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

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.