Preclinical Characterization of the Tau PET Tracer [¹⁸F]SNFT-1: Comparison of Tau PET Tracers

Abstract

Tau PET tracers are expected to be sufficiently sensitive to track the progression of age-related tau pathology in the medial temporal cortex. The tau PET tracer N-(4-[ 18 F]fluoro-5-methylpyridin-2-yl)-7-aminoimidazo[1,2-a]pyridine ([ 18 F]SNFT-1) has been successfully developed by optimizing imidazo[1,2-a]pyridine derivatives. We characterized the binding properties of [ 18 F]SNFT-1 using a head-to-head comparison with other reported 18 F-labeled tau tracers. Methods: The binding affinity of SNFT-1 to tau, amyloid, and monoamine oxidase A and B was compared with that of the second-generation tau tracers MK-6240, PM-PBB3, PI-2620, RO6958948, JNJ-64326067, and flortaucipir. In vitro binding properties of 18 F-labeled tau tracers were evaluated through the autoradiography of frozen human brain tissues from patients with diverse neurodegenerative disease spectra. Pharmacokinetics, metabolism, and radiation dosimetry were assessed in normal mice after intravenous administration of [ 18 F]SNFT-1. Results: In vitro binding assays demonstrated that [ 18 F]SNFT-1 possesses high selectivity and high affinity for tau aggregates in Alzheimer disease (AD) brains. Autoradiographic analysis of tau deposits in medial temporal brain sections from patients with AD showed a higher signal-to-background ratio for [ 18 F]SNFT-1 than for the other tau PET tracers and no significant binding with non-AD tau, a-synuclein, transactiviation response DNA-binding protein-43, and transmembrane protein 106B aggregates in human brain sections. Furthermore, [ 18 F]SNFT-1 did not bind significantly to various receptors, ion channels, or transporters. [ 18 F]SNFT-1 showed a high initial brain uptake and rapid washout from the brains of normal mice without radiolabeled metabolites. Conclusion: These preclinical data suggest that [ 18 F]SNFT-1 is a promising and selective tau radiotracer candidate that allows the quantitative monitoring of age-related accumulation of tau aggregates in the human brain.

Early Diagnosis of Neurodegenerative Diseases: What Has Been Undertaken to Promote the Transition from PET to Fluorescence Tracers

“…With regard to biomarkers monitoring, most of the progress observed so far has come from the introduction of techniques enabling the identification of Tau species in large populations of patients, in non-invasive fluids, and the simultaneous monitoring of multiple Tau-related biomarkers. In addition, the discovery of PET tracers such as [ 18 F]-MK-6240, [ 18 F]-PI-2620, [ 18 F]-RO-948, and [ 18 F]-APN-1607 has enabled the discrimination of AD patients from controls, as displayed by in vivo studies [131][132][133][134]. Similarly, fluorescent probes such as Q-Tau 1 to 4, pTP-TFE and BT1 showed a low toxicity and high affinity for Tau aggregates towards Aβ 1-42 [157,161,164].…”

“…Moreover, several of these compounds showed improved pharmacokinetic properties and the ability to discriminate AD from non-AD tauopathies. Examples in this regard are the compounds [ 18 F]-MK-6240, [ 18 F]-PI-2620, [ 18 F]-RO-948, and [ 18 F]-APN-1607, which showed good performances in discriminating AD from non-AD patients in in vivo PET imaging studies [131][132][133][134], and also helping to detect low levels of Tau. Altogether, these data can offer insights into the design of compounds targeting Tau aggregates [135][136][137][138].…”

“…The utility of Tau PET tracers for the early diagnosis and monitoring of AD has also been studied in combination with assessments of phosphorylated Tau, providing remarkable results [139]. However, further research is needed to better assess their utility in clinical settings [103,119,131]. In particular, most of the studies reported so far focused on AD and related dementias, and, to a lesser extent, CBD (Corticobasal Degeneration), CTE (Chronic Traumatic Encephalopathy), FTLD (Frontotemporal Lobar Degeneration), PiD (Pick's Disease), and PSP (Progressive Supranuclear Palsy).…”