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

The Journal of Nuclear Medicine

article

Victor L. Villemagne¹  Ryuichi Harada²  Vincent Doré³  Shozo Furumoto⁴  Rachel Mulligan³  Yukitsuka Kudo⁵  Samantha Burnham⁶  Natasha Krishnadas³  Svetlana Bozinovski³  Kun Huang³  Brian J. Lopresti⁷  Kazuhiko Yanai²  Christopher C. Rowe³  Nobuyuki Okamura^1,10 

[1] Department of Psychiatry, University of Pittsburgh;Department of Pharmacology, Tohoku University School of Medicine;Department of Molecular Imaging and Therapy, Austin Health;Cyclotron and Radioisotope Center, Tohoku University;Institute of Development of Aging and Cancer, Tohoku University;CSIRO Health and Biosecurity Flagship: Australian e-Health Research Centre;Department of Radiology, University of Pittsburgh;Florey Institute of Neuroscience and Mental Health, University of Melbourne;Australian Dementia Network;Division of Pharmacology, Faculty of Medicine, Tohoku Medical and Pharmaceutical University

关键词: reactive astrogliosis;    MAO-B;    Alzheimer disease;    amyloid;    brain imaging;   

DOI  :  10.2967/jnumed.121.263254

学科分类：医学（综合）

来源: Society of Nuclear Medicine

【 摘 要 】

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 18F-(S)-(2-methylpyrid-5-yl)-6-[(3-fluoro-2-hydroxy)propoxy]quinoline (18F-SMBT-1), a novel MAO-B PET tracer as a potential surrogate marker of reactive astrogliosis. Methods: 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 18F-SMBT-1 PET. To ascertain 18F-SMBT-1 selectivity to MAO-B, 9 participants underwent 2 18F-SMBT-1 scans, before and after receiving 5 mg of selegiline twice daily for 5 d. To compare selectivity, 18F-THK5351 studies were also conducted before and after selegiline. Amyloid-β burden was expressed in centiloids. 18F-SMBT-1 outcomes were expressed as SUV, as well as tissue ratios and binding parameters using the subcortical white matter as a reference region. Results: 18F-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 (R2 = 0.84). More than 85% of 18F-SMBT-1 signal was blocked by selegiline across the brain, and in contrast to 18F-THK5351, no residual cortical activity was observed after the selegiline regimen, indicating high selectivity for MAO-B and low nonspecific binding. 18F-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 18F-SMBT-1 binding were strongly associated (R2 0.94), suggesting that a simplified tissue-ratio approach could be used to generate outcome measures. Conclusion: 18F-SMBT-1 is a highly selective MAO-B tracer, with low nonspecific binding, high entry into the brain, and reversible kinetics. Moreover, 18F-SMBT-1 brain distribution matches the reported in vitro distribution and captures the known MAO-B increases with age, suggesting that 18F-SMBT-1 can potentially be used as a surrogate marker of reactive astrogliosis. Further validation of these findings with 18F-SMBT-1 will require examination of a much larger series, including participants with mild cognitive impairment and AD.

【 授权许可】

CC BY