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

• Published in: European journal of medicinal chemistry Vol. 46; no. 6; pp. 2295 - 2309
• Main Authors: Labas, Romain, Gilbert, Gwénaëlle, Nicole, Olivier, Dhilly, Martine, Abbas, Ahmed, Tirel, Olivier, Buisson, Alain, Henry, Joël, Barré, Louisa, Debruyne, Danièle, Sobrio, Franck
• Format: Journal Article
• Language: English
• Published: Kidlington Elsevier Masson SAS 01.06.2011; Elsevier
• Subjects: Animals; Antagonist; Biological and medical sciences; Contrast media. Radiopharmaceuticals; Fluorine Radioisotopes - chemistry; Fluorine Radioisotopes - metabolism; Fluorine Radioisotopes - pharmacokinetics; Fluorine-18; Male; Medical sciences; Molecular Structure; NMDA; NR2B; PET; Pharmacology. Drug treatments; Piperidines - chemistry; Piperidines - metabolism; Piperidines - pharmacokinetics; Positron-Emission Tomography; Radiopharmaceuticals - chemistry; Radiopharmaceuticals - metabolism; Radiopharmaceuticals - pharmacokinetics; Radiotracer; Rats; Rats, Sprague-Dawley; Receptors, N-Methyl-D-Aspartate - antagonists & inhibitors; Receptors, N-Methyl-D-Aspartate - metabolism; Stereoisomerism; NR2B; NMDA; Fluorine-18; Antagonist; Radiotracer; PET; Intravenous administration; Fluorine 18; Rat; Nitrogen heterocycle; Amides; Glutamate receptor; Organic carbamate; Tissue; Scintigraphic agent; Six membered ring; Bicyclic compound; Aromatic compound; Chemical synthesis; Oxygen nitrogen heterocycle; Fluorine Isotopes; Radiolabelling; Rodentia; Vertebrata; Mammalia; Animal; Distribution; Phenols; Affinity; Pharmacokinetics; NMDA receptor
• ISSN: 0223-5234; 1768-3254
• DOI: 10.1016/j.ejmech.2011.03.013

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. [Display omitted] ► Fluorinated antagonists for the NR2B subunit of the NMDA receptors were developed. ► Two PET radiotracers containing the 4-(4-[18F]fluorobenzyl)piperidine moiety were synthesized. ► The in vivo evaluation by PET imaging demonstrated radiodefluorination. ► Metabolism of the 4-(4-[18F]fluorobenzyl)piperidine was studied by LC-MS.