Evaluation of [¹¹C]TAZA for amyloid β plaque imaging in postmortem human Alzheimer's disease brain region and whole body distribution in rodent PET/CT

Abstract

Objective Alzheimer’s disease (AD) is a neurodegenerative disease characterized by Aβ plaques in the brain. The aim of this study was to evaluate the effectiveness of a novel radiotracer, 4-[11C]methylamino-4′-N,N-dimethylaminoazo-benzene ([11C]TAZA), for binding to Aβ plaques in postmortem human brain (AD and normal control (NC)). Methods Radiosyntheses of [11C]TAZA, related [11C]Dalene (11C-methylamino-4′-dimethylaminostyrylbenzene), and reference [11C]PIB were carried out using [11C]methyltriflate prepared from [11C]CO2 and purified using HPLC. In vitro binding affinities were carried out in human AD brain homogenate with Aβ plaques labeled with [3H]PIB. In vitro autoradiography studies with the three radiotracers were performed on hippocampus of AD and NC brains. PET/CT studies were carried out in normal rats to study brain and whole body distribution. Results The three radiotracers were produced in high radiochemical yields (>40%) and had specific activities >37 GBq/μmol. TAZA had an affinity, Ki = 0.84 nM and was five times more potent than PIB. [11C]TAZA bound specifically to Aβ plaques present in AD brains with gray matter to white matter ratios >20. [11C]TAZA was displaced by PIB (>90%), suggesting similar binding site for [11C]TAZA and [11C]PIB. [11C]TAZA exhibited slow kinetics of uptake in the rat brain and whole body images showed uptake in interscapular brown adipose tissue (IBAT). Binding in brain and IBAT were affected by preinjection of atomoxetine, a norepinephrine transporter blocker. Conclusion [11C]TAZA exhibited high binding to Aβ plaques in human AD hippocampus. Rat brain kinetics was slow and peripheral binding to IBAT needs to be further evaluated.

Dual targeting agents for Aβ plaque/P-glycoprotein and Aβ plaque/nicotinic acetylcholine α4β2* receptors—potential approaches to facilitate Aβ plaque removal in Alzheimer’s disease brain

“…Displacement of [ 3 H]PIB by TAZA (Fig. 7) was greater than observed by CUR and is consistent with our previous findings of the high affinity of TAZA for Aβ plaques (Pan et al 2016). Compared to both CUR and TAZA, FA exhibited little displacement of [ 3 H]PIB, suggesting weaker affinity for Aβ plaques and is consistent with reported findings of FA.…”

“…7a), which was greater in the GM regions compared to WM regions with GM/WM ratio of ~2. In the presence of 4-methylamino-4'-N,N-dimethylaminoazobenzene (TAZA) (1 μM), which is known to bind to Aβ amyloid plaques with high affinity (Pan et al 2016), significant displacement of [ 3 H]PIB occurred from the GM regions (Fig. 7c), with GM/WM ratio reducing to 1:3.…”

Development and evaluation of [125I]IPPI for Tau imaging in postmortem human Alzheimer's disease brain

“…Alzheimer's disease (AD) is the most common type of dementia, accounting for 50 to 80 percent of dementia cases characterized by the accumulation of amyloid β (Aβ) plaques and neurofibrillary tangles (NFT) in the brain (Braak & Braak, 1991; Braak, Thal, Ghebremedhin, & Tredici, 2011). Several PET radiotracers have been developed for imaging of Aβ and some of them are currently in clinical use (Pan et al., 2016). Alongside progress in Aβ imaging, efforts have been underway on the development and use of NFT PET imaging agents (Lemoine et al., 2017).…”

Advances in BAT physiology for understanding and translating into Pharmacotherapies for obesity and comorbidities

“…24 Different studies have reported on increased metabolic activity of BAT Uptake of 2-deoxo-2-18 F-Fluoro-D-Glucose( 18 F-FDG), In human BAT positron emission tomography / computed tomography (PET/CT) studies. [26][27][28] Simultaneously ways were found of examining BAT in rats with the use of 123+ I MIBG, that is an analog of norepinephrine, 29 followed by norepinephrine trasporters, which got visualized with the use of 11 C -Methyl reboxitine (MRB) and 11 30,31 Use of 11 C -acetate, 11 C-palmitate along with using radiolabelled fatty acids as metabolic substrates was done by other researchers. 32,33 For getting newer strategies to be able to act regarding obesity therapy it is important to be able to measure the metabolic activity of BAT.…”

“…30 Also 11 C-TAZA via the NET in the BAT along with IBAT and other BAT regions also gets taken up as is shown by PET. 31 Quantification of atomoxetine's effects on BAT metabolism was done using 18 F-FDG PET/CT recently. 81 Much more increase occurs as compared to ephedrine.…”