Synthesis and biological evaluation of curcumin analogs as ß-amyloid imaging agents.

AIM: Detection of ß-amyloid (Aß) plaques in the brain is a very promising biomarker approach for early diagnosis of Alzheimer's disease (AD). MATERIALS & METHODS: A series of curcumin analogs (1,5-diphenyl-1,4-pentadien-3-one derivatives) were synthesized and evaluated. Specific binding to Aß plaques was demonstrated in vitro using postmortem AD homogenates, and the fluorescent staining and autoradiography in vitro of postmortem AD brain sections were performed. RESULTS: Some compounds showed high binding affinities with Aß plaques. Fluorescent staining indicated that compound 4e clearly stained Aß plaques within AD brain sections. In biodistribution, radioiodinated ligand [125I]4e exhibited high brain uptake and favorable clearance from the brain. Autoradiography in vitro further confirmed the high affinities of [125I]4e. CONCLUSION: The results strongly suggested that [125I]4e might be developed into potential amyloid imaging agent for the detection of senile plaques in AD. [Formula: see text].

A peptide-based near-infrared fluorescence probe for dynamic monitoring senile plaques in Alzheimer's disease mouse model.

In vivo monitoring neuropathological changes in Alzheimer's disease (AD) animal model is critical for drug development. Here, by integrating blood-brain barrier penetrable peptide, we have developed a peptide probe which based on angiopep-2. Angiopep-based probe exhibited high binding affinity to Aß aggregates and labeled senile plaques in vivo. Remarkably, the in vivo near-infrared imaging data revealed that fluorescence signals of this probe were nearly 3-fold higher in the brains of 16-month-old APP/PS1 transgenic mice compared to C57 mice and exhibited linear correlation with the senile plaques load process in 4-, 8-, 16-month-old APP/PS1 transgenic mice. Moreover, senile plaques load was detected in vivo as early as 4 months of age that even at the very beginning of plaques developed in APP/PS1 transgenic mice. Taken together, this novel peptide-based probe achieved dynamic monitoring senile plaques in APP/PS1 transgenic mice and have been ready to use in drug development in AD mouse model.

6-Methoxy-indanone derivatives as potential probes for ß-amyloid plaques in Alzheimer's disease.

A series of 6-methoxy indanone derivatives was synthesized and evaluated as potential probes for ß-amyloid plaque imaging in Alzheimer's disease (AD). Two derivatives (5d and 5k) displayed significant binding abilities in fluorescent staining experiments using the brain sections of AD patients. Two derivatives showed high binding affinities to ß-amyloid aggregates (5j, Ki = 5.82 ± 0.19 nM) and brain homogenates of AD patients (5j, Ki = 18.96 ± 0.28 nM) in in vitro binding assay. With a log P value of 3.45, [125I]5k exhibited an excellent initial brain uptake (5.29%ID g-1, 2 min after i.v.) and a fast clearance from the brain in biodistribution experiments in normal mice. In autoradiography, [125I]5k exhibited an obvious binding ability to ß-amyloid plaques and a relatively low nonspecific binding in the brain sections of AD patients (in vitro) and APP/PS1 transgenic mice (in vitro and ex vivo). Results suggest that 5k is a potential probe for detecting ß-amyloid plaques in vivo.

Homoisoflavonoids as potential imaging agents for ß-amyloid plaques in Alzheimer's disease.

A series of homoisoflavonoids [(E)-3-benzylidenechroman-4-ones, 3a-l] as novel potential diagnostic imaging agents targeting ß-amyloid (Aß) plaques in Alzheimer's disease (AD) were synthesized and evaluated. In vitro binding studies using Aß1₋40 aggregates with [(125)I]IMPY as the reference ligand showed that these compounds demonstrated high to low binding affinities at the K(i) values ranged from 9.10 to 432.03 nM, depending on the substitution of the phenyl ring. Fluorescent staining in vitro indicated that one compound with a N,N-dimethylamino group intensely stained Aß plaques within brain sections of postmortem AD patients. Biodistribution studies in normal mice after i.v. injection of the radioiodinated homoisoflavonoid displayed good initial brain uptake (2.61% ID/g at 2 min postinjection) and rapid clearance from the brain (0.18% ID/g at 60 min), which is desirable for amyloid imaging agents. The results strongly suggest that these derivatives are worthy of further study and may be useful amyloid imaging agents for early detection of amyloid plaques in the brain of AD.

Novel indanone derivatives as potential imaging probes for ß-amyloid plaques in the brain.

Molecular imaging probes to detect senile plaques (SPs) might help the early diagnosis of Alzheimer's disease (AD). In this study, a novel series of indanone derivatives were synthesized and characterized. In in vitro binding studies, compound 2e exhibited a K(i) value of 16 nM with a human AD brain homogenate. Although they displayed relatively low affinities for 2i and 2j--with K(i) values of 99 and 237 nM, respectively--the SPs in AD brain sections were positively stained by 2j. A method for in situ micro-autoradiography of AD brain was developed in this study and showed clear labeling of SPs by [(125)I]2i and [(125)I]2j. Both [(125)I]2i and [(125)I]2j had suitable lipophilicities and displayed high initial uptake and rapid clearance from the mouse brains. Furthermore, [(125)I]2i and [(125)I]2j were more stable in human brain homogenates than in mouse brain homogenates. These data suggest that such indanone derivatives might represent potential amyloid imaging agents for the detection of SPs in AD.