title: Preclinical Evaluation of18F-JNJ64349311, a Novel PET Tracer for Tau Imaging.
abstract: In this study, we have synthesized and evaluated18F-JNJ64349311, a tracer with high affinity for aggregated tau (inhibition constant value, 8 nM) and high (≥500×) in vitro selectivity for tau over β-amyloid, in comparison with the benchmark compound18F-AV1451 (18F-T807) in mice, rats, and a rhesus monkey.Methods:In vitro binding characteristics were determined for Alzheimer's disease, progressive supranuclear palsy, and corticobasal degeneration patient brain tissue slices using autoradiography studies. Ex vivo biodistribution studies were performed in mice. Radiometabolites were quantified in the brain and plasma of mice and in the plasma of a rhesus monkey using high-performance liquid chromatography. Dynamic small-animal PET studies were performed in rats and a rhesus monkey to evaluate tracer pharmacokinetics in the brain.Results:Mouse biodistribution studies showed moderate initial brain uptake and rapid brain washout. Radiometabolite analyses after injection of18F-JNJ64349311 in mice showed the presence of a polar radiometabolite in plasma, but not in the brain. Semiquantitative autoradiography studies on postmortem tissue sections of human Alzheimer's disease brains showed highly displaceable binding to tau-rich regions. No specific binding was, however, found on human progressive supranuclear palsy and corticobasal degeneration brain slices. Small-animal PET scans of Wistar rats revealed moderate initial brain uptake (SUV, ∼1.5 at 1 min after injection) and rapid brain washout. Gradual bone uptake was, however, also observed. Blocking and displacement did not affect brain time-activity curves, suggesting no off-target specific binding of the tracer in the healthy rat brain. A small-animal PET scan of a rhesus monkey revealed moderate initial brain uptake (SUV, 1.9 at 1 min after injection) with a rapid washout. In the monkey, no bone uptake was detected during the 120-min scan.Conclusion:This biologic evaluation suggests that18F-JNJ64349311 is a promising tau PET tracer candidate, with a favorable pharmacokinetic profile, as compared with18F-AV1451.
authors.affiliation: Laboratory for Radiopharmacy, Department of Pharmaceutical and Pharmacological Sciences, KU Leuven, Leuven, Belgium.
authors.forename: Lieven
authors.initials: L
authors.lastname: Declercq
authors.affiliation: Neuroscience Discovery, Janssen Research and Development, a division of Janssen Pharmaceutica NV, Beerse, Belgium.
authors.forename: Frederik
authors.initials: F
authors.lastname: Rombouts
authors.affiliation: Nuclear Medicine & Molecular Imaging, Department of Imaging and Pathology, KU Leuven and University Hospital Leuven, Leuven, Belgium.
authors.forename: Michel
authors.initials: M
authors.lastname: Koole
authors.affiliation: Discovery Sciences, Janssen Research and Development, a division of Janssen Pharmaceutica NV, Beerse, Belgium.
authors.forename: Katleen
authors.initials: K
authors.lastname: Fierens
authors.affiliation: Neuroscience Discovery, Janssen Research and Development, a division of Janssen Pharmaceutica NV, Beerse, Belgium.
authors.forename: Jonas
authors.initials: J
authors.lastname: Mariën
authors.affiliation: Neuroscience Discovery, Janssen Research and Development, a division of Janssen Pharmaceutica NV, Beerse, Belgium.
authors.forename: Xavier
authors.initials: X
authors.lastname: Langlois
authors.affiliation: Discovery Sciences, Janssen Research and Development, a division of Janssen-Cilag NV, Toledo, Spain.
authors.forename: José Ignacio
authors.initials: JI
authors.lastname: Andrés
authors.affiliation: Janssen Early Development, a division of Janssen Pharmaceutica NV, Beerse, Belgium.
authors.forename: Mark
authors.initials: M
authors.lastname: Schmidt
authors.affiliation: Neuroscience Discovery, Janssen Research and Development, a division of Janssen Pharmaceutica NV, Beerse, Belgium.
authors.forename: Gregor
authors.initials: G
authors.lastname: Macdonald
authors.affiliation: Neuroscience Discovery, Janssen Research and Development, a division of Janssen Pharmaceutica NV, Beerse, Belgium dmoechar@its.jnj.com.
authors.forename: Diederik
authors.initials: D
authors.lastname: Moechars
authors.affiliation: Laboratory for Neuro- and Psychophysiology, Department of Neurosciences, KU Leuven, Leuven, Belgium.
authors.forename: Wim
authors.initials: W
authors.lastname: Vanduffel
authors.affiliation: Translational Cell & Tissue Research, Department of Imaging & Pathology, KU Leuven, Leuven, Belgium; and.
authors.forename: Thomas
authors.initials: T
authors.lastname: Tousseyn
authors.affiliation: Laboratory for Cognitive Neurology, Department of Neurosciences, KU Leuven, Leuven, Belgium.
authors.forename: Rik
authors.initials: R
authors.lastname: Vandenberghe
authors.affiliation: Nuclear Medicine & Molecular Imaging, Department of Imaging and Pathology, KU Leuven and University Hospital Leuven, Leuven, Belgium.
authors.forename: Koen
authors.initials: K
authors.lastname: Van Laere
authors.affiliation: Laboratory for Radiopharmacy, Department of Pharmaceutical and Pharmacological Sciences, KU Leuven, Leuven, Belgium.
authors.forename: Alfons
authors.initials: A
authors.lastname: Verbruggen
authors.affiliation: Laboratory for Radiopharmacy, Department of Pharmaceutical and Pharmacological Sciences, KU Leuven, Leuven, Belgium.
authors.forename: Guy
authors.initials: G
authors.lastname: Bormans
mesh_terms: D000818:Animals; D001921:Brain / Q000000981:diagnostic imaging* / Q000378:metabolism*; D005260:Female; D005462:Fluorine Radioisotopes / Q000493:pharmacokinetics*; D008253:Macaca mulatta; D008297:Male; D008657:Metabolic Clearance Rate; D051379:Mice; D057054:Molecular Imaging / Q000379:methods*; D009928:Organ Specificity / Q000502:physiology; D049268:Positron-Emission Tomography / Q000379:methods*; D019275:Radiopharmaceuticals / Q000493:pharmacokinetics; D051381:Rats; D017208:Rats, Wistar; D015203:Reproducibility of Results; D012680:Sensitivity and Specificity; D013045:Species Specificity; D014018:Tissue Distribution; D016875:tau Proteins / Q000378:metabolism*
chemical_list: D005462:Fluorine Radioisotopes; D019275:Radiopharmaceuticals; D016875:tau Proteins
keywords: 18F-AV1451; 18F-JNJ64349311; Alzheimer’s disease; PET; PHFs; biomarker; brain; corticobasal degeneration; diagnostic; progressive supranuclear palsy; tau