title: Radiolabelling of 1,4-disubstituted 3-[18F]fluoropiperidines and its application to new radiotracers for NR2B NMDA receptor visualization.
abstract: In order to develop a novel and useful building block for the development of radiotracers for positron emission tomography (PET), we studied the radiolabelling of 1,4-disubstituted 3-[(18)F]fluoropiperidines. Indeed, 3-fluoropiperidine became a useful building block in medicinal chemistry for the pharmacomodulation of piperidine-containing compounds. The radiofluorination was studied on substituted piperidines with electron-donating and electron-withdrawing N-substituents. In the instance of electron-donating N-substituents such as benzyl or butyl, configuration retention and satisfactory fluoride-18 incorporation yields up to 80% were observed. In the case of electron-withdrawing N-substituents leading to carbamate or amide functions, the incorporation yields depend on the 4-susbtitutent (2 to 63%). The radiolabelling of this building block was applied to the automated radiosynthesis of NR2B NMDA receptor antagonists and effected by a commercially available radiochemistry module. The in vivo evaluation of three radiotracers demonstrated minimal brain uptakes incompatible with the imaging of NR2B NMDA receptors in the living brain. Nevertheless, moderate radiometabolism was observed and, in particular, no radiodefluorination was observed which demonstrates the stability of the 3-position of the fluorine-18 atom. In conclusion, the 1,4-disubstituted 3-[(18)F]fluoropiperidine moiety could be of value in the development of other radiotracers for PET even if the evaluation of the NR2B NMDA receptor antagonists failed to demonstrate satisfactory properties for PET imaging of this receptor.
authors.affiliation: CEA, I2BM, LDM-TEP, UMR 6302 ISTCT, GIP Cyceron, BP5229, F-14074 Caen, France.
authors.forename: Radouane
authors.initials: R
authors.lastname: Koudih
authors.forename: Gwénaëlle
authors.initials: G
authors.lastname: Gilbert
authors.forename: Martine
authors.initials: M
authors.lastname: Dhilly
authors.forename: Ahmed
authors.initials: A
authors.lastname: Abbas
authors.forename: Louisa
authors.initials: L
authors.lastname: Barré
authors.forename: Danièle
authors.initials: D
authors.lastname: Debruyne
authors.forename: Franck
authors.initials: F
authors.lastname: Sobrio
mesh_terms: D000818:Animals; D001921:Brain / Q000000981:diagnostic imaging* / Q000378:metabolism; D005462:Fluorine Radioisotopes / Q000737:chemistry* / Q000378:metabolism / Q000493:pharmacokinetics*; D010880:Piperidines / Q000737:chemistry* / Q000378:metabolism / Q000493:pharmacokinetics*; D049268:Positron-Emission Tomography / Q000379:methods; D051381:Rats; D016194:Receptors, N-Methyl-D-Aspartate / Q000032:analysis* / Q000037:antagonists & inhibitors
chemical_list: D005462:Fluorine Radioisotopes; C121001:NR2B NMDA receptor; D010880:Piperidines; D016194:Receptors, N-Methyl-D-Aspartate