title: Characterization and first human investigation of FIBT, a novel fluorinated Aβ plaque neuroimaging PET radioligand.
abstract: Imidazo[2,1-b]benzothiazoles (IBTs) are a promising novel class of amyloid positron emission tomography (PET) radiopharmaceuticals for diagnosis of neurodegenerative disorders like Alzheimer's disease (AD). Their good in vivo imaging properties have previously been shown in preclinical studies. Among IBTs, fluorinated [(18)F]FIBT was selected for further characterization and advancement toward use in humans. [(18)F]FIBT characteristics were analyzed in relation to Pittsburgh compound B (PiB) as reference ligand. [(18)F]FIBT and [(3)H]PiB were coinjected to an APP/PS1 mouse for ex vivo dual-label autoradiographic correlation. Acute dose toxicity of FIBT was examined in two groups of healthy mice. Preexisting in vivo stability and biodistribution studies in mice were complemented with analogous studies in rats. [(18)F]FIBT was titrated against postmortem human AD brain homogenate in a saturation binding assay previously performed with [(3)H]PiB. Binding of [(18)F]FIBT to human AD brain was further analyzed by in vitro incubation of human AD brain sections in comparison to [(11)C]PiB in relation to standard immunohistochemistry. Finally, [(18)F]FIBT was administered to two human subjects for a dynamic 90 min PET/MR brain investigation. Ex vivo autoradiography confirmed good uptake of [(18)F]FIBT to mouse brain and its excellent correlation to [(3)H]PiB binding. No toxicity of FIBT could be found in mice at a concentration of 33.3 nmol/kg. As in mice, [(18)F]FIBT was showing high in vivo stability in rats and comparable regional brain biodistribution dynamics to [(3)H]PiB. Radioligand saturation binding confirmed at least one high-affinity binding component of [(18)F]FIBT around 1 nM. Good binding of FIBT relative to PiB was further confirmed in binding assays and autoradiographies using post-mortem AD brain. First use of [(18)F]FIBT in humans successfully yielded clinical [(18)F]FIBT PET/MR images with very good contrast. In summary, [(18)F]FIBT has been characterized to be a new lead compound with improved binding characteristics and pharmacokinetics on its own as well as in comparison to PiB. A pilot human PET investigation provided high-quality images with a plausible tracer distribution pattern. Detailed clinical investigations are needed to confirm these first results and to explore the specific qualities of [(18)F]FIBT PET for dementia imaging in relation to established ligands.
authors.affiliation: †Department of Pharmaceutical Radiochemistry, ‡Department of Nuclear Medicine, and §Department of Psychiatry and Psychotherapy, Technische Universität München, Munich, Germany.|∥Centre for Neuropathology and Prion Research and ⊥Department of Psychiatry and Psychotherapy, Ludwig-Maximilians Universität München, Munich, Germany.
authors.forename: Behrooz Hooshyar
authors.initials: BH
authors.lastname: Yousefi
authors.affiliation: †Department of Pharmaceutical Radiochemistry, ‡Department of Nuclear Medicine, and §Department of Psychiatry and Psychotherapy, Technische Universität München, Munich, Germany.|∥Centre for Neuropathology and Prion Research and ⊥Department of Psychiatry and Psychotherapy, Ludwig-Maximilians Universität München, Munich, Germany.
authors.forename: André
authors.initials: A
authors.lastname: Manook
authors.affiliation: †Department of Pharmaceutical Radiochemistry, ‡Department of Nuclear Medicine, and §Department of Psychiatry and Psychotherapy, Technische Universität München, Munich, Germany.|∥Centre for Neuropathology and Prion Research and ⊥Department of Psychiatry and Psychotherapy, Ludwig-Maximilians Universität München, Munich, Germany.
authors.forename: Timo
authors.initials: T
authors.lastname: Grimmer
authors.affiliation: †Department of Pharmaceutical Radiochemistry, ‡Department of Nuclear Medicine, and §Department of Psychiatry and Psychotherapy, Technische Universität München, Munich, Germany.|∥Centre for Neuropathology and Prion Research and ⊥Department of Psychiatry and Psychotherapy, Ludwig-Maximilians Universität München, Munich, Germany.
