Synthesis and in vivo characterization of 18F-labeled difluoroboron-curcumin derivative for β-amyloid plaque imaging

Abstract

Positron emission tomography imaging of β-amyloid (Aβ) plaques has proven useful in the diagnosis of Alzheimer’s disease. A previous study from our group showed that 4′- O -[ 18 F]fluoropropylcurcumin has poor brain permeability, which is thought to be due to its rapid metabolism. In this study, we synthesized difluoroboron complexes of fluorine-substituted curcumin derivatives ( 1 – 4 ) and selected one of them based on the in vitro binding assays. The selected ligand 2 was found to distinctively stain Aβ plaques in APP/PS1 transgenic mouse brain sections. Radioligand [ 18 F] 2 was synthesized via a two-step reaction consisting of [ 18 F]fluorination and subsequent aldol condensation. Biodistribution and metabolism studies indicated that radioligand [ 18 F] 2 was converted to polar radioactive products and trapped in the normal mouse brain. In contrast, optical images of mice acquired after injection of 2 showed moderate fluorescence signal intensity in the mouse brain at 2 min with a decrease in the signal within 30 min. In the ex vivo optical images, the fluorescence signals in major tissues disappeared within 30 min. Taken together, these results suggest that [ 18 F] 2 may be converted to polar 18 F-labeled blue-shifted fluorescent products. Further structural modifications are thus needed to render the radioligand metabolically stable.

Non-Cytotoxic Dibenzyl and Difluoroborate Curcuminoid Fluorophores Allow Visualization of Nucleus or Cytoplasm in Bioimaging

“…Benzylated curcumin derivatives 2 and 5 are useful fluorophores since they show the following properties: minimal cytotoxic activity, derivative 5 falls within the NIR region, both can be detected in defined wavelength ranges, preserve morphological integrity of cells and, depending on the laser source used, selectively reveal subcellular structures. Therefore, 2 and 5 can be classified as imaging tools for studying and monitoring living cells or tissues, e.g., cancer cell lines or amyloid-β (Aβ) deposits, as indicated in the literature [ 25 , 42 ].…”

Curcumin in Health and Diseases: Alzheimer’s Disease and Curcumin Analogues, Derivatives, and Hybrids

“…Kim et al [115] selected 4 -dimethylamino-4 -(2-(2-fluoroethoxy)ethoxy) curcuminoid for radiolabeling, in vitro and in vivo. Although the ligand was able to distinctively stain Aβ plaques in transgenic mouse brain sections and presented suitable lipophilicity, the in vivo studies of [ 18 F]4 -dimethylamino-4 -(2-(2-fluoroethoxy)ethoxy) curcuminoid did not presentsatisfactory brain pharmacokinetics in normal mice.…”

Fluorine-18-Labeled Fluorescent Dyes for Dual-Mode Molecular Imaging

“…Tracers 19 and 20 were obtained with d.c. RCYs around 20% and 51% and A m of 1.16 and 1.19 Ci/μmol, respectively. During the development of these tracers, Kim et al investigated the acid-mediated IEX radiofluorination in a similar manner as for BODIPYs, however, it was unsuccessful and only decomposition occurred [ 114 ]. Recently, Ting’s group patented a radiofluorinated curcumin derivative labeled via IEX using SnCl 4 [ 116 ].…”

“…Although hydrazinocurcumins tend to show improved potency compared to regular curcumins, which is the reason of their use in this study, their fluorescence emission is centered in the blue region, reducing their use in OPI. In parallel, the recent emergence of [ 18 F]BF 2 -curcuminoids displaying red-shifted emission and higher fluorescence quantum yields compared to classical curcumins might encourage tumor dual mode imaging with this family of dyes [ 114 , 115 ]. An and coworkers also described the preferential accumulation of an unconjugated 18 F-labeled sulfoCy5 in an A549 xenograft tumor model (adenocarcinoma model) [ 97 ].…”

“…18 F-labeled curcuminoids and their difluoroborate analogs have been investigated as PET ligands and used for brain section imaging. Notably, Yang et al and Kim et al respectively used [ 18 F]CRANAD-101 ( 20 ) and [ 18 F]CRANAD-2 ( 19 ) derivatives for brain imaging of APP/PS1 model mice [ 114 , 115 ]. [ 18 F] 20 allowed for clear identification of Aβ plaques by fluorescence microscopy of brain sections and by in vivo two-photon microscopy.…”