Rhenium and technetium complexes that bind to amyloid-β plaques

Abstract

Alzheimer's disease is associated with the presence of insoluble protein deposits in the brain called amyloid plaques. The major constituent of these deposits is aggregated amyloid-β peptide. Technetium-99m complexes that bind to amyloid-β plaques could provide important diagnostic information on amyloid-β plaque burden using Single Photon Emission Computed Tomography (SPECT). Tridentate ligands with a stilbene functional group were used to form complexes with the fac-[M(I)(CO)3](+) (M = Re or (99m)Tc) core. The rhenium carbonyl complexes with tridentate co-ligands that included a stilbene functional group and a dimethylamino substituent bound to amyloid-β present in human frontal cortex brain tissue from subjects with Alzheimer's disease. This chemistry was extended to make the analogous [(99m)Tc(I)(CO)3](+) complexes and the complexes were sufficiently stable in human serum. Whilst the lipophilicity (log D7.4) of the technetium complexes appeared ideally suited for penetration of the blood-brain barrier, preliminary biodistribution studies in an AD mouse model (APP/PS1) revealed relatively low brain uptake (0.24% ID g(-1) at 2 min post injection).

Recent progress on NHC-stabilized early transition metal (group 3–7) complexes: Synthesis and applications

“…196,197 They also are used as analogues of potential Tc-99m diagnostic imaging agents for Alzheimer's disease. 198 It seemed natural that the incorporation of NHC ligands for this purpose should be studied. It has been found that bidentate and tridentate ligands bearing NHC ligands are suitable for biological applications, including the possibility to functionalize the corresponding Re (I) complexes with biologically active molecules.…”

Recent progress in the development of metal complexes as β-amyloid imaging probes in the brain

“…60 Donnelly et al synthesized two pyridylamine-carboxylate tridentate ligands and two dipyridylamine ligands conjugated with stilbene-like Aβ binding motifs via a short alkyl linker. 61 In the 99m Tc-labeling reaction, the carboxylate-containing ligands displayed a higher radiochemical yield (>98%) than the dipyridylamine ligands (40-50%). The binding affinity of the rhenium complexes to the Aβ plaques was measured by fluorescence staining in human brain tissue.…”

Metals in Imaging of Alzheimer’s Disease

“…Further, the authors of Reference [86] applied coordination compounds [ 99m Tc]96-99 to CAAspecific imaging probes and evaluated their utility for CAA-specific imaging. An in vitro inhibition Hayne et al reported [87] tridentate ligands L101-L104 designed to bind to the [M(CO)3] + core (M = Tc/Re) conjugated with a stilbene Aβ-binding moiety (Figure 25). The complexes 101 and 103 showed little to no plaque binding in brain tissue from AD-positive subjects.…”

“…Hayne et al reported [87] tridentate ligands L101-L104 designed to bind to the [M(CO)3] + core (M = Tc/Re) conjugated with a stilbene Aβ-binding moiety (Figure 25). The complexes 101 and 103 showed little to no plaque binding in brain tissue from AD-positive subjects.…”