Lieven Declercq1, Frederik Rombouts2, Michel Koole3, Katleen Fierens4, Jonas Mariën2, Xavier Langlois2, José Ignacio Andrés5, Mark Schmidt6, Gregor Macdonald2, Diederik Moechars7, Wim Vanduffel8, Thomas Tousseyn9, Rik Vandenberghe10, Koen Van Laere3, Alfons Verbruggen1, Guy Bormans1. 1. Laboratory for Radiopharmacy, Department of Pharmaceutical and Pharmacological Sciences, KU Leuven, Leuven, Belgium. 2. Neuroscience Discovery, Janssen Research and Development, a division of Janssen Pharmaceutica NV, Beerse, Belgium. 3. Nuclear Medicine & Molecular Imaging, Department of Imaging and Pathology, KU Leuven and University Hospital Leuven, Leuven, Belgium. 4. Discovery Sciences, Janssen Research and Development, a division of Janssen Pharmaceutica NV, Beerse, Belgium. 5. Discovery Sciences, Janssen Research and Development, a division of Janssen-Cilag NV, Toledo, Spain. 6. Janssen Early Development, a division of Janssen Pharmaceutica NV, Beerse, Belgium. 7. Neuroscience Discovery, Janssen Research and Development, a division of Janssen Pharmaceutica NV, Beerse, Belgium dmoechar@its.jnj.com. 8. Laboratory for Neuro- and Psychophysiology, Department of Neurosciences, KU Leuven, Leuven, Belgium. 9. Translational Cell & Tissue Research, Department of Imaging & Pathology, KU Leuven, Leuven, Belgium; and. 10. Laboratory for Cognitive Neurology, Department of Neurosciences, KU Leuven, Leuven, Belgium.
Abstract
In this study, we have synthesized and evaluated 18F-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 compound 18F-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 of 18F-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 that 18F-JNJ64349311 is a promising tau PET tracer candidate, with a favorable pharmacokinetic profile, as compared with 18F-AV1451.
In this study, we have synthesized and evaluated 18F-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 compound 18F-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 of 18F-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 humanAlzheimer'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 that 18F-JNJ64349311 is a promising tau PET tracer candidate, with a favorable pharmacokinetic profile, as compared with 18F-AV1451.
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