Author:

Keywords:

Science & Technology, Life Sciences & Biomedicine, Radiology, Nuclear Medicine & Medical Imaging, Alzheimer's disease, progressive supranuclear palsy, corticobasal degeneration, tau, PET, biomarker, PHFs, brain, diagnostic, F-18-JNJ64349311, F-18-AV1451, F-18-AV-1451, PROFILES, 18F-AV1451, 18F-JNJ64349311, Alzheimer’s disease, Animals, Brain, Female, Fluorine Radioisotopes, Macaca mulatta, Male, Metabolic Clearance Rate, Mice, Molecular Imaging, Organ Specificity, Positron-Emission Tomography, Radiopharmaceuticals, Rats, Rats, Wistar, Reproducibility of Results, Sensitivity and Specificity, Species Specificity, Tissue Distribution, tau Proteins, KUL-CoE-IMIR, 1103 Clinical Sciences, Nuclear Medicine & Medical Imaging, 3202 Clinical sciences

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.