Imaging of Reactive Astrogliosis by Positron Emission Tomography

• Published in: Frontiers in neuroscience Vol. 16; p. 807435
• Main Authors: Harada, Ryuichi, Furumoto, Shozo, Kudo, Yukitsuka, Yanai, Kazuhiko, Villemagne, Victor L, Okamura, Nobuyuki
• Format: Journal Article
• Language: English
• Published: Switzerland Frontiers Research Foundation 08.02.2022; Frontiers Media S.A
• Subjects: Alzheimer's disease; Amine oxidase (flavin-containing); Amyotrophic lateral sclerosis; Astrocytes; Binding sites; Brain; Creutzfeldt-Jakob disease; Cytokines; Differential diagnosis; Gene expression; Glial cells; Gliosis; imidazoline2 binding site; Inflammation; Ischemia; Kinases; MAO-B; Microglia; Mitochondria; Morphology; Neurodegeneration; Neurodegenerative diseases; Neuronal-glial interactions; Neuroscience; Neurotoxicity; Paralysis; Parkinson's disease; PET; Plaques; Positron emission tomography; Progressive supranuclear palsy; Protein folding; Proteins; radiotracers; reactive astrogliosis; Reactive oxygen species; Tau protein; Tomography; Tracers; Tumor necrosis factor-TNF; β-Amyloid; imidazoline2 binding site; radiotracers; reactive astrogliosis; MAO-B; PET
• ISSN: 1662-4548; 1662-453X; 1662-453X
• DOI: 10.3389/fnins.2022.807435

Many neurodegenerative diseases are neuropathologically characterized by neuronal loss, gliosis, and the deposition of misfolded proteins such as β-amyloid (Aβ) plaques and tau tangles in Alzheimer's disease (AD). In postmortem AD brains, reactive astrocytes and activated microglia are observed surrounding Aβ plaques and tau tangles. These activated glial cells secrete pro-inflammatory cytokines and reactive oxygen species, which may contribute to neurodegeneration. Therefore, imaging of glial response by positron emission tomography (PET) combined with Aβ and tau PET would provide new insights to better understand the disease process, as well as aid in the differential diagnosis, and monitoring glial response disease-specific therapeutics. There are two promising targets proposed for imaging reactive astrogliosis: monoamine oxidase-B (MAO-B) and imidazoline binding site (I BS), which are predominantly expressed in the mitochondrial membranes of astrocytes and are upregulated in various neurodegenerative conditions. PET tracers targeting these two MAO-B and I BS have been evaluated in humans. [ F]THK-5351, which was originally designed to target tau aggregates in AD, showed high affinity for MAO-B and clearly visualized reactive astrocytes in progressive supranuclear palsy (PSP). However, the lack of selectivity of [ F]THK-5351 binding to both MAO-B and tau, severely limits its clinical utility as a biomarker. Recently, [ F]SMBT-1 was developed as a selective and reversible MAO-B PET tracer via compound optimization of [ F]THK-5351. In this review, we summarize the strategy underlying molecular imaging of reactive astrogliosis and clinical studies using MAO-B and I BS PET tracers.