Synthesis of Oxorhenium(V) and Oxotechnetium(V) Complexes That Bind to Amyloid-β Plaques

Abstract

Alzheimer's disease is characterized by the presence of amyloid plaques in the brain. The primary constituents of the plaques are aggregated forms of the amyloid-β (Aβ) peptide. With the goal of preparing technetium-99(m) complexes that bind to Aβ plaques with the potential to be diagnostic imaging agents for Alzheimer's disease, new tetradentate ligands capable of forming neutral and lipophilic complexes with oxotechentium(V) and oxorhenium(V) were prepared. Nonradioactive isotopes of technetium are not available so rhenium was used as a surrogate for exploratory chemistry. Two planar tetradentate N3O ligands were prepared that form charge-neutral complexes with oxorhenium(v) as well as a ligand featuring a styrylpyridyl functional group designed to bind to Aβ plaques. All three ligands formed complexes with oxorhenium(V), and each complex was characterized by NMR spectroscopy, mass spectrometry, and X-ray crystallography. The oxorhenium(V) complex with a styrylpyridyl functional group binds to Aβ plaques present in post-mortem human brain tissue. The chemistry was extrapolated to technetium-99(m) at the tracer level for two of the ligands. The resulting oxotechnetium(V) complexes were sufficiently lipophilic and charge-neutral to suggest that they have the potential to cross the blood-brain barrier but exhibited modest stability with respect to exchange with histidine. The chemistry presented here identifies a strategy to integrate styrylpyridyl functional groups into tetradentate ligands capable of forming complexes with [M═O](3+) cores (M = Re or Tc).

Chemoselective Attachment of the Water-Soluble Dark Quencher Hydrodabcyl to Amino Groups in Peptides and Preservation of Its Spectroscopic Properties over a Wide pH Range

“…Therefore, the significant drop in absorbance at 450 nm below pH = 6 (red arrow in Figure b) was mainly due to the precipitation of 1b . The formation of visible aggregates due to precipitation results in spectral deformation. Not only is the absorbance at 450 nm drastically diminished, but the gain in absorbance at 580 nm is attenuated as well, due to fewer absorbing molecules in the illuminated volume (blue arrow).…”

Metals in Imaging of Alzheimer’s Disease

“…[ 99m Tc]122 brain accumulation in rhesus monkeys (M04: 4-year-old, male; F27: 27-year-old, female). [91] ( Figure 29). The affinity of 133 for Aβ 1−42 fibrils was estimated to be K i = 855 nM using a fluorescence competition assay against Thioflavin T. It was also shown that 133 binds to Aβ plaques in human brain tissue using human AD brain sections.…”

Oxorhenium(V) and Oxotechnetium(V) Complexes of N3S Tetradentate Ligands with a Styrylpyridyl Functional Group: Toward Imaging Agents to Assist in the Diagnosis of Alzheimer’s Disease

“…Previous work from our laboratory investigated the potential of the incorporation of an Aβ-targeting styrylpyridyl functional group within the ligand framework . Charge-neutral tetradentate rhenium and technetium complexes featuring pyridyl, amide, and phenol donor atoms were formed where the styrylpyridyl group was directly coordinated to the metal center and the rhenium complexes were able to interact with Aβ plaques present in human brain tissue .…”