Synthesis, evaluation and metabolic studies of radiotracers containing a 4-(4-[18[F]-fluorobenzyl)piperidin-1-yl moiety for the PET imaging of NR2B NMDA receptors

被引：25
|
作者：
Labas, Romain [2 ]
Gilbert, Gwenaelle [2 ]
Nicole, Olivier [2 ]
Dhilly, Martine [2 ]
Abbas, Ahmed [2 ,4 ]
Tirel, Olivier [2 ]
Buisson, Alain [2 ]
Henry, Joel [3 ]
Barre, Louisa [2 ]
Debruyne, Daniele [2 ]
Sobrio, Franck [1 ,2 ]
机构：
[1] CEA, Ctr Cyceron, CI NAPS, LDM TEP,I2BM,UMR 6232, F-14074 Caen, France
[2] Univ Caen Basse Normandie, CNRS, Ctr Cyceron, CI NAPS,UMR 6232, F-14074 Caen, France
[3] Univ Caen Basse Normandie, IFREMER, UMR 100, F-14000 Caen, France
[4] Univ Caen Basse Normandie, Ctr Cyceron, INSERM, EPHE,Unite 923, F-14074 Caen, France
来源：
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY | 2011年 / 46卷 / 06期
关键词：
NR2B; NMDA; PET; Radiotracer; Fluorine-18; Antagonist; D-ASPARTATE RECEPTOR; IN-VITRO; DRUG DISCOVERY; ANTAGONISTS; PHARMACOLOGY; SUBUNIT; RADIOSYNTHESIS; DERIVATIVES; MECHANISMS; SYSTEM;
D O I：
10.1016/j.ejmech.2011.03.013
中图分类号：
R914 [药物化学];
学科分类号：
100701 ;
摘要：
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.
引用
收藏
页码：2295 / 2309
页数：15
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