Development of a Novel [(11)C]CO-Labeled Positron Emission Tomography Radioligand [(11)C]BIO-1819578 for the Detection of O-GlcNAcase Enzyme Activity

[Image: see text] Imaging O-GlcNAcase OGA by positron emission tomography (PET) could provide information on the pathophysiological pathway of neurodegenerative diseases and important information on drug-target engagement and be helpful in dose selection of therapeutic drugs. Our aim was to develop an efficient synthetic method for labeling BIO-1819578 with carbon-11 using (11)CO for evaluation of its potential to measure levels of OGA enzyme in non-human primate (NHP) brain using PET. Radiolabeling was achieved in one-pot via a carbon-11 carbonylation reaction using [(11)C]CO. The detailed regional brain distribution of [(11)C]BIO-1819578 binding was evaluated using PET measurements in NHPs. Brain radioactivity was measured for 93 min using a high-resolution PET system, and radiometabolites were measured in monkey plasma using gradient radio HPLC. Radiolabeling of [(11)C]BIO-1819578 was successfully accomplished, and the product was found to be stable at 1 h after formulation. [(11)C]BIO-1819578 was characterized in the cynomolgus monkey brain where a high brain uptake was found (7 SUV at 4 min). A pronounced pretreatment effect was found, indicating specific binding to OGA enzyme. Radiolabeling of [(11)C]BIO-1819578 with [(11)C]CO was successfully accomplished. [(11)C]BIO-1819578 binds specifically to OGA enzyme. The results suggest that [(11)C]BIO-1819578 is a potential radioligand for imaging and for measuring target engagement of OGA in the human brain.