Evaluation Of The Novel F-18-Labeled Pet Tracer Smbt-1 For Imaging Astrogliosis In Alzheimer'S Disease

457 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.