18F-labeled benzimidazopyridine derivatives for PET imaging of tau pathology in Alzheimer's disease. Issue 16 (15th August 2019)

• Record Type: Journal Article
• Authors: Kaide, Sho; Watanabe, Hiroyuki; Shimizu, Yoichi; Tatsumi, Haruka; Iikuni, Shimpei; Nakamoto, Yuji; Togashi, Kaori; Ihara, Masafumi; Saji, Hideo; Ono, Masahiro
• Is Part Of: Bioorganic & medicinal chemistry. Volume 27:Issue 16(2019)
• Page Start: 3587
• Page End: 3594
• Publication Date: 2019-08-15
• Subjects: AD Alzheimer's disease -- SP senile plaque -- NFT neurofibrillary tangle -- Aβ amyloid β -- PET positron emission tomography -- SPECT single photon emission computed tomography -- BIP benzimidazopyridine -- HPLC high-performance liquid chromatography -- ARG autoradiography -- cpm counts per minute -- BBB blood-brain barrier -- % ID/g percentage injected dose per gram -- TFA trifluoroacetic acid -- DMF N, N-dimethylformamide -- THF tetrahydrofuran -- DMAP N, N-dimethyl-4-aminopyridine -- DMSO dimethyl sulfoxide -- PBS phosphate buffered saline -- TBS tert-butyldimethylsilyl -- Boc tert-butoxycarbonyl; Alzheimer's disease -- Tau -- Benzimidazopyridine -- Positron emission tomography -- 18F-labeling -- Imaging; Bioorganic chemistry -- Periodicals; Pharmaceutical chemistry -- Periodicals; Biochemistry -- Periodicals; Chemistry, Clinical -- Periodicals; Chemistry, Organic -- Periodicals; Chimie bio-organique -- Périodiques; Chimie pharmaceutique -- Périodiques; 615.19
• DOI: 10.1016/j.bmc.2019.06.039
• Languages: English
• ISSNs: 0968-0896

Abstract

Graphical abstract: Abstract: Hyperphosphorylated tau proteins are one of the neuropathological hallmarks in the Alzheimer's disease (AD) brain. The in vivo imaging of tau aggregates with nuclear medical imaging probes is helpful for the further comprehension of and medical intervention in the AD pathology. For tau-selective PET imaging, we newly designed and synthesized 18 F-labeled benzimidazopyridine (BIP) derivatives with fluoroalkylamino groups, [ 18 F]IBIPF1 and [ 18 F]IBIPF2, and evaluated their utilities as tau imaging probes. They both bound selectively to tau against amyloid β (Aβ) aggregates in AD brain sections in vitro, and showed good pharmacokinetics in mouse brains in vivo . Notably, [ 18 F]IBIPF1 exhibited high tau-selectivity (Tau/Aβ ratio = 34.8), high brain uptake (6.22% ID/g at 2 min postinjection), and subsequent washout (2.77% ID/g at 30 min postinjection). In vivo analysis of radiometabolites indicated that [ 18 F]IBIPF1 was stable against metabolism in the mouse brain. These encouraging preclinical results suggest that further structural optimization based on the BIP scaffold may lead to the development of more useful tau imaging probes.