Evaluation of Fluorinated TAZA Analogs as Potential Ligands for Aβ Plaques

Objectives Alzheimer’s disease (AD) is a neurodegenerative disease characterized by Aβ plaques and Tau aggregates in the brain. The aim of this study was to evaluate fluorinated analog of the novel radiotracer, 4-[¹¹C]methylamino-4’-N,N-dimethylaminoazobenzene ([¹¹C]TAZA), for binding to Aβ plaques in postmortem human brain.

Methods 4-Amino-4’-N,N-dimethylaminoazobenzene (DAZA) was reacted with ¹¹C-methyl triflate to provide [¹¹C]TAZA with FDG in the presence of sodium cyanoborohydride using reported procedures (Baranwal et al., 2015) to produce the related compound, fluorodeoxyglucamine, FDGluDAZA. In vitro binding affinities were carried out in human AD brain homogenate with Aβ plaques labeled with [³H]PIB. In vitro autoradiography studies were performed on postmortem human brains of AD and Normal Controls (NC).

Results TAZA had an affinity, Ki= 0.84 nM and was presented to be 5 times more potent than PIB (Ki= 6.67 nM) for the human Aβ binding site whereas FDGluDAZA had a weak micro-molar affinity for the [³H]PIB labeled sites in human AD brains. [¹¹C]TAZA bound specifically to Aβ plaques present in AD brains with grey matter to white matter ratios >20. [¹¹C]TAZA was displaced by PIB (>90%), suggesting similar binding site for [¹¹C]TAZA and [¹¹C]PIB. Incorporation of the 6-carbon chain in FDGluDAZA adversely effects the affinity for binding to Aβ plaques, contrary to that reported for the pegylated stilbene derivatives, such as [¹⁸F]florbetapir and [¹⁸F]florbetaben. The hydroxyl groups in FDGluDAZA may be unsuitable for the Aβ plaque binding site. Future binding affinity measures of the compounds to Tau aggregates are planned, since we have previously observed selective binding of related [¹⁸F]fluorinated derivatives in the human AD frontal cortex (Baranwal et al., 2014).

Conclusions /b> TAZA exhibited high affinity and binding to Aβ plaques in human AD hippocampus while the fluorinated analog, FDGluDAZA had significantly weaker affinity. Pegylated derivatives of DAZA are currently being pursued in order to assess the influence of the hydroxyl groups in lowering the binding affinity. Further in vitro evaluation of these fluorinated derivatives is in progress since it has been shown that small modifications may affect the selectivity of the DAZA derivatives from Aβ plaques to Tau aggregates (Matsumura et al., 2011).