First-in-Humans Evaluation of F-SMBT-1, a Novel F-Labeled Monoamine Oxidase-B PET Tracer for Imaging Reactive Astrogliosis.

Reactive gliosis, characterized by reactive astrocytes and activated microglia, contributes greatly to neurodegeneration throughout the course of Alzheimer disease (AD). Reactive astrocytes overexpress monoamine oxidase B (MAO-B). We characterized the clinical performance of F-()-(2-methylpyrid-5-yl)-6-[(3-fluoro-2-hydroxy)propoxy]quinoline (F-SMBT-1), a novel MAO-B PET tracer as a potential surrogate marker of reactive astrogliosis. Seventy-seven participants-53 who were elderly and cognitively normal, 7 with mild cognitive impairment, 7 with AD, and 10 who were young and cognitively normal-were recruited for the different aspects of the study. Older participants underwent 3-dimensional magnetization-prepared rapid gradient-echo MRI and amyloid-β, tau, and F-SMBT-1 PET. To ascertain F-SMBT-1 selectivity to MAO-B, 9 participants underwent 2 F-SMBT-1 scans, before and after receiving 5 mg of selegiline twice daily for 5 d. To compare selectivity, F-THK5351 studies were also conducted before and after selegiline. Amyloid-β burden was expressed in centiloids. F-SMBT-1 outcomes were expressed as SUV, as well as tissue ratios and binding parameters using the subcortical white matter as a reference region. F-SMBT-1 showed robust entry into the brain and reversible binding kinetics, with high tracer retention in basal ganglia, intermediate retention in cortical regions, and the lowest retention in cerebellum and white matter, which tightly follows the known regional brain distribution of MAO-B ( = 0.84). More than 85% of F-SMBT-1 signal was blocked by selegiline across the brain, and in contrast to F-THK5351, no residual cortical activity was observed after the selegiline regimen, indicating high selectivity for MAO-B and low nonspecific binding. F-SMBT-1 also captured the known MAO-B increases with age, with an annual rate of change (∼2.6%/y) similar to the in vitro rates of change (∼1.9%/y). Quantitative and semiquantitative measures of F-SMBT-1 binding were strongly associated ( > 0.94), suggesting that a simplified tissue-ratio approach could be used to generate outcome measures. F-SMBT-1 is a highly selective MAO-B tracer, with low nonspecific binding, high entry into the brain, and reversible kinetics. Moreover, F-SMBT-1 brain distribution matches the reported in vitro distribution and captures the known MAO-B increases with age, suggesting that F-SMBT-1 can potentially be used as a surrogate marker of reactive astrogliosis. Further validation of these findings with F-SMBT-1 will require examination of a much larger series, including participants with mild cognitive impairment and AD.