Synthesis, evaluation and metabolic studies of radiotracers containing a 4-(4-[18F]-fluorobenzyl)piperidin-1-yl moiety for the PET imaging of NR2B NMDA receptors
| Autor: | Alain Buisson, Romain Labas, Franck Sobrio, Ahmed Abbas, Danièle Debruyne, Gwénaëlle Gilbert, Olivier Tirel, Martine Dhilly, Joël Henry, Louisa Barré, Olivier Nicole |
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| Rok vydání: | 2011 |
| Předmět: |
Male
Biodistribution Fluorine Radioisotopes Stereochemistry Chemical synthesis Receptors N-Methyl-D-Aspartate Hydroxylation Rats Sprague-Dawley chemistry.chemical_compound Piperidines In vivo Drug Discovery Moiety Animals Receptor Pharmacology Bicyclic molecule Molecular Structure Organic Chemistry Stereoisomerism General Medicine Rats chemistry Positron-Emission Tomography Piperidine Radiopharmaceuticals |
| Zdroj: | European journal of medicinal chemistry. 46(6) |
| ISSN: | 1768-3254 |
| Popis: | In this study, novel specific PET radioligands containing the 4-(4-fluorobenzyl)piperidine moiety and selectively antagonistic for the NR2B subunit containing NMDA receptors were developed. Two antagonists, RGH-896 (1a) and 4-(4-fluorobenzyl)piperidinyl-1-methyl-2-benzimidazol-5-ol (2a), belonging to two different structural families, were radiolabeled by an aromatic nucleophilic radiofluorination followed by a reduction of the para-position carbonyl function. Radiotracers [18F]1a, [18F]2a or the pattern 4-(4-[18F]-fluorobenzyl)piperidine ([18F]6) demonstrated an identical in vivo behavior with high accumulation of radioactivity in bone and cartilage which would suggest a radiodefluorination of the radiotracers. The identification of metabolites from 6 by LC-MS-MS confirmed the significant degree of defluorination as a result of the in vivo hydroxylation in the benzyl ring. In conclusion, [18F]1a or [18F]2a are not suitable for imaging the NR2B NMDA receptors due to their poor brain penetration. We also argue for a cautious use of the radiolabeled pattern, 4-(4-[18F]-fluorobenzyl)piperidine, to develop PET radiotracers. |
| Databáze: | OpenAIRE |
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