Imaging of Reactive Astrogliosis by Positron Emission Tomography

Abstract

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, in vivo 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 imidazoline₂ binding site (I₂BS), 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 I₂BS have been evaluated in humans. [¹⁸F]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 [¹⁸F]THK-5351 binding to both MAO-B and tau, severely limits its clinical utility as a biomarker. Recently, [¹⁸F]SMBT-1 was developed as a selective and reversible MAO-B PET tracer via compound optimization of [¹⁸F]THK-5351. In this review, we summarize the strategy underlying molecular imaging of reactive astrogliosis and clinical studies using MAO-B and I₂BS PET tracers.

Keywords: MAO-B; PET; imidazoline2 binding site; radiotracers; reactive astrogliosis.

FIGURE 1

Molecular targets for imaging reactive astrogliosis: monoamine oxidase-B (MAO-B) and imidazoline₂ binding site (I₂BS). Chemical structures of selective PET tracers for MAO-B and I₂BS tested in humans.

FIGURE 2

[¹⁸F]THK-5351 PET images in AD, CBS, and PSP subjects. [¹⁸F]THK-5351 retention in the precentral gyrus clearly can distinguish CBS from PSP and AD. [¹⁸F]THK-5351 retention in the midbrain distinguished PSP and CBS from AD (Okamura et al., 2018).

FIGURE 3

Crystal structure of MAO-B complex with L-deprenyl. Molecular image of 2BYB (De Colibus et al., 2005) created using PyMOL software. Yellow: β-strands. Red: L-derepnyl. Chemical structures of clinically used MAO-B inhibitors (selegiline, rasagiline, and safinamide), β-sheets ligands that binds to MAO-B ([¹⁸F]THK-5351 and [¹⁸F]MK-3328), and a novel MAO-B PET tracer, [¹⁸F]SMBT-1. Although the detailed binding site of β-sheets ligands such as [¹⁸F]THK-5351 and [¹⁸F]MK-3328 remains unknown, the evidence suggest that β-sheet ligands are potential MAO-B binders. In fact, lead optimization of one of β-sheet ligands, [¹⁸F]THK-5351, generated a novel MAO-B PET tracer, [¹⁸F]SMBT-1.

FIGURE 4

Axial, coronal, and sagittal images showing higher and widespread binding of [¹⁸F]SMBT-1 in an Aβ-positive Alzheimer’s disease patient (Aβ + AD, right) compared to an age-matched Aβ-negative cognitive unimpaired control (Aβ- CN, left). (Courtesy of Drs. Victor Villemagne and Christopher Rowe).