title: 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.
abstract: 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.
authors: CEA, I2BM, CI-NAPS, LDM-TEP, F-14074 Caen, France.
authors: Romain
authors: R
authors: Labas
authors: Gwénaëlle
authors: G
authors: Gilbert
authors: Olivier
authors: O
authors: Nicole
authors: Martine
authors: M
authors: Dhilly
authors: Ahmed
authors: A
authors: Abbas
authors: Olivier
authors: O
authors: Tirel
authors: Alain
authors: A
authors: Buisson
authors: Joël
authors: J
authors: Henry
authors: Louisa
authors: L
authors: Barré
authors: Danièle
authors: D
authors: Debruyne
authors: Franck
authors: F
authors: Sobrio
mesh_terms: D000818:Animals; D005462:Fluorine Radioisotopes / Q000737:chemistry / Q000378:metabolism* / Q000493:pharmacokinetics; D008297:Male; D015394:Molecular Structure; D010880:Piperidines / Q000737:chemistry / Q000378:metabolism* / Q000493:pharmacokinetics; D049268:Positron-Emission Tomography; D019275:Radiopharmaceuticals / Q000737:chemistry / Q000378:metabolism* / Q000493:pharmacokinetics; D051381:Rats; D017207:Rats, Sprague-Dawley; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors / Q000378:metabolism*; D013237:Stereoisomerism
chemical_list: D005462:Fluorine Radioisotopes; D010880:Piperidines; D019275:Radiopharmaceuticals; D016194:Receptors, N-Methyl-D-Aspartate