Development of [¹⁸F]SNFT‐1, a novel tau PET tracer with little off‐target binding

Abstract

Background [18F]THK‐5351, which was originally designed to detect tau aggregates, bound to monoamine oxidase B (MAO‐B) with high affinity. Lead optimization toward selective binding profiles to tau has resulted in the development of novel selective tau PET tracer named [18F]SNFT‐1 (THK‐5562). Here we present the preclinical characteristics of this tracer. Method In vitro competitive binding assays against MAO‐A, MAO‐B, amyloid, and tau were performed. In vitro autoradiography of the human brain tissues of various neurodegenerative diseases was performed. Receptor panel screen was performed to confirm the binding selectivity of this compound. Biodistribution study was performed in mice. In addition, an acute toxicity with intravenous administration of a single dose of this compound in mice was also investigated. Result SNFT‐1 showed high affinity (K d = 0.47 nM) and selectivity for tau aggregates over other misfolding proteins as well as MAO enzymes. In vitro autoradiography demonstrated the intense laminar binding of [18F]SNFT‐1 to tau pathology in AD and less off‐target binding than currently available tau PET tracers. No remarkable binding inhibition on various receptors ion channels, and transporters was observed at 1 μM concentration. [18F]SNFT‐1 showed good initial brain uptake and rapid washout without defluorination and troublesome radiolabeled metabolites in mice. In acute toxicity study, no drug‐related changes were noted after intravenous administration of this compound in mice. Conclusion [18F]SNFT‐1 is highly selective tau PET tracer, which will enable accurate monitoring of abnormal tau pathology in AD brain.

Amyloid and Tau Positron Emission Tomography Imaging in Alzheimer’s Disease and Other Tauopathies

“…Other off-target binding sites include neuromelanin and melanincontaining cells (Aguero et al, 2019), which [ 18 F]MK6240 tends to bind. The novel tracer [ 18 F]SNFT-1 (THK5562) might have overcome this drawback, as it demonstrated reduced off-target binding to MAO enzymes in preclinical animal experiments (Ishiki et al, 2020). While eminent research has been conducted on Aβ imaging, more insight into how Aβ structures, such as fibrils or protofibrils, are associated with pathology are to be provided.…”