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
European Journal of Medicinal Chemistry. 2011-06-01; 46(6): 2295-2309
DOI: 10.1016/j.ejmech.2011.03.013
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1. Eur J Med Chem. 2011 Jun;46(6):2295-309. doi: 10.1016/j.ejmech.2011.03.013. Epub
2011 Mar 15.
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.
Labas R(1), Gilbert G, Nicole O, Dhilly M, Abbas A, Tirel O, Buisson A, Henry J,
Barré L, Debruyne D, Sobrio F.
Author information:
(1)CEA, I2BM, CI-NAPS, LDM-TEP, F-14074 Caen, France.
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.
Copyright © 2011 Elsevier Masson SAS. All rights reserved.
DOI: 10.1016/j.ejmech.2011.03.013
PMID: 21453995 [Indexed for MEDLINE]