Evaluation of the novel 18F‐labeled PET tracer SMBT‐1 for imaging astrogliosis in healthy elderly controls and A+/T+/(N+) Alzheimer's disease patients: Neuroimaging: Novel imaging methods. (7th December 2020)

• Record Type: Journal Article
• Authors: Villemagne, Victor LL; Harada, Ryuichi; Dore, Vincent; Furumoto, Shozo; Mulligan, Rachel S; Kudo, Yukitsuka; Burnham, Samantha C; Krishnadas, Natasha; Huang, Kun; Yanai, Kazuhiko; Rowe, Christopher C; Okamura, Nobuyuki
• Is Part Of: Alzheimer's & dementia. Volume 16(2020)Supplement 4
• Page Start: n/a
• Page End: n/a
• Publication Date: 2020-12-07
• Subjects: Alzheimer's disease -- Periodicals; Alzheimer Disease -- Periodicals; Dementia -- Periodicals; Démence; Maladie d'Alzheimer; Périodique électronique (Descripteur de forme); Ressource Internet (Descripteur de forme); 616.83
• DOI: 10.1002/alz.039858
• Languages: English
• ISSNs: 1552-5260

Abstract

Abstract: 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 18 F‐SMBT‐1. We aimed to investigate the binding properties of 18 F‐SMBT‐1 in healthy elderly controls and AD patients. Methods: After in silico preclinical evaluation were performed for the assessment of binding affinity and selectivity of 18 F‐SMBT‐1, 9 participants, 5 healthy elderly controls (3F/2M, 78.5±6.0 yrs, 3 A‐/T‐/(N‐) and 2 A+/T‐/(N‐)) and 4 A+/T+/(N+) AD patients (3F/1M, 76.8±1.4 yrs), underwent 18 F‐SMBT‐1 PET, amyloid PET with 18 F‐NAV4694, tau PET with either 18 F‐MK6240 (n=7) or 18 F‐PI2620 (n=2), and 3D‐MPRAGE MRI. While Ab burden was expressed in Centiloids, tau tissue ratios were generated using the cerebellar cortex as reference region. 18 F‐SMBT‐1 studies were expressed as SUV or as tissue ratios using the cerebellar white matter as reference region. To ascertain 18 F‐SMBT‐1 selective binding to MAO‐B, participants underwent a second 18 F‐SMBT‐1 scan after receiving 5mg selegiline twice daily for 5 days. Results: SMBT‐1 showed strong and reversible binding to MAO‐B, and low binding affinity to other enzymes, receptors and misfolded proteins such as amyloid‐β and tau. 18 F‐SMBT‐1 yielded high contrast images at 60‐90 min post injection, with high tracer retention in basal ganglia, intermediate in neocortical regions, and lowest in cerebellum which tightly follows the known regional brain distribution of MAO‐B (R 2 =0.82). In AD patients, 18 F‐SMBT‐1 retention was significantly higher in parahippocampus, fusiform and inferior temporal gyrus. More than 85% of 18 F‐SMBT‐1 signal was blocked and no residual cortical activity was observed after the selegiline regimen, indicating high selectivity for MAO‐B. Conclusions: 18 F‐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 18 F‐SMBT‐1 will require examination of a much larger series, including participants with MCI and prodromal AD.