Copper Bis(thiosemicarbazonato)-stilbenyl Complexes That Bind to Amyloid-β Plaques

Noor, Asif; Hayne, David J.; Lim, SinChun; Zuylekom, Jessica Van; Cullinane, Carleen; Roselt, Peter; McLean, Catriona; White, Jonathan M.; Donnelly, Paul S.

doi:10.1021/acs.inorgchem.0c01520

“…Several studies have reported that Aβ-targeting bifunctional chelators can be utilized as potential 64 Cu PET imaging agents for AD. − With the introduction of the hydrophilic metal-chelating azamacrocycle, the developed amphiphilic compound LS-4 could serve as a bifunctional chelator. Given the promising results from the ex vivo studies using the nonradioactive Cu-LS-4 complex, we set out to explore whether the radioactive 64 Cu-LS-4 complex could be used as a potential PET imaging agent for AD.…”

Section: Results and Discussionmentioning

confidence: 99%

Amphiphilic Distyrylbenzene Derivatives as Potential Therapeutic and Imaging Agents for Soluble and Insoluble Amyloid β Aggregates in Alzheimer’s Disease

Sun

¹

,

Cho

²

,

Sen

³

et al. 2021

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Alzheimer’s Disease (AD) is the most common neurodegenerative disease, and efficient therapeutic and early diagnostic agents for AD are still lacking. Herein, we report the development of a novel amphiphilic compound, LS-4, generated by linking a hydrophobic amyloid-binding distyrylbenzene fragment with a hydrophilic triazamacrocycle, which dramatically increases the binding affinity toward various amyloid β (Aβ) peptide aggregates, especially for soluble Aβ oligomers. Moreover, upon the administration of LS-4 to 5xFAD mice, fluorescence imaging of LS-4-treated brain sections reveals that LS-4 can penetrate the blood-brain barrier and bind to the Aβ oligomers in vivo. In addition, the treatment of 5xFAD mice with LS-4 reduces the amount of both amyloid plaques and associated phosphorylated tau aggregates vs the vehicle-treated 5xFAD mice, while microglia activation is also reduced. Molecular dynamics simulations corroborate the observation that introducing a hydrophilic moiety into the molecular structure of LS-4 can enhance the electrostatic interactions with the polar residues of the Aβ species. Finally, exploiting the Cu2+-chelating property of the triazamacrocycle, we performed a series of imaging and biodistribution studies that show the 64Cu-LS-4 complex binds to the amyloid plaques and can accumulate to a significantly larger extent in the 5xFAD mouse brains vs the wild-type controls. Overall, these results illustrate that the novel strategy, to employ an amphiphilic molecule containing a hydrophilic moiety attached to a hydrophobic amyloid-binding fragment, can increase the binding affinity for both soluble and insoluble Aβ aggregates and can thus be used to detect and regulate various Aβ species in AD.

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“…Numerous studies have reported that Aβ-targeting bifunctional chelators can be utilized as potential 64 Cu PET imaging agents for AD. [85][86][87][88][89] With the introduction of the hydrophilic metalchelating azamacrocycle, the developed amphiphilic compound LS-4 could serve as a bifunctional chelator. Given the promising results from the ex vivo studies using the non-radioactive Cu-LS-4 complex, we set out to explore whether the radioactive 64 Cu-LS-4 complex could be used as a potential PET imaging agent for AD.…”

Section: Logd Determination Of the 64 Cu-ls-4 Complexmentioning

confidence: 99%

Amphiphilic Distyrylbenzene Derivatives as Potential Therapeutic and Imaging Agents for the Soluble Amyloid-β Oligomers in Alzheimer’s Disease

Sun¹,

Cho²,

Sen³

et al. 2021

Preprint

View full text Add to dashboard Cite

Alzheimer’s Diseases (AD) is the most common neurodegenerative disease, but efficient therapeutic and early diagnosis agents for this neurological disorder are still lacking. <a>Herein, we report the development of a novel amphiphilic compound, LS-4, generated linking a hydrophobic amyloid fibril-binding fragment with a hydrophilic azamacrocycle that can dramatically increase the binding affinity towards various amyloid β (Aβ) peptide aggregates. The developed compound exhibits uncommon fluorescence turn-on and high binding affinity for Aβ aggregates, especially for soluble Aβ oligomers. Moreover, upon the administration of LS-4 to 5xFAD mice, fluorescence imaging of the LS-4-treated brain sections reveals that LS-4 can readily penetrate the blood-brain-barrier (BBB) and bind to the Aβ oligomers in vivo, as confirmed by immunostaining with an Aβ oligomer-specific antibody. In addition, the treatment of 5xFAD mice with LS-4 significantly reduces the amount of both amyloid plaques and associated phosphorylated tau (p-tau) aggregates vs. the vehicle-treated 5xFAD mice, while microglia activation is also reduced. Furthermore, molecular dynamics simulations corroborate the observation that introducing a hydrophilic moiety into the molecular structure can significantly enhance the electrostatic interactions with the polar residues of the Aβ peptide species. Finally, taking advantage of the strong Cu-chelating property of the azamacrocycle, we performed a series of radioimaging and biodistribution studies that show the 64Cu-LS-4 complex binds to the amyloid plaques and can accumulate a significantly larger extent in the 5xFAD mice brains vs. the WT controls. Overall, these in vitro and in vivo studies illustrate that the novel strategy to employ an amphiphilic molecule containing a hydrophilic fragment attached to a hydrophobic amyloid fibril-binding fragment </a><a>can increase the binding affinity of these compounds for the soluble Aβ oligomers and can thus be used </a>to detect and regulate the soluble Aβ species in AD.

show abstract

“…Numerous studies have reported that Aβ-targeting bifunctional chelators can be utilized as potential 64 Cu PET imaging agents for AD. [85][86][87][88][89] With the introduction of the hydrophilic metalchelating azamacrocycle, the developed amphiphilic compound LS-4 could serve as a bifunctional chelator. Given the promising results from the ex vivo studies using the non-radioactive Cu-LS-4 complex, we set out to explore whether the radioactive 64 Cu-LS-4 complex could be used as a potential PET imaging agent for AD.…”

Section: Logd Determination Of the 64 Cu-ls-4 Complexmentioning

confidence: 99%

Amphiphilic Distyrylbenzene Derivatives as Potential Therapeutic and Imaging Agents for the Soluble Amyloid-β Oligomers in Alzheimer’s Disease

Sun¹,

H²,

Sen³

et al. 2021

Preprint

0

View full text Add to dashboard Cite

Alzheimer’s Diseases (AD) is the most common neurodegenerative disease, but efficient therapeutic and early diagnosis agents for this neurological disorder are still lacking. <a>Herein, we report the development of a novel amphiphilic compound, LS-4, generated linking a hydrophobic amyloid fibril-binding fragment with a hydrophilic azamacrocycle that can dramatically increase the binding affinity towards various amyloid β (Aβ) peptide aggregates. The developed compound exhibits uncommon fluorescence turn-on and high binding affinity for Aβ aggregates, especially for soluble Aβ oligomers. Moreover, upon the administration of LS-4 to 5xFAD mice, fluorescence imaging of the LS-4-treated brain sections reveals that LS-4 can readily penetrate the blood-brain-barrier (BBB) and bind to the Aβ oligomers in vivo, as confirmed by immunostaining with an Aβ oligomer-specific antibody. In addition, the treatment of 5xFAD mice with LS-4 significantly reduces the amount of both amyloid plaques and associated phosphorylated tau (p-tau) aggregates vs. the vehicle-treated 5xFAD mice, while microglia activation is also reduced. Furthermore, molecular dynamics simulations corroborate the observation that introducing a hydrophilic moiety into the molecular structure can significantly enhance the electrostatic interactions with the polar residues of the Aβ peptide species. Finally, taking advantage of the strong Cu-chelating property of the azamacrocycle, we performed a series of radioimaging and biodistribution studies that show the 64Cu-LS-4 complex binds to the amyloid plaques and can accumulate a significantly larger extent in the 5xFAD mice brains vs. the WT controls. Overall, these in vitro and in vivo studies illustrate that the novel strategy to employ an amphiphilic molecule containing a hydrophilic fragment attached to a hydrophobic amyloid fibril-binding fragment </a><a>can increase the binding affinity of these compounds for the soluble Aβ oligomers and can thus be used </a>to detect and regulate the soluble Aβ species in AD.

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Copper Bis(thiosemicarbazonato)-stilbenyl Complexes That Bind to Amyloid-β Plaques

Cited by 18 publications

References 64 publications

Amphiphilic Distyrylbenzene Derivatives as Potential Therapeutic and Imaging Agents for Soluble and Insoluble Amyloid β Aggregates in Alzheimer’s Disease

Amphiphilic Distyrylbenzene Derivatives as Potential Therapeutic and Imaging Agents for Soluble and Insoluble Amyloid β Aggregates in Alzheimer’s Disease

Amphiphilic Distyrylbenzene Derivatives as Potential Therapeutic and Imaging Agents for the Soluble Amyloid-β Oligomers in Alzheimer’s Disease

Amphiphilic Distyrylbenzene Derivatives as Potential Therapeutic and Imaging Agents for the Soluble Amyloid-β Oligomers in Alzheimer’s Disease

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