[18F]Lansoprazole and [11C]N-methyl lansoprazole: High affinity radiotracers for imaging tau pathology
Abstract
322 Objectives The high affinities of lansoprazole (Ki = 2.5 nM) and N-methyl lansoprazole (Kd = 700 pM) for heparin induced tau make radiolabeled versions attractive candidates for PET imaging of tau pathology in Alzheimer’s disease and related tauopathies. We recently reported initial pre-clinical evaluation of [11C]N-methyl lansoprazole (Shao et al., ACS Med Chem Lett, 2012). However, reflecting issues associated with the short half-life of carbon-11, it was important to prepare [18F]lansoprazole. Herein we report the first synthesis of [18F]lansoprazole (by radiolabeling the -CF3 group) and progress in the pre-clinical evaluation of both radiotracers. Methods [18F]Lansoprazole was prepared from the corresponding gem-difluoroalkene precursor on a GE TRACERlab FXFN module by adaptation of chemistry reported by Riss et al (Org Biomol Chem, 2012). [11C]N-Methyl lansoprazole was prepared as previously reported (ACS Med Chem Lett, 2012). Standard pre-clinical evaluation was conducted as follows: - Rodent and primate MicroPET imaging studies - Rodent metabolism and biodistribution studies - In vitro autoradiography / immunocytochemistry with human brain samples (tau positive, amyloid positive, and age matched healthy controls) using mouse anti-human monoclonal tau antibody - Determination of binding affinities for both tau and amyloid. Results Non-decay-corrected yields of [11C]N-methyl lansoprazole and [18F]lansoprazole were 7% (from 900 mCi of [11C]MeI, n= 15) and 7% (from…
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