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

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• 作者：Romain Labas ; Gwé ; naë ; lle Gilbert ; Olivier Nicole ; Martine Dhilly ; Ahmed Abbas ; Olivier Tirel ; Alain Buisson ; Joë ; l Henry ; Louisa Barré ; Daniè ; le Debruyne ; Franck Sobrio
• 关键词：NR2B ; NMDA ; PET ; Radiotracer ; Fluorine-18 ; Antagonist
• 刊名：European Journal of Medicinal Chemistry
• 出版年：2011
• 出版时间：June 2011
• 年：2011
• 卷：46
• 期：6
• 页码：2295-2309
• 全文大小：1194 K

文摘

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.