Abstract
In this study we have synthesized and evaluated 18F-JNJ64349311, a tracer with high affinity for aggregated tau (Ki value of 8 nM) and high (≥ 500x) 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: Using autoradiography studies in vitro binding characteristics were determined on Alzheimer’s disease (AD), Progressive supranuclear palsy (PSP) and Corticobasal degeneration (CBD) patient brain tissue slices. Ex vivo biodistribution studies were performed in mice. Radiometabolites were quantified in brain and plasma of mice and in plasma of a rhesus monkey using high performance liquid chromatography. Dynamic micro positron-emission tomography (µPET) studies were performed in rats and in a rhesus monkey to evaluate tracer pharmacokinetics in brain. Results: Mouse biodistribution studies showed moderate initial brain uptake and rapid brain wash-out. Radiometabolite analyses after injection of 18F-JNJ64349311 in mice showed the presence of a polar radiometabolite in plasma, but not in brain. Semi-quantitative autoradiography studies on post-mortem tissue sections of human AD brains showed highly displaceable binding to tau-rich regions. No specific binding was, however, found on human PSP and CBD brain slices. µPET-scans on Wistar rats revealed moderate initial brain uptake (standardized uptake value, SUV of ~ 1.5 at 1 min p.i.) and rapid brain wash-out. 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 healthy rat brain. A µPET scan on a rhesus monkey revealed moderate initial brain uptake (SUV of 1.9 at 1 min p.i.) with a rapid wash-out. In monkey, no bone uptake was detected during the 120-min scan. Conclusion: This biological evaluation suggests that 18F-JNJ64349311 is a promising tau PET tracer candidate, with a favourable pharmacokinetic profile as compared to 18F-AV1451.
- Autoradiography
- Animal Imaging
- PET
- Radiopharmaceuticals
- 18F-AV1451
- 18F-JNJ64349311
- Alzheimers disease
- PET
- tau
- Copyright © 2017 by the Society of Nuclear Medicine and Molecular Imaging, Inc.