Open AccessHigh Affinity Radiopharmaceuticals Based Upon Lansoprazole for PET Imaging of Aggregated Tau in Alzheimer’s Disease and Progressive Supranuclear Palsy: Synthesis, Preclinical Evaluation, and Lead Selection
Author(s) -
Maria V. Fawaz,
Allen F. Brooks,
Melissa E. Rodnick,
Garrett Carpenter,
Xia Shao,
Timothy J. Desmond,
Phillip Sherman,
Carole Quesada,
Brian G. Hockley,
Michael R. Kilbourn,
Roger L. Albin,
Kirk A. Frey,
Peter J. H. Scott
Publication year - 2014
Publication title -
acs chemical neuroscience
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.158
H-Index - 69
ISSN - 1948-7193
DOI - 10.1021/cn500103u
Subject(s) - tauopathy , progressive supranuclear palsy , lansoprazole , chemistry , positron emission tomography , neuroscience , pharmacology , disease , medicine , psychology , neurodegeneration , pathology , omeprazole
Abnormally aggregated tau is the hallmark pathology of tauopathy neurodegenerative disorders and is a target for development of both diagnostic tools and therapeutic strategies across the tauopathy disease spectrum. Development of carbon-11- or fluorine-18-labeled radiotracers with appropriate affinity and specificity for tau would allow noninvasive quantification of tau burden using positron emission tomography (PET) imaging. We have synthesized [(18)F]lansoprazole, [(11)C]N-methyl lansoprazole, and [(18)F]N-methyl lansoprazole and identified them as high affinity radiotracers for tau with low to subnanomolar binding affinities. Herein, we report radiosyntheses and extensive preclinical evaluation with the aim of selecting a lead radiotracer for translation into human PET imaging trials. We demonstrate that [(18)F]N-methyl lansoprazole, on account of the favorable half-life of fluorine-18 and its rapid brain entry in nonhuman primates, favorable kinetics, low white matter binding, and selectivity for binding to tau over amyloid, is the lead compound for progression into clinical trials.