Evaluation of the novel ¹⁸F-labeled PET tracer SMBT-1 for imaging astrogliosis in Alzheimer's disease

Background: Neuroinflammatory changes, characterized by reactive astrocytes and activated microglia, contribute greatly to neurodegeneration throughout the course of Alzheimer’s diseases (AD). Reactive astrocytes overexpress monoamine oxidase-B (MAO-B) in the outer mitochondrial membrane. For imaging astrogliosis in the human brain, we developed the novel MAO-B PET tracer named ¹⁸F-SMBT-1. We aimed to investigate the binding properties of ¹⁸F-SMBT-1 in healthy elderly controls and AD patients.

Methods: In vitro binding assays and autoradiography using postmortem brain tissues were performed for the assessment of binding affinity and selectivity of ¹⁸F-SMBT-1. Nine participants, 5 healthy elderly controls (3F/2M, 78.5±6.0 yrs) and 4 AD patients (3F/1M, 76.8±1.4 yrs), underwent ¹⁸F-SMBT-1 PET, amyloid PET with ¹⁸F-NAV4694, tau PET with either ¹⁸F-MK6240 or ¹⁸F-PI2620. ¹⁸F-SMBT-1 studies were expressed as SUV or as tissue ratios using the cerebellar white matter as reference region. To ascertain ¹⁸F-SMBT-1 selective binding to MAO-B, participants underwent a second ¹⁸F-SMBT-1 scan after receiving 5mg selegiline twice daily for 5 days.

Results: SMBT-1 showed strong and reversible binding to MAO-B (Kd = 3.7 nM), and low binding affinity to other enzymes, receptors and misfolded proteins such as amyloid-β and tau. Greater amount of ¹⁸F-SMBT-1 binding was observed in AD brain tissues than in control brains and these bindings were completely displaced with MAO-B inhibitor lazabemide. In clinical studies, ¹⁸F-SMBT-1 yielded high contrast images at 60-90 min post injection. In AD patients, ¹⁸F-SMBT-1 retention was significantly higher in parahippocampus, fusiform and inferior temporal gyrus. More than 85% of ¹⁸F-SMBT-1 signal was blocked and no residual cortical activity was observed after the selegiline regimen, indicating high selectivity for MAO-B.

Conclusions: ¹⁸F-SMBT-1 is the highly selective MAO-B tracer, which will enable the assessment of astrogliosis in the human brain. The confirmation of these preliminary findings with ¹⁸F-SMBT-1 will require examination of a much larger series, including participants with MCI and prodromal AD.