Preclinical Evaluation of 18F-JNJ64349311, a Novel PET Tracer for Tau Imaging.
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.
['Declercq|Lieven|L|', 'Rombouts|Frederik|F|', 'Koole|Michel|M|', 'Fierens|Katleen|K|', 'Mariën|Jonas|J|', 'Langlois|Xavier|X|', 'Andrés|José Ignacio|JI|', 'Schmidt|Mark|M|', 'Macdonald|Gregor|G|', 'Moechars|Diederik|D|', 'Vanduffel|Wim|W|', 'Tousseyn|Thomas|T|', 'Vandenberghe|Rik|R|', 'Van Laere|Koen|K|', 'Verbruggen|Alfons|A|', 'Bormans|Guy|G|']
D000818:Animals D001921:Brain D005260:Female D005462:Fluorine Radioisotopes D008253:Macaca mulatta D008297:Male D008657:Metabolic Clearance Rate D051379:Mice D057054:Molecular Imaging D009928:Organ Specificity D049268:Positron-Emission Tomography D019275:Radiopharmaceuticals D051381:Rats D017208:Rats, Wistar D015203:Reproducibility of Results D012680:Sensitivity and Specificity D013045:Species Specificity D014018:Tissue Distribution D016875:tau Proteins
18F-JNJ64349311 PET tau 18F-AV1451 progressive supranuclear palsy corticobasal degeneration brain Alzheimer’s disease PHFs biomarker diagnostic