Journal of Medicinal Chemistry
Journal of Medicinal Chemistry
5 years ago

Identification of Three Novel Radiotracers for Imaging Aggregated Tau in Alzheimer’s Disease with Positron Emission Tomography

Identification of Three Novel Radiotracers for Imaging Aggregated Tau in Alzheimer’s Disease with Positron Emission Tomography
Andreas Koblet, Michael Honer, Thomas Hartung, Edilio Borroni, Isabella Erbsmehl, Dieter Muri, Sara Belli, Henner Knust, William B. Mathews, Daniel P. Holt, Luca C. Gobbi, Sandra Grall-Ulsemer, Marianne Rueher, Hiroto Kuwabara, Sandra Steiner, Martin R. Edelmann, Matthias Körner, Christian Czech, Dean F. Wong, Robert F. Dannals, Hayden T. Ravert, Heather Valentine
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-[11C]methoxyphenyl)imidazo[1,2-a]pyridin-7-amine 7 ([11C]RO6924963), N-[11C]methyl-2-(3-methylphenyl)imidazo[1,2-a]pyrimidin-7-amine 8 ([11C]RO6931643), and [18F]2-(6-fluoropyridin-3-yl)pyrrolo[2,3-b:4,5-c′]dipyridine 9 ([18F]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.

Publisher URL: http://dx.doi.org/10.1021/acs.jmedchem.7b00632

DOI: 10.1021/acs.jmedchem.7b00632

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