Rhodanine and thiohydantoin derivatives for detecting tau pathology in Alzheimer's brains

Abstract

A novel series of rhodanin (RH) and thiohydantoin (TH) derivatives were designed and synthesized for detecting tau pathology in the brains of patients with Alzheimer's disease (AD). In experiments in vitro using tau and β-amyloid (Aβ) aggregates, the TH derivative, TH2, showed high specific binding to tau aggregates. In hippocampal sections obtained from AD patients, TH2 intensely stained neurofibrillary tangles. In experiments using normal mice, [(125)I]TH2 showed good uptake (1.54%ID/g, 2 min postinjection) into and a rapid washout (0.25%ID/g, 60 min postinjection) from the brain. [(123)I]TH2 should be further investigated as a potential imaging agent for detecting tau pathology.

Keywords: Alzheimer’s disease; imaging; rhodanine; tau; thiohydantoin.

Figure 1

Chemical structure of rhodanine and thiohydantoin derivatives reported in this study.

Scheme 1

Figure 2

Binding of [¹²⁵I]RH1, [¹²⁵I]TH1, and [¹²⁵I]TH2 to tau aggregates and tau monomers.

Figure 3

Comparison of brain uptake of [¹²⁵I]RH1, [¹²⁵I]TH1, and [¹²⁵I]TH2 in normal mice.

Figure 4

In vitro autoradiograms of sections of AD brain labeled with [¹²⁵I]TH2 (A). The same sections were immunostained using an antibody against hyperphosphorylated tau (AT8) (B).

Figure 5

Neuropathological staining of TH2 in 6 μm sections from the hippocampus of an AD patient (A). The same sections were immunostained using an antibody against hyperphosphorylated tau (AT8) (B).