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Kumar, Amit; Koistinen, Niina A; Malarte, Mona-Lisa; Nennesmo, Inger; Ingelsson, Martin; Ghetti, Bernardino; Lemoine, Laetitia; Nordberg, Agneta
Molecular psychiatry, 10/2021, Volume: 26, Issue: 10Journal Article
With reactive astrogliosis being established as one of the hallmarks of Alzheimer's disease (AD), there is high interest in developing novel positron emission tomography (PET) tracers to detect early astrocyte reactivity. BU99008, a novel astrocytic PET ligand targeting imidazoline-2 binding sites (I BS) on astrocytes, might be a suitable candidate. Here we demonstrate for the first time that BU99008 could visualise reactive astrogliosis in postmortem AD brains and propose a multiple binding site Super-high-affinity (SH), High-affinity (HA) and Low-affinity (LA) model for BU99008, I BS specific ligands (2-BFI and BU224) and deprenyl in AD and control (CN) brains. The proportion (%) and affinities of these sites varied significantly between the BU99008, 2-BFI, BU224 and deprenyl in AD and CN brains. Regional binding studies demonstrated significantly higher H-BU99008 binding in AD brain regions compared to CN. Comparative autoradiography studies reinforced these findings, showing higher specific binding for H-BU99008 than H-Deprenyl in sporadic AD brain compared to CN, implying that they might have different targets. The data clearly shows that BU99008 could detect I BS expressing reactive astrocytes with good selectivity and specificity and hence be a potential attractive clinical astrocytic PET tracer for gaining further insight into the role of reactive astrogliosis in AD.
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