Novel ¹⁸F-Labeled Benzofuran Derivatives with Improved Properties for Positron Emission Tomography (PET) Imaging of β-Amyloid Plaques in Alzheimer’s Brains

Abstract

In vivo imaging of β-amyloid plaques in the brain may lead to the early diagnosis of Alzheimer's disease (AD) and monitoring of the progression and effectiveness of treatment. In the present study, we report on the development of two potential PET probes, [(18)F]FPYBF-2 ([(18)F]10) and [(18)F]FPHBF-2 ([(18)F]21), for imaging of β-amyloid plaques in AD brain. In experiments in vitro, 10 and 21 displayed high affinity for Aβ(1-42) aggregates (K(i) = 2.41 and 3.85 nM, respectively). In biodistribution experiments using normal mice, they displayed high uptake in the brain (7.38 and 8.18% ID/g at 2 min postinjection, respectively), and the radioactivity washed out from the brain rapidly (3.15 and 3.87% ID/g at 60 min postinjection, respectively), which is highly desirable for β-amyloid imaging agents. In vivo, they clearly labeled β-amyloid plaques in Tg2576 mice. Furthermore, the specific labeling of β-amyloid plaques by 10 and 21 was observed in autoradiographs of sections of autopsied AD brain. These new fluorinated benzofuran derivatives are promising PET probes for imaging cerebral β-amyloid plaques.

<i>In Vivo</i> Molecular Imaging

“…Thus we designed molecular probes for nuclear medicinal imaging the distribution of aggregates of Aβ and hyperphosphorylated tau protein in the brain of a patient with AD, which satisfied the following requirements: 1) high blood-brain barrier permeability; 2) high and specific binding ability to Aβ and tau aggregates; and 3) rapid elimination from normal regions of the brain. Consequently, we succeeded in developing 18 F-labeled pyridyl benzofuran derivative, 18 F-FPYBF-2, as a probe for PET imaging of Aβ plaques [28][29][30][31][32][33][34][35][36] and 123 I-labeled benzo imidazopyridine (BIP) derivative, BIP-3, as a probe for SPECT imaging of tau aggregates [37][38][39][40][41] (Fig. 3).…”

A Synthetic Overview of Radiolabeled Compounds for β‐Amyloid Targeting

“…[46] In contrast, the same backbone was introduced in FPHBF-2 (Scheme 15) through the base-promoted condensation of 2-hydroxy-5-methoxybenzaldehyde (90) with 4-nitrobenzyl bromide (91). [47] These compounds exhibited good affinities for Aβ plaques but pharmacokinetic profiles with unfavorable target/non-target ratios.…”

“…The key step in the formation of FPYBF-1 and FPYBF-2 was achieved by Suzuki coupling between 5-methoxybenzofuran-2-boronic acid and 1-amino-5-iodopyridine. [47][48] Although compound FPYBF-2 shows a weaker binding affinity to Aβ plaques than FPYBF-1 (2.41 nm vs. 0.95 nM), the former displays improved brain uptake and faster clearance from normal mouse brain, and is currently the first […”

2-Phenylbenzo[ b ]furans: Synthesis and promoting activity on estrogen biosynthesis

“…2). Introduction of bromine at C-4 was favorable, which could be explained by the highest activity of compound 6 among the egonol derived compounds (1)(2)(3)(4)(5)(6)(7)(8)(9)(10)(11)(12)(13)(14). It is promising that the alkyl group at C-5 of egonol could be replaced with halogen.…”