Curcumin and Dehydrozingerone Derivatives:  Synthesis, Radiolabeling, and Evaluation for β-Amyloid Plaque Imaging^†

Abstract

Alzheimer's disease (AD) is pathologically characterized by the accumulation of amyloid plaques and neurofibrillary tangles in the brain, and thus, the in vivo imaging of plaques and tangles would be beneficial for the early diagnosis of AD. It has been suggested that 5-hydroxy-1,7-bis(4-hydroxy-3-methoxyphenyl)-1,4,6-heptatrien-3-one (curcumin) may be responsible for low age-adjusted prevalence of AD in India. In the present study, eight novel derivatives of curcumin and 4-(4-hydroxy-3-methoxyphenyl)-3-buten-2-one (dehydrozingerone) were synthesized and their binding affinities for beta-amyloid (Abeta) aggregates were measured. Of these ligands, fluoropropyl-substituted curcumin (8) showed the highest binding affinity (Ki=0.07 nM), and therefore, 8 was radiolabeled and evaluated as a potential probe for Abeta plaque imaging. Partition coefficient measurement and biodistribution in normal mice demonstrated that [18F]8 has a suitable lipophilicity and reasonable initial brain uptake. Metabolism studies also indicated that [18F]8 is metabolically stable in the brain. These results suggest that [18F]8 is a suitable radioligand for Abeta plaque imaging.

Curcumin as “Curecumin”: From kitchen to clinic

“…More recently, in a study examining the tissue distribution of radiolabeled fluoropropyl-substituted curcumin mice, Ryu et al found that curcumin bound to b-amyloid plaques in the brain, thereby suggesting its possible use for brain imaging (Fig. 2) [158].…”

“…Data are expressed as the percent injected dose per gram of tissue (% ID/g). The data is replotted from [158].…”

Retinal amyloid pathology and proof-of-concept imaging trial in Alzheimer’s disease

“…To visualize retinal Aβ pathology in vivo, we had previously developed a noninvasive retinal amyloid imaging method for rodent ADtg models, using curcumin as a contrast agent (40,51). Curcumin is a natural and safe phytopolylphenol fluorochrome that binds to Aβ fibrils and oligomers with high affinity and specificity (62)(63)(64)(65)(66)(67)(68). This approach enabled noninvasive detection and monitoring of individual retinal Aβ deposits in live ADtg mice (40,51).…”

Can the retina be used to diagnose and plot the progression of Alzheimer's disease?

“…Methods have been developed recently to increase the stability and increase the availability in vivo (Anand et al 2007). Curcumin derivatives can be used as a marker in PET scanning as suggested by Ryu et al (2006). Researchers at the Commonwealth Scientific and Industrial Research Organization in Australia used curcumin fluorescence imaging to highlight beta-amyloid in the retina and correlated them with the PET findings in the brain.…”