[¹⁸F]Lansoprazole and [¹¹C]N-methyl lansoprazole: High affinity radiotracers for imaging tau pathology

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 FX_FN 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 1.5 Ci of [¹⁸F]fluoride, n= 5), respectively. Doses passed all other quality control, confirming their suitability for future clinical PET imaging. Autoradiography and immunocuctochemistry confirmed co-localization of both radiotracers with tau (as globose tangles) in brain samples from PSP patients. MicroPET imaging showed pharmacokinetics compatible with brain imaging applications.

Conclusions [¹¹C]N-Methyl lansoprazole and [¹⁸F]lansoprazole are radiotracers with high affinity for tau that have potential for in vivo imaging of tau pathology.

Research Support Financial support of this work by the University of Michigan Office for the Vice President of Research (OVPR#6354) and NIBIB (T32EB005172-02) are gratefully acknowledged.