TY - JOUR
T1 - Identification of Three Novel Radiotracers for Imaging Aggregated Tau in Alzheimer's Disease with Positron Emission Tomography
AU - Gobbi, Luca C.
AU - Knust, Henner
AU - Körner, Matthias
AU - Honer, Michael
AU - Czech, Christian
AU - Belli, Sara
AU - Muri, Dieter
AU - Edelmann, Martin R.
AU - Hartung, Thomas
AU - Erbsmehl, Isabella
AU - Grall-Ulsemer, Sandra
AU - Koblet, Andreas
AU - Rueher, Marianne
AU - Steiner, Sandra
AU - Ravert, Hayden T.
AU - Mathews, William B.
AU - Holt, Daniel P.
AU - Kuwabara, Hiroto
AU - Valentine, Heather
AU - Dannals, Robert F.
AU - Wong, Dean F.
AU - Borroni, Edilio
N1 - Funding Information:
We sincerely thank Roland Humm and the scientists at Chembiotek for the synthesis of compounds. We acknowledge the excellent technical assistance in generating the biological data of Patricia Glaentzlin, Ceĺ ine Sutter, Svenja Moes, and Jennifer Beck. We thank Christian Bartelmus for collecting HR-MS spectroscopical data and Bjoern Wagner for testing compounds in the LIMBA assay. Additionally we thank the staff of the Johns Hopkins PET Radiotracer Center for their radiochemistry expertise. This study was funded by F. Hoffmann-La Roche Ltd. contract to The Johns Hopkins University (JHU). JHU faculty receive salary support through a number of sponsored research sources including DFW NIH Career Award K24 DA000412, and none receive direct funding from Roche except via sponsored JHU contracts.
Publisher Copyright:
© 2017 American Chemical Society.
PY - 2017/9/14
Y1 - 2017/9/14
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85029477959&partnerID=8YFLogxK
U2 - 10.1021/acs.jmedchem.7b00632
DO - 10.1021/acs.jmedchem.7b00632
M3 - Article
C2 - 28654263
AN - SCOPUS:85029477959
SN - 0022-2623
VL - 60
SP - 7350
EP - 7370
JO - Journal of Medicinal Chemistry
JF - Journal of Medicinal Chemistry
IS - 17
ER -