AZD2184: a radioligand for sensitive detection of β‐amyloid deposits

Abstract

The presence of β‐amyloid plaques in brain is a hallmark of Alzheimer’s disease (AD) and serves as a biomarker for confirmation of diagnosis postmortem. Positron emission tomography (PET) radioligands such as Pittsburgh compound B ([11C]‐2‐(3‐fluoro‐4‐methylamino‐phenyl)‐benzothiazol‐6‐ol) (PIB) binds selectively to β‐amyloid and are promising new tools supporting the clinical diagnoses of AD. In addition, such methodology may be useful for evaluation of new drugs aiming at reduction of amyloid plaque load. The objective of this study is to develop a new amyloid selective PET radioligand with higher signal‐to‐background ratio when compared with existing amyloid PET ligands. The lead compound, AZD2184, (2‐[6‐(methylamino)pyridin‐3‐yl]‐1,3‐benzothiazol‐6‐ol) was found to have high affinity for amyloid fibrils in vitro (Kd: 8.4 ± 1.0 nM). Two minutes after i.v. administration in rats, about 1% of the dose was in brain. In vitro autoradiography on cortical brain sections from amyloid‐beta precursor protein/presenilin 1 (APP/PS1) mice and AD patients showed that while [3H]AZD2184 and [3H]PIB are mutually displaceable, [3H]AZD2184 displays a higher signal‐to‐background ratio primarily by virtue of lower background binding levels. The ratio of binding ability in prefrontal cortex (high plaque load) to subcortical white matter (background) was 4.5 for [3H]AZD2184 and 0.8 for [3H]PIB at 1 nM. In adjacent cortical sections from APP/PS1 mouse as well as from AD cortical tissue, [3H]AZD2184 and antibodies to human β‐amyloid labeled identical structures. In vivo administration of [3H]AZD2184 to APP/PS1 mice further showed that [3H]AZD2184 labels amyloid deposits with low non‐specific background binding. Taken together, the pre‐clinical profile of AZD2184 in relation to the reference ligand PIB, suggests that 11C‐labeled AZD2184 is a potential radioligand for PET‐visualization of β‐amyloid deposits in the living human brain.

Detection of Aβ Plaques by a Novel Specific MRI Probe Precursor CR‐BSA‐(Gd‐DTPA)n in APP/PS1 Transgenic Mice

“…Fifteen micrometer thick sections were serially cut using a cryostat. The histochemistry staining of AD brain sections with CR-BSA-(Gd-DTPA)n was improved stepwise in the experiment according the staining method of the traditional CR dye (Schmidt et al, 2001;Johnson et al, 2009). The process was stopped by immersion in distilled water.…”

Quantum dots and prion proteins

“…About a decade ago, the first successful Aβ plaque-specific PET imaging study was conducted in a living human subject clinically diagnosed with probable AD using the 74 It is clear that this type of PrP diagnostics related diseases has a great potential to be further developed and new imaging assays are still being looked for. Some of them could be based on quantum dots (QDs).…”

Synthesis and In Vitro Evaluation of Imidazo[1,2-b]pyridazines as Ligands for β-Amyloid Plaques

“…[4][5][6][7] The development of amyloid-specific imaging agents is generally based on conjugated dyes, such as Congo red, Chrysamine G, and thioflavin-T, which have been used in fluorescent staining of plaques and tangles in postmortem AD brain sections. Several radioligands for positron emission tomography (PET) and single photon emission computerized tomography (SPECT), including [ (2-[6-(methylamino)pyridin-3-yl]-1,3-benzothiazol-6-ol), 12 [ 17,18 and [ 19 have been tested in clinical trials and demonstrated the potential utility as in vivo imaging agents for Aβ plaque deposition in the living human brain (Figure 1).…”