First-in-Humans Evaluation of ¹⁸F-SMBT-1, a Novel ¹⁸F-Labeled Monoamine Oxidase-B PET Tracer for Imaging Reactive Astrogliosis

Abstract

Background: 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 18 F-SMBT-1, a novel MAO-B PET tracer as a potential surrogate marker of reactive astrogliosis.Methods: 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 A, tau, and 18 F-SMBT-1 imaging with PET. To ascertain 18 F-SMBT-1 selectivity to MAO-B, 9 participants underwent two 18 F-SMBT-1 scans, before and after receiving 5mg selegiline twice daily for 5 days. To compare selectivity, 18 F-THK5351 studies were also conducted before and after selegiline. A burden was expressed in Centiloids. 18 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.Results: 18 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 (R 2 =0.84). More than 85% of 18 F-SMBT-1 signal was blocked by selegiline across the brain and, in contrast to 18 F-THK5351, no residual cortical activity was observed after the selegiline regimen, indicating high selectivity for MAO-B and low non-specific binding. 18 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 18 F-SMBT-1 binding were highly associated (R 2 >0.94), suggesting a simplified tissue ratio approach could be used to generate outcome measures.Conclusions: 18 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, 18 F-SMBT-1 brain distribution matches the reported in vitro distribution and captures the known MAO-B increases with age, suggesting 18 F-SMBT-1 can potentially be used as a surrogate marker of reactive astrogliosis. Further validation of these findings with 18 F-SMBT-1 will require examination of a much larger series, including participants with MCI and AD.

Assessing Reactive Astrogliosis with 18F-SMBT-1 Across the Alzheimer Disease Spectrum

“…Thresholds of 1.19 SUVR for 18 F-MK6240 and 1.20 SUVR for 18 F-PI2620 in the meta-temporal composite region (42) were used to categorize participants as high tau (T+) or low tau (T-). As previously described (31), assessment of the stability of potential reference regions for 18 F-SMBT-1 across age and across groups showed no associations with age, but the cerebellar cortex was significantly higher in A+ CN when compared to A-CN, precluding its use as reference region. Therefore, 18 F-SMBT-1 regional standard uptake values (SUV) at 60-80 min post injection were normalized using the subcortical white matter (SWM) as reference region to generate semiquantitative tissue ratios/SUVR.…”

“…Some participants (46 CN,6 MCI and 4 AD) were included in a previous study. (31) All participants were screened for unstable medical and/or psychiatric disease and concomitant medication. Participants with known use MAO-B inhibitors or with a diagnosis of a psychiatric disorder were excluded from the study.…”

“…In first-in-human studies, (31) 18 F-SMBT-1 showed robust entry into the brain and reversible binding kinetics, where quantitative and semiquantitative measures of 18 F-SMBT-1 binding were highly associated. More than 85% of 18 F-SMBT-1 signal was blocked by selegiline across the brain indicating high selectivity for MAO-B and low non-specific binding.…”

Astrocytes in Neurodegeneration: Inspiration From Genetics

“…A selective monoamine oxidase-B (MAO-B) tracer is also used to detect reactive astrogliosis since MAO-B is overexpressed in reactive astrocytes. The tracer identified the reactive astrogliosis in mild cognitive impairment (MCI) and AD (Vilemagne et al, 2022b) when compared to controls, and it was detectable at the preclinical stages of Aβ accumulation (Vilemagne et al, 2022a). Markers secreted by reactive astrocytes could also be implemented as a diagnostic tool in patients.…”

[64Cu]Cu-ATSM: an emerging theranostic agent for cancer and neuroinflammation

“…The first generation of MAO-B tracer of L-[ 11 C]deprenyl was originally developed in the 1980s [29]. Recently, a novel MAO-B tracer, [ 18 F] SMBT-1, was developed from the tau tracer, [ 18 F]THK-5351 [30,31]. [ 18 F]SMBT-1 displayed high binding affinity and COX is essential in the synthesis process of pro-inflammatory prostanoids, and their release as inflammatory mediators is significant to neuroinflammation.…”