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In vivo quantification of [11C]BIO-1819578 in non-human primates, a novel radioligand for O-GlcNAcase

Martin Bolin,S. Nag,Ryosuke Arakawa,Andrea Varrone,L. Farde,Laurent Martarello,Maciej Kaliszczak,C. Halldin,A. Morén

Published 2025 in Journal of Cerebral Blood Flow and Metabolism

ABSTRACT

Neurofibrillary tangles (NFTs), composed of aggregated tau protein, in the brain is a neuropathological hallmark and feature of Alzheimer’s disease (AD) and other tauopathies. One promising approach to prevent tau aggregates is to inhibit O-GlcNAcase (OGA), an enzyme that regulates tau O-GlcNAcylation. [11C]BIO-1819578 has emerged as a promising candidate to determine target occupancy of such OGA inhibitor drugs. The aim of this study was to further evaluate the pharmacokinetic properties of [11C]BIO-1819578 in non-human primates (NHPs) and to estimate its effective dose. Kinetic compartment analyses of [11C]BIO-1819578 binding to OGA in the brain were performed on positron emission tomography (PET) measurements conducted in three cynomolgus NHPs. Whole-body PET measurements were carried out in two NHPs to estimate the effective radiation dose. Both the 1-tissue-compartment (1TCM) and 2-tissue-compartment model (2TCM) could describe the regional time activity curves of [11C]BIO-1819578. The 2TCM was the statistically preferred model. The effective radiation dose was estimated to be 0.0033 mSv/MBq. The results showed that [11C]BIO-1819578 has suitable characteristics for reliable quantification of OGA using full kinetic modelling. The effective dose was on par with other 11C radioligands and is unlikely to pose an issue for human use.

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