authors.forename: Thomas
authors.initials: T
authors.lastname: Arzberger
authors.affiliation: †Department of Pharmaceutical Radiochemistry, ‡Department of Nuclear Medicine, and §Department of Psychiatry and Psychotherapy, Technische Universität München, Munich, Germany.|∥Centre for Neuropathology and Prion Research and ⊥Department of Psychiatry and Psychotherapy, Ludwig-Maximilians Universität München, Munich, Germany.
authors.forename: Boris
authors.initials: B
authors.lastname: von Reutern
authors.affiliation: †Department of Pharmaceutical Radiochemistry, ‡Department of Nuclear Medicine, and §Department of Psychiatry and Psychotherapy, Technische Universität München, Munich, Germany.|∥Centre for Neuropathology and Prion Research and ⊥Department of Psychiatry and Psychotherapy, Ludwig-Maximilians Universität München, Munich, Germany.
authors.forename: Gjermund
authors.initials: G
authors.lastname: Henriksen
authors.affiliation: †Department of Pharmaceutical Radiochemistry, ‡Department of Nuclear Medicine, and §Department of Psychiatry and Psychotherapy, Technische Universität München, Munich, Germany.|∥Centre for Neuropathology and Prion Research and ⊥Department of Psychiatry and Psychotherapy, Ludwig-Maximilians Universität München, Munich, Germany.
authors.forename: Alexander
authors.initials: A
authors.lastname: Drzezga
authors.affiliation: †Department of Pharmaceutical Radiochemistry, ‡Department of Nuclear Medicine, and §Department of Psychiatry and Psychotherapy, Technische Universität München, Munich, Germany.|∥Centre for Neuropathology and Prion Research and ⊥Department of Psychiatry and Psychotherapy, Ludwig-Maximilians Universität München, Munich, Germany.
authors.forename: Stefan
authors.initials: S
authors.lastname: Förster
authors.affiliation: †Department of Pharmaceutical Radiochemistry, ‡Department of Nuclear Medicine, and §Department of Psychiatry and Psychotherapy, Technische Universität München, Munich, Germany.|∥Centre for Neuropathology and Prion Research and ⊥Department of Psychiatry and Psychotherapy, Ludwig-Maximilians Universität München, Munich, Germany.
authors.forename: Markus
authors.initials: M
authors.lastname: Schwaiger
authors.affiliation: †Department of Pharmaceutical Radiochemistry, ‡Department of Nuclear Medicine, and §Department of Psychiatry and Psychotherapy, Technische Universität München, Munich, Germany.|∥Centre for Neuropathology and Prion Research and ⊥Department of Psychiatry and Psychotherapy, Ludwig-Maximilians Universität München, Munich, Germany.
authors.forename: Hans-Jürgen
authors.initials: HJ
authors.lastname: Wester
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000814:Aniline Compounds / Q000493:pharmacokinetics; D000818:Animals; D001345:Autoradiography; D052160:Benzothiazoles / Q000493:pharmacokinetics*; D001921:Brain / Q000000981:diagnostic imaging* / Q000187:drug effects; D002247:Carbon Isotopes / Q000493:pharmacokinetics; D019788:Fluorodeoxyglucose F18 / Q000493:pharmacokinetics; D006801:Humans; D007093:Imidazoles / Q000493:pharmacokinetics*; D008297:Male; D008875:Middle Aged; D058225:Plaque, Amyloid / Q000378:metabolism*; D049268:Positron-Emission Tomography; D051381:Rats; D013844:Thiazoles / Q000493:pharmacokinetics; D014018:Tissue Distribution
chemical_list: C475519:2-(4'-(methylamino)phenyl)-6-hydroxybenzothiazole; D000814:Aniline Compounds; D052160:Benzothiazoles; D002247:Carbon Isotopes; D007093:Imidazoles; D013844:Thiazoles; C559797:imidazo(2,1-b)(1,3)benzothiazole; D019788:Fluorodeoxyglucose F18
keywords: 18F-labeled radiopharmaceutical; Alzheimer’s disease; FIBT; PET; PiB; amyloid-beta; autoradiography; binding assay