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

Imaging O-GlcNAcase OGA by positronemission tomography(PET) could provide information on the pathophysiological pathwayof neurodegenerative diseases and important information on drug-targetengagement and be helpful in dose selection of therapeutic drugs.Our aim was to develop an efficient synthetic method for labelingBIO-1819578 with carbon-11 using (CO)-C-11 for evaluation ofits potential to measure levels of OGA enzyme in non-human primate(NHP) brain using PET. Radiolabeling was achieved in one-pot via acarbon-11 carbonylation reaction using [C-11]CO. The detailedregional brain distribution of [C-11]BIO-1819578 bindingwas evaluated using PET measurements in NHPs. Brain radioactivitywas measured for 93 min using a high-resolution PET system, and radiometaboliteswere measured in monkey plasma using gradient radio HPLC. Radiolabelingof [C-11]BIO-1819578 was successfully accomplished, andthe product was found to be stable at 1 h after formulation. [C-11]BIO-1819578 was characterized in the cynomolