Abstract View

Objectives: Prior studies have established [¹⁸F]SMBT-1 as a selective, reversible MAO-B radiotracer for imaging reactive astrogliosis, with first-in-human, kinetic, and Alzheimer’s disease (AD) studies supporting feasible in vivo quantification and clinical applicability [1–4]. Preclinical and postmortem multi-tracer studies further link [¹⁸F]SMBT-1 uptake with amyloid-β, tau, TSPO, glucose metabolism, and disease-associated astrogliosis [5–7]. However, whether [¹⁸F]SMBT-1 binding reveals disease- and region-specific patterns of reactive astrogliosis in postmortem human brain tissue across AD and related dementias remains unclear. Here, we used [¹⁸F]SMBT-1 autoradiography to assess MAO-B–defined reactive astrogliosis in postmortem AD parietal cortex tissue. 

Methods: Synthesis: Manual ¹⁸F-fluorination was performed on the tosylated precursor, (S)-(2-methylpyrid-5-yl)-6-[[2-(tetrahydro-2H-pyran-2-yloxy)-3-tosyloxy]propoxy]quinoline, according to a previously published protocol [8] (Scheme 1). Briefly, cyclotron-produced [¹⁸F]fluoride was trapped, eluted, dried, and reacted with the precursor in DMSO at 110°C for 10 min. After acid deprotection at 110°C for 3 min, the product was purified by solid-phase extraction and analyzed by radio-HPLC. Autoradiography: In vitro autoradiography was performed according to a previously published protocol [8]. Unfixed frozen postmortem brain sections were thawed, preincubated, incubated with radioligand, washed, dried, exposed to phosphor imaging plates, and scanned for image analysis.

Results: Synthesis: Initial synthesis of [¹⁸F]SMBT-1 using a commercially available precursor was unsuccessful. Using validated precursor and reference materials from the original developers at Tohoku University, we established an optimized manual radiosynthesis method that produced [¹⁸F]SMBT-1 with >95% radiochemical purity, 62% average decay-corrected radiochemical yield, and 33.13 GBq/µmol molar activity. Autoradiography: In the AD parietal cortex sections, blocking with 1 µM non-radioactive SMBT-1, lazabemide, and deprenyl partially reduced binding, with deprenyl producing the greatest blockade under these conditions. A representative AD autoradiography set is shown in Figure 1.

Conclusion: We have established an optimized [¹⁸F]SMBT-1 radiosynthesis and autoradiography workflow for postmortem human brain tissue. Successful precursor validation and manual ¹⁸F-fluorination produced radiochemically pure [¹⁸F]SMBT-1 suitable for downstream autoradiography, where our preliminary studies suggest differential binding in AD parietal cortex and deprenyl-sensitive blockade. Future studies will compare MAO-B-derived signal across six neurodegenerative disorders (AD, Lewy body disease, progressive supranuclear palsy, corticobasal degeneration, Pick’s disease, and frontotemporal lobar degeneration-TDP) vs. control brains  and five brain regions (frontal, temporal, parietal, occipital, and cerebellar cortex and white matter) to assess disease- and region-specific differences.

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