¹⁸F-SMBT-1: A Selective and Reversible PET Tracer for Monoamine Oxidase-B Imaging

Abstract

Reactive astrocytes play a key role in the pathogenesis of various neurodegenerative diseases. Monoamine oxidase-B (MAO-B) is one of the promising targets for the imaging of astrogliosis in the human brain. A novel selective and reversible MAO-B tracer, (S)-(2-methylpyrid-5-yl)-6-[(3-[ 18 F]fluoro-2hydroxy)propoxy]quinoline, ( 18 F-SMBT-1), was successfully developed via lead optimization from firstgeneration tau positron-emission tomography (PET) tracer 18 F-THK-5351. Methods: SMBT-1 was radiolabeled with fluorine-18 using the corresponding precursor. The binding affinity of radiolabeled compounds to MAO-B was assessed using saturation and competitive binding assays. The binding selectivity of 18 F-SMBT-1 to MAO-B was evaluated by autoradiography of frozen human brain tissues. The pharmacokinetics (PK) and metabolism were assessed in normal mice after intravenous administration of 18 F-SMBT-1. A 14-day toxicity study following the intravenous administration of SMBT-1 was performed using rats and mice. Results: In vitro binding assays demonstrated a high binding affinity of SMBT-1 to MAO-B (K D = 3.7 nM). In contrast, it showed low binding affinity to MAO-A and protein aggregates such as amyloid-β and tau fibrils. Autoradiographic analysis showed higher amounts of 18 F-SMBT-1 binding in the Alzheimer's disease (AD) brain sections than in the control brain sections. 18 F-SMBT-1 binding was completely displaced with reversible MAO-B inhibitor lazabemide, demonstrating the high selectivity of 18 F-SMBT-1 for MAO-B. Furthermore, 18 F-SMBT-1 showed a high uptake by brain, rapid washout, and no 4 radiolabeled metabolites in the brain of normal mice. SMBT-1 showed no significant binding to various receptors, ion channels, and transporters, and no toxic effects related to its administration were observed in mice and rats. Conclusion: 18 F-SMBT-1 is a promising and selective MAO-B PET tracer candidate, which would be useful for quantitative monitoring of astrogliosis in the human brain.

In vitro Characterization of the Regional Binding Distribution of Amyloid PET Tracer Florbetaben and the Glia Tracers Deprenyl and PK11195 in Autopsy Alzheimer’s Brain Tissue

“…Novel TSPO tracers with improved binding specificity, SNR and higher brain uptake was pursued, such as 18 F-GE-180 [73], 11 C-PBR28 [74], 11 C-DAA1106 [34], 11 C-vinpocetine [75], 18 F-DPA-714 [76], 18 F-FEPPA [77], and 11 C-AC5216 [78]. In addition, new tracers for imaging neuroinflammation beyond TSPO are under development for microgliosis [79,80] and astrogliosis [4] (including novel MAO-B tracer [81]). Elucidating the cellular origin of the radiotracer binding such as TSPO binding [82] and whether they are selective for pro-inflammatory astrocytes and microglia will be critical [83].…”

Reactive astrocytes: The nexus of pathological and clinical hallmarks of Alzheimer’s disease

“…In humans, most of the evidence supporting the early emergence of reactive astrocytes comes from studies on postmortem tissue showing that GFAP and/or a number of other astrocyte-related proteins and mRNA species are altered in individuals with mild cognitive impairment (MCI) or pre-clinical AD ( Schipper et al, 2006 ; Assaraf et al, 2007 ; Abdul et al, 2009 ; Owen et al, 2009 ). In the last decade, postmortem evidence for the early appearance of astrocyte reactivity has been confirmed in human subjects using positron emission tomography (PET) and novel PET tracers, like 11 C-deuterium-L-deprenyl ( 11 C-DED) and (S)-(2-methylpyrid-5-yl)-6-[(3-[ 18 F]fluoro-2-hydroxy)propoxy]quinoline ( 18 F-SMBT-1), which bind to the reactive astrocyte marker monoamine oxidase B (MAO-B) ( Carter et al, 2012 ; Harada et al, 2020 ). Nordberg and colleagues have used 11 C-DED to reveal significant elevations in astrocyte reactivity throughout many cortical and subcortical regions in living humans with MCI, relative to age-matched healthy controls ( Carter et al, 2012 ).…”

Investigation of reactive astrogliosis effect on post-stroke cognitive impairment

“…The utility of 11 C-DED radiotracer is limited by the short half-life of carbon-11 and their suboptimal binding specificity [56]. The 18 F-SMBT-1 radiotracer is a derivative of the 18 F-THK-5351 compound, and has shown high specificity to astrogliosis in an animal study recently [57]. The application of 18 F-SMBT-1 PET in stroke patients may further substantiate the role of RA in PSCI occurrence.…”