A Novel ¹⁸F-Labeled Imidazo[2,1-b]benzothiazole (IBT) for High-Contrast PET Imaging of β-Amyloid Plaques

Abstract

18F-labeled imidazo[2,1-b]benzothiazole ([18F]8) was synthesized and evaluated as a tracer for cerebral β-amyloid deposits (Aβ) by means of positron emission tomography (PET). [18F]8 exhibits a high affinity to Aβ and suitable brain uptake kinetics combined with a high metabolic stability in the brain. In a double transgenic APP/PS1 mouse model of Alzheimer's disease, we demonstrated a specific uptake of [18F]8 in Aβ-containing telencephalic brain regions. The specific binding of [18F]8 to Aβ was confirmed by regional brain biodistribution and autoradiography and correlated to immunohistochemistry staining. Analysis of brain sections of APP/PS1 mouse injected with a cocktail of [18F]8 and reference compound [3H]PiB revealed that the two tracers bind to Aβ plaques in the brain of mouse in a comparable binding pattern. [18F]8 represents the first high-contrast PET imaging agent for detection of Aβ plaques in transgenic mouse model of Alzheimer's disease and holds promise for transfer to a clinical evaluation.

Characterization and First Human Investigation of FIBT, a Novel Fluorinated Aβ Plaque Neuroimaging PET Radioligand

“…8,9 In rats, metabolism of FIBT in blood and brain seemed comparable to PiB (Table 1). Previously, blood metabolism of FIBT in mice had been slightly higher than PiB 8 suggesting that FIBT in blood of mice was metabolized slightly faster than PiB.…”

“…The first report on [ 18 F]FIBT presented in vivo stability data in blood and brain at 10 and 30 min time points yielded in mice 8 H]PiB in blood and brain of rats. The fraction of intact [ 18 F]FIBT in rat brain after 90 min still is higher than 70%.…”

“…7 Selected compounds from this series ( Figure 1) succeeded to enter preclinical studies. 7,8 The best 18 F-labeled candidate ([ 18 F]FIBT) was selected for further investigations heading toward clinical application.…”

“…More importantly a phenolic oxygen on IBT is suitable for stable introduction of 18 8 Previously, we reported high binding affinities of FIBT to synthetic Aβ aggregates (K i = 2 nM for Aβ 1−40 and K i = 3 nM for Aβ 1−42 ), its suitable lipophilicity (log P = 1.9) and good initial brain uptake and desirable pharmacokinetics in Balb-C mice. 8 FIBT demonstrated good in vivo stability in mice, excellent brain penetration and suitable washout and high-contrast PET imaging in APP/PS1 mice. Furthermore, high binding selectivity of FIBT for Aβ (>300-fold) versus recombinant tau (K i ≫ 1000 nM) and α-synuclein aggregates (K i ≫ 1000 nM) were documented.…”

Catalyst‐free one‐pot regioselective synthesis of benzo[d]imidazo[2,1‐b]thiazoles by heating or grinding

“…Benzo[ d ]imidazo[2,1‐ b ]thiazole is an important bicyclic sulfur containing scaffold present in some natural alkaloids, agrochemicals, and pharmacologically active molecules . A number of benzo[ d ]imidazo[2,1‐ b ]thiazoles have been reported as potent pharmaceutically active molecules such as 11 C‐labeled compound I , which was used in PET imaging of Alzheimer patients as well as in β ‐amyloid plaques . Compounds II and III (YM‐201627) have been reported as potent antitumor agents, IV as antiallergic agent, and V was used as antimicrobial agent .…”