Successful Design of a Multivalent Bifunctional Chelator for Diagnostic 64Cu PET Imaging in Alzheimer’s Disease

Cho, Hong‐Jun; Huynh, Truc T.; Rogers, Buck E.; Mirica, Liviu M.

doi:10.26434/chemrxiv.12425267

Cited by 2 publications

(2 citation statements)

References 48 publications

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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,

H²,

Sen³

et al. 2021

Preprint

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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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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

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“…24 We have recently reported the development of bifunctional chelators (BFCs), which contain an Aβ-binding motif (2-phenylbenzothiazole derivative) and strong Cu(II)-chelating macrocyclic ligands, such as 1,4-dimethyl-1,4,7-triazacyclononane (TACN) and 2,11diaza [3.3](2,6)pyridinophane (N4) macrocycles. [28][29][30][31] These BFCs exhibit high affinities for Aβ aggregates and Cu(II) ion, which could be used as 64 Cu amyloid PET imaging agents. The 2phenylbenzothiazole derivative has shown appreciable Aβ-binding and fluorescent properties, therefore we continue to take advantage of this molecule as the amyloid binding motif and carry out the modification on the metal chelating fragment, by attaching two ester carboxylate pendant arms to the TACN backbone (Figure 1), in order to increase the lipophilicity of the bifunctional chelators (BFCs).…”

Section: Introductionmentioning

confidence: 99%

Benzothiazole Carboxylate Diester Bifunctional Chelators for 64Cu PET Imaging in Alzheimer’s Disease

Wang¹,

Huynh²,

Bandara³

et al. 2021

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Herein we report a new series of bifunctional chelators (BFCs) with high affinity for amyloid β aggregates, strong binding affinity towards Cu(II), and favorable lipophilicity for potential blood-brain barrier (BBB) penetration. The alkyl carboxylate ester pendant arms enable high binding affinity towards Cu(II). The BFCs form stable 64Cu-radiolabeled complexes and exhibit favorable partition coefficient (log D) values of 0.75-0.95. Among the five compounds tested, the 64Cu-YW-1 and 64Cu-YW-13 complexes exhibit significant staining of amyloid plaques in ex vivo autoradiography studies.

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Successful Design of a Multivalent Bifunctional Chelator for Diagnostic 64Cu PET Imaging in Alzheimer’s Disease

Cited by 2 publications

References 48 publications

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

Benzothiazole Carboxylate Diester Bifunctional Chelators for 64Cu PET Imaging in Alzheimer’s Disease

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