Identification of three novel radiotracers for imaging aggregated tau in Alzheimer's disease with positron emission tomography
Abstract
Aggregates of tau and beta amyloid (Aβ) plaques constitute the histopathological hallmarks of Alzheimer’s disease and are prominent targets for novel therapeutics as well as for biomarkers for diagnostic in vivo imaging. In recent years much attention has been devoted to the discovery and development of new PET tracers to image tau aggregates in the living human brain. Access to a selective PET tracer to image and quantify tau aggregates represents a unique tool to support the development of any novel therapeutic agent targeting pathological forms of tau. The objective of the study described herein was to identify such a novel radiotracer. As a result of this work, we discovered three novel PET tracers (2-(4-[ 11 C]methoxyphenyl)imidazo[1,2- a ]pyridin-7-amine 7 ([ 11 C]RO6924963), N -[ 11 C]methyl-2-(3-methylphenyl)imidazo[1,2- a ]pyrimidin-7-amine 8 ([ 11 C]RO6931643), and [ 18 F]2-(6-fluoropyridin-3-yl)pyrrolo[2,3- b:4,5- c ′]dipyridine 9 ([ 18 F]RO6958948)) with high affinity for tau neurofibrillary tangles, excellent selectivity against Aβ plaques, and appropriate pharmacokinetic and metabolic properties in mice and non-human primates.
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QC-01-175 and T807 displayed significantly lower affinity for recombinant immobilized tau forms than the reported KD of T807 for native, aggregated tau filaments from AD brain sections (KD 15 nM).
“As expected, in vitro QC-01–175 and T807 displayed a significantly lower affinity for all recombinant immobilized tau forms than the reported KD of T807 for native, aggregated tau filaments from AD brain sections (KD15 nM)”
From Targeted degradation of aberrant tau in frontotemporal dementia patient-derived neuronal cell models (2019) · cites this paper as Gobbi et al., 2017
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Targeted degradation of aberrant tau in frontotemporal dementia patient-derived neuronal cell models
Silva, M. C., Ferguson, F. M., Cai, Q., Donovan, K. A., Nandi, G., Patnaik, D., Zhang, T., Huang, H.-T., Lucente, D. E., Dickerson, B. C., et al. (2019) · eLife · doi:10.7554/elife.45457 · Cited by 283 · see citing works
- Authors
- Gobbi, L. C., Knust, H., Körner, M., Honer, M., Czech, C., Belli, S., Muri, D., Edelmann, M. R., Hartung, T., Erbsmehl, I., Grall-Ulsemer, S., Koblet, A., Rueher, M., Steiner, S., Ravert, H. T., Mathews, W. B., Holt, D. P., Kuwabara, H., Valentine, H., Dannals, R. F., Wong, D. F., & Borroni, E.
- Affiliations
- Pharma Research and Early Development, Roche Innovation Center Basel, F. Hoffmann-La Roche Ltd., CH-4070 Basel, Switzerland
- F. Hoffmann-La Roche AG (CH)
- ORCID
- Venue
- Journal of Medicinal Chemistry
- Publisher
- American Chemical Society (ACS)
- Published
- 2017-07-12
- Volume
- 60
- Issue
- 17
- Pages
- 7350-7370
- ISSN
- 0022-2623 (ISSN-L)
- 1520-4804
- OpenAlex
- W2725950123
- Cited by
- 89
- References
- 47
- Citations by year
- 2026: 4 · 2025: 7 · 2024: 5 · 2023: 12 · 2022: 12 · 2021: 12 · 2020: 11 · 2019: 11 · 2018: 11 · 2017: 4
- FWCI
- 7.49
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Journal of Medicinal Chemistry (publishedVersion)
- PubMed (publishedVersion)
- Funders
- F. Hoffmann-La Roche
- Johns Hopkins University
- Ministry of Earth Sciences
- Ministry of Education, India
- National Institutes of Health
- Topics
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Health Sciences › Medicine › Radiology, Nuclear Medicine and Imaging › Radiopharmaceutical Chemistry and Applications
- Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
- Keywords
- Alzheimer's disease, PET radiotracer, neurofibrillary tangles, tau PET tracers, amyloid plaques, pharmacokinetics, non-human primates
- MeSH terms
- Alzheimer Disease, Animals, Carbon Radioisotopes, Fluorine Radioisotopes, Humans, Male, Papio, Pyrimidines, tau Proteins, Positron-Emission Tomography, Mice, Protein Aggregation, Pathological
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