title: Synthesis of a [2-pyridinyl-18F]-labelled fluoro derivative of (-)-cytisine as a candidate radioligand for brain nicotinic alpha4beta2 receptor imaging with PET.
abstract: In recent years, there has been considerable effort to design and synthesize radiotracers suitable for use in Positron Emission Tomography (PET) imaging of the alpha4beta2 neuronal nicotinic acetylcholine receptor (nAChR) subtype. A new fluoropyridinyl derivative of (-)-cytisine (1), namely (-)-9-(2-fluoropyridinyl)cytisine (3, K(i) values of 24 and 3462 nM for the alpha4beta2 and alpha7 nAChRs subtypes, respectively) has been synthesized in four chemical steps from (-)-cytisine and labelled with fluorine-18 (T(1/2): 119.8 min) using an efficient two-step radiochemical process [(a). nucleophilic heteroaromatic ortho-radiofluorination using the corresponding N-Boc-protected nitro-derivative, (b). TFA removal of the Boc protective group]. Typically, 20-45 mCi (0.74-1.67 GBq) of (-)-9-(2-[18F]fluoropyridinyl)cytisine ([18F]-3, 2-3 Ci/micromol or 74-111 GBq/micromol) were easily obtained in 70-75 min starting from a 100 mCi (3.7 GBq) aliquot of a cyclotron-produced [18F]fluoride production batch (20-45% non decay-corrected yield based on the starting [18F]fluoride). The in vivo pharmacological profile of (-)-9-(2-[18F]fluoropyridinyl)cytisine ([18F]-3) was evaluated in rats with biodistribution studies and brain radioactivity monitoring using intracerebral radiosensitive beta-microprobes. The observed in vivo distribution of the radiotracer in brain was rather uniform, and did not match with the known regional densities of nAChRs. It was also significantly different from that of the parent compound (-)-[3H]cytisine. Moreover, competition studies with (-)-nicotine (5 mg/kg, 5 min before the radiotracer injection) did not reduce brain uptake of the radiotracer. These experiments clearly indicate that (-)-9-(2-[18F]fluoropyridinyl)cytisine ([18F]-3) does not have the required properties for imaging nAChRs using PET.
authors.affiliation: Département de Recherche Médicale, CEA/DSV, 4 place du Général Leclerc, F-91401 Orsay, France.
authors.forename: Gaëlle
authors.initials: G
authors.lastname: Roger
authors.forename: Béatrice
authors.initials: B
authors.lastname: Lagnel
authors.forename: Jacques
authors.initials: J
authors.lastname: Rouden
authors.forename: Laurent
authors.initials: L
authors.lastname: Besret
authors.forename: Héric
authors.initials: H
authors.lastname: Valette
authors.forename: Stéphane
authors.initials: S
authors.lastname: Demphel
authors.forename: JaganMohan
authors.initials: J
authors.lastname: Gopisetti
authors.forename: Christine
authors.initials: C
authors.lastname: Coulon
authors.forename: Michele
authors.initials: M
authors.lastname: Ottaviani
authors.forename: Lori A
authors.initials: LA
authors.lastname: Wrenn
authors.forename: Sharon R
authors.initials: SR
authors.lastname: Letchworth
authors.forename: Georg A
authors.initials: GA
authors.lastname: Bohme
authors.forename: Jesus
authors.initials: J
authors.lastname: Benavides
authors.forename: Marie-Claire
authors.initials: MC
authors.lastname: Lasne
authors.forename: Michel
authors.initials: M
authors.lastname: Bottlaender
authors.forename: Frédéric
authors.initials: F
authors.lastname: Dollé
mesh_terms: D000818:Animals; D001392:Azocines / Q000138:chemical synthesis* / Q000737:chemistry; D001923:Brain Chemistry; D005260:Female; D005462:Fluorine Radioisotopes; D007553:Isotope Labeling; D007700:Kinetics; D008024:Ligands; D008297:Male; D015394:Molecular Structure; D011725:Pyridines / Q000138:chemical synthesis* / Q000737:chemistry; D051381:Rats; D017207:Rats, Sprague-Dawley; D011978:Receptors, Nicotinic / Q000032:analysis*; D014055:Tomography, Emission-Computed; D000093843:Quinolizidine Alkaloids
chemical_list: D001392:Azocines; D005462:Fluorine Radioisotopes; D008024:Ligands; D011725:Pyridines; D011978:Receptors, Nicotinic; C488632:9-(2-fluoropyridinyl)cytisine; D000093843:Quinolizidine Alkaloids; C403531:nicotinic receptor alpha4beta2