開發具診斷阿茲海默症潛力的新穎分子探針

Abstract

Tau protein is a microtubule-related proteins which was found in the neurons of the central nervous system. Its role is to stabilize the structure of the microtubules of the neurons. Abnormal degeneration of the tau protein often leads to dysfunction and causes several neurodegenerative disorders, such as Alzheimer’s disease. 7-(6-Fluoropyridin-3-yl)-5H-pyrido[4,3-b]indole ([18F]T807) is a potential tau protein molecular imaging probe for positron emission tomography (PET). In this study, the precursor 8 for radiosynthesis of [18F]T807 was synthesized using 3-bromopyridine as starting material. The overall chemical yield was increased from 8% to 17% through the optimization process. N-Alkylation of pyrido[4,3-b]indole 6 with appropriate alkyl halides yielded compounds 11a-c, 14 and 17. Treatment of 11a-c, 14 and 17 with boronic ether or acid under Suzuki reaction condition yielded nitro precursors 12a-c and the fluoro-substituted standards 13a-c and 15. In this series, the log D values of 13a-c and 15 were within the desired range for blood-brain barrier penetration (2.0 ≤ log D ≤ 3.5). All compounds possessed high blood brain barrier penetration potential (Pe ≥ 10 × 10-6 cm/s) in PAMPA assay. These compounds are now being investigated as novel Tau protein PET radiotracer in collaboration with Department of Nuclear medicine, National Taiwan University Hospital.