PET tracer SMBT‐1 discriminates between BU99008 and Deprenyl binding sites on reactive astrocytes in Alzheimer's disease brains

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AbstractBackgroundAstrocytes are the homeostatic cells of the mammalian brain. We recently proposed a “two‐wave” hypothetical model in which reactive astrocytes (RA) are early‐responders to Alzheimer’s disease (AD) pathology and may support a perpetual brain inflammatory state1. Advances in positron emission tomography (PET) imaging biomarkers allow for detecting RA in the early stages of AD (e.g., [11C]‐L‐Deprenyl and [11C]BU99008, which target MAO‐B and the imidazole binding sites 2 – I2Bs, respectively). However, RA assume multiple states, thus, a very heterogenous population of RA exist. Based on a recent consensus, the development of novel PET‐tracers targeting different RA populations is a priority in the field. [18F]‐SMBT‐1, a selective MAO‐B PET‐tracer, was recently designed as an alternative to detect RA in the human brain. However, further studies using [18F]‐SMBT‐1 are needed to evaluate its sensitivity to image RA in AD. We aimed at evaluating the binding properties of SMBT‐1 versus two PET‐tracers targeting RA ‐ [3H]‐L‐Deprenyl and [3H]‐BU99008 ‐ using in vitro human brain techniques.MethodCompetition binding assays for [3H]‐L‐Deprenyl and [3H]‐BU99008 versus SMBT‐1 were performed in postmortem temporal cortex brain homogenate. The number of binding sites and their affinities (IC50 ; half‐maximal inhibitory concentration) as well as percentage were calculated in AD and control brainsResultOur competition binding assays in temporal cortex tissue revealed that SMBT‐1 competes for a single binding site versus [3H]‐L‐Deprenyl in AD (IC50 = 1.141 x 10‐8) and control (IC50 = 1.93 x 10‐8) human brains. Remarkably, SMBT‐1 also competes for [3H]‐BU99008 binding sites in both AD (IC50 = 1.09 x 10‐13 and IC50 = 3.36 x 10‐8, 31% in the high fraction) and control (IC50 = 3.51 x 10‐13 and IC50 = 1.06 x 10‐6, 30% in the high fraction) cases.ConclusionSMBT‐1 competes with [3H]‐L‐Deprenyl for the high affinity MAO‐B binding site and displaces [3H]‐BU99008 binding to the I2Bs. The presence of I2Bs in the entrance channel of MAO‐B may explain this behavior, as SMBT‐1 potentially causes steric hinderance, affecting the availability of this binding site.