leipzig, Germany;1. Department of Fibrosis Discovery, Research and Development, Bristol–Myers Squibb, Princeton, NJ 08543, USA;2. Department of Discovery Chemistry, Research and Development, Bristol–Myers Squibb, Princeton, NJ 08543, USA;3. Department of Mechanistic Biochemistry, Research and Development, Bristol–Myers Squibb, Princeton, NJ 08543, USA;1. Linnaeus University, Kalmar, Sweden;2. Department of Neurosciences, Psychology, Drug Research and Child Health Section of Pharmaceutical and Nutraceutical Sciences, University of Florence, Italy;3. Department of Basic Sciences, California Northstate University College of Medicine, CA, USA |
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| Abstract: | The radiosynthesis of [N-methyl-11C]Org 34850 as a potential brain glucocorticoid receptor (GR)-binding radiotracer is described. The radiosynthesis was accomplished via N-methylation of the corresponding desmethyl precursor with [11C]methyl triflate in a remotely controlled synthesis module to give the desired compound in a radiochemical yield of 23±5% (decay-corrected, based upon [11C]CO2) at a specific activity of 47±12 GBq/μmol (n=15) at the end-of-synthesis (EOS). The radiochemical purity after semi-preparative HPLC purification exceeded 95%. The total synthesis time was 35–40 min after end-of-bombardment (EOB).The radiotracer is rapidly metabolized in rat plasma leading to the formation of two more hydrophilic metabolites as the major metabolites. Radiopharmacological evaluation involving biodistribution and small animal PET imaging in normal Wistar rats showed that the compound [N-methyl-11C]Org 34850 is not able to sufficiently penetrate the blood–brain barrier. Therefore, compound [N-methyl-11C]Org 34850 seems not to be a suitable PET radiotracer for imaging rat brain GRs. However, involvement of Pgp or species differences requires further clarification to establish whether the radiotracer [N-methyl-11C]Org 34850 may still represent a suitable candidate for imaging GRs in humans. |
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