Journal
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
Volume 46, Issue 6, Pages 2295-2309Publisher
ELSEVIER FRANCE-EDITIONS SCIENTIFIQUES MEDICALES ELSEVIER
DOI: 10.1016/j.ejmech.2011.03.013
Keywords
NR2B; NMDA; PET; Radiotracer; Fluorine-18; Antagonist
Categories
Funding
- Ministere de l'Enseignement Superieur et de la Recherche
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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 [F-18]1a, [F-18]2a or the pattern 4-(4-[(18)[F]-fluorobenzyl)piperidine ([(18)[F]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, [(18)[F]1a or [(18)[F]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-[(18)[F]-fluorobenzyl)piperidine, to develop PET radiotracers.(C) 2011 Elsevier Masson SAS. All rights reserved.
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