title: The development of potential new fluorine-18 labelled radiotracers for imaging the GABA(A) receptor.
abstract: Positron emission tomography (PET) using the tracer [(11)C]Flumazenil has shown changes in the distribution and expression of the GABA(A) receptor in a range of neurological conditions and injury states. We aim to develop a fluorine-18 labelled PET agent with comparable properties to [(11)C]Flumazenil. In this study we make a direct comparison between the currently known fluorine-18 labelled GABA(A) radiotracers and novel imidazobenzodiazepine ligands. A focussed library of novel compound was designed and synthesised where the fluorine containing moiety and the position of attachment is varied. The in vitro affinity of twenty-two compounds for the GABA(A) receptor was measured. Compounds containing a fluoroalkyl amide or a longer chain ester group were eliminated due to low potency. The fluorine-18 radiochemistry of one compound from each structural type was assessed to confirm that an automated radiosynthesis in good yield was feasible. Eleven of the novel compounds assessed appeared suitable for in vivo assessment as PET tracers.
authors.affiliation: GE Healthcare, Medical Diagnostics, The Grove Centre, White Lion Road, Amersham, Buckinghamshire HP7 9LL, UK. Alex.Jackson@GE.com
authors.forename: Alexander
authors.initials: A
authors.lastname: Jackson
authors.forename: Benedicte B
authors.initials: BB
authors.lastname: Guilbert
authors.forename: Stuart D
authors.initials: SD
authors.lastname: Plant
authors.forename: Julian
authors.initials: J
authors.lastname: Goggi
authors.forename: Mark R
authors.initials: MR
authors.lastname: Battle
authors.forename: John L
authors.initials: JL
authors.lastname: Woodcraft
authors.forename: Alessandra
authors.initials: A
authors.lastname: Gaeta
authors.forename: Clare L
authors.initials: CL
authors.lastname: Jones
authors.forename: Denis R
authors.initials: DR
authors.lastname: Bouvet
authors.forename: Paul A
authors.initials: PA
authors.lastname: Jones
authors.forename: Dennis M
authors.initials: DM
authors.lastname: O'Shea
authors.forename: Penny Hao
authors.initials: PH
authors.lastname: Zheng
authors.forename: Samantha L
authors.initials: SL
authors.lastname: Brown
authors.forename: Amanda L
authors.initials: AL
authors.lastname: Ewan
authors.forename: William
authors.initials: W
authors.lastname: Trigg
mesh_terms: D005442:Flumazenil / Q000737:chemistry; D005462:Fluorine Radioisotopes / Q000737:chemistry*; D006801:Humans; D049268:Positron-Emission Tomography; D019275:Radiopharmaceuticals / Q000737:chemistry*; D011963:Receptors, GABA-A / Q000737:chemistry* / Q000378:metabolism; D054852:Small Molecule Libraries
chemical_list: D005462:Fluorine Radioisotopes; D019275:Radiopharmaceuticals; D011963:Receptors, GABA-A; D054852:Small Molecule Libraries; D005442:Flumazenil