Fluorinated and iodinated ( Z)-2-(4-(2-fluoroethoxy)benzylidene)-5-iodobenzofuran-3(2 H)-one
Liang Shan
PMID: 22220320
Abstract:
Fluorinated and iodinated (Z)-2-(4-(2-fluoroethoxy)benzylidene)-5-iodobenzofuran-3(2H)-one (compound 3), abbreviated as [18F]3 and [125I]3, respectively, is an aurone derivative synthesized by Watanabe et al. for single-photon emission computed tomography (SPECT) and positron emission tomography (PET) of Alzheimer's disease (AD) by targeting β-amyloid (Aβ) plaques (1).
AD is characterized in pathology by the presence of extracellular Aβ plaques, intraneuronal neurofibrillary tangles, and neuronal loss in the cerebral cortex (2, 3). Of them, Aβ deposit is the earliest neuropathological marker and is relatively specific to AD and closely related disorders. Aβ plaques are composed of abnormal paired helical filaments 5-10 nm in size. These filaments are largely made of insoluble Aβ peptides that are 40 or 42 amino acids in length (4).
In recent years, molecular imaging by targeting the extracellular Aβ has been intensively investigated in attempts to detect early AD, assess Aβ content in vivo, determine the timing of anti-plaque therapy, and evaluate the therapeutic efficacy (4). Radiolabeled Aβ40 peptides were tested first, but they showed poor penetration ability to cross the blood-brain barrier (BBB) (4). Based on the fact that Aβ can be specifically stained in vitro with dyes of Congo red, chrysamine G, and thioflavin-T, an effort was made to develop imaging agents with these dyes. This effort, however, was in general unsuccessful because the bulky ionic groups of heteroatoms in these dyes prevent them from crossing the BBB (2). Importantly, a large class of derivatives (e.g., aminonaphthalenes, benzothiazoles, stilbenes, and imidazopyridines) was synthesized with these dyes as templates (4). Clinical and preclinical studies have shown that these derivatives not only possess a high binding affinity with Aβ plaques as their parent compounds, but also exhibit good penetration ability through the BBB and rapid washout from brain.
Ono et al. first synthesized a class of radioiodinated flavone derivatives that present a high binding affinity with Aβ plaques and good penetration ability through the BBB (5). However, these flavone derivatives display poor clearance from the brain, which leads to a high brain background. The investigators then explored another class of flavonoids with aurone as the core structure (6, 7). Aurone is a heterocyclic chemical compound that contains a benzofuran element associated with a benzylidene linked in position 2 and a chalcone-like group being closed into a five-member ring. The aurone derivatives possess a nucleophilic group (NH2, NHMe, or NMe2) at the 4' position and a radioiodine at the 5 position. Although these aurone derivatives exhibit a strong binding affinity with Aβ (inhibition constant (Ki) = 1.2-6.8 nM), high penetration ability through the BBB (1.9%−4.6% injected dose per gram tissue (ID/g) at 2 min), and a fast washout from the brain (0.3%−0.5% ID/g at 30 min), the pharmacokinetics of these compounds are less favorable for brain imaging than the pharmacokinetics of the agent [123I]IMPY (6-iodo-2-(4'-dimethylamino)phenyl-imidazo[1,2]pyridine), which is the only SPECT agent to be tested in humans to date (1, 8, 9). The investigators also modified the flavone and aurone derivatives by pegylating them with 1-3 units of ethylene glycol at the 4' position or by conjugating them with the chelating agent bis-amino-bis-thiol (BAT) (7). Favorable pharmacokinetics for brain imaging was observed for the pegylated derivatives ([18F]8(a-c)) but not for the BAT-chelated derivatives ([99mTc]BAT-FL and [99mTc]BAT-AR) (6, 7).
This series of chapters summarizes the data obtained with flavone and aurone derivatives, including [125I]15, [125I]9, [125I]14, [125I]16, [125I]17, [99mTc]BAT-FL, [99mTc]BAT-AR, [18F]8(a-c), [125I]3, and [18F]3 (1, 6-8). This chapter presents the data obtained with [125I]3 and [18F]3 (1).
Chemicals Related in the Paper:
| Catalog Number |
Product Name |
Structure |
CAS Number |
Price |
| AP6472919 |
Chrysamine G |
 |
6472-91-9 |
Price |
