First-in-Humans Evaluation of <sup>18</sup>F-SMBT-1, a Novel <sup>18</sup>F-Labeled Monoamine Oxidase-B PET Tracer for Imaging Reactive Astrogliosis
Bibliographic record
Abstract
<b>Background:</b> Reactive gliosis changes, characterized by reactive astrocytes and activated microglia, contribute greatly to neurodegeneration throughout the course of Alzheimer’s disease (AD). Reactive astrocytes overexpress monoamine oxidase-B (MAO-B). We characterized the clinical performance of <sup>18</sup>F-SMBT-1, a novel MAO-B PET tracer as a potential surrogate marker of reactive astrogliosis. <b>Methods:</b> Seventy-seven participants –53 controls (CN), 7 mild cognitively impaired (MCI), 7 AD patients, and 10 young controls (YCN)– were recruited for the different aspects of the study. Older participants underwent 3D-MPRAGE MRI and Aβ, tau, and <sup>18</sup>F-SMBT-1 imaging with PET. To ascertain <sup>18</sup>F-SMBT-1 selectivity to MAO-B, 9 participants underwent two <sup>18</sup>F-SMBT-1 scans, before and after receiving 5mg selegiline twice daily for 5 days. To compare selectivity, <sup>18</sup>F-THK5351 studies were also conducted before and after selegiline. Aβ burden was expressed in Centiloids. <sup>18</sup>F-SMBT-1 outcomes were expressed as standard uptake value, as well as tissue ratios and binding parameters using the subcortical white matter as reference region. <b>Results:</b><sup>18</sup>F-SMBT-1 showed robust entry into the brain and reversible binding kinetics, with high tracer retention in basal ganglia, intermediate in cortical regions, and lowest in cerebellum and white matter which tightly follows the known regional brain distribution of MAO-B (R2=0.84). More than 85% of <sup>18</sup>F-SMBT-1 signal was blocked by selegiline across the brain and, in contrast to <sup>18</sup>F-THK5351, no residual cortical activity was observed after the selegiline regimen, indicating high selectivity for MAO-B and low non-specific binding. <sup>18</sup>F-SMBT-1 also captured the known MAO-B increases with age, with an annual rate of change (~2.6%/yr), similar to the in vitro rates of change (~1.9%/yr). Quantitative and semiquantitative measures of <sup>18</sup>F-SMBT-1 binding were highly associated (R2>0.94), suggesting a simplified tissue ratio approach could be used to generate outcome measures. <b>Conclusion:</b><sup>18</sup>F-SMBT-1 is a highly selective MAO-B tracer, with low non-specific binding, high entry into the brain and displaying reversible kinetics. Moreover, <sup>18</sup>F-SMBT-1 brain distribution matches the reported in vitro distribution and captures the known MAO-B increases with age, suggesting <sup>18</sup>F-SMBT-1 can potentially be used as a surrogate marker of reactive astrogliosis. Further validation of these findings with <sup>18</sup>F-SMBT-1 will require examination of a much larger series, including participants with MCI and AD.
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How this classification was reachedexpand
Full frame distilled prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. Learned from the 10,348 direct Codex labels and 10,348 direct Gemma labels. Candidate is the union of thresholded teacher heads; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels or direct frontier model labels.
Codex and Gemma teacher scores by category
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.003 | 0.001 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.001 | 0.000 |
| Bibliometrics | 0.001 | 0.001 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.001 |
| Insufficient payload (model declined to judge) | 0.004 | 0.000 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one teacher head, not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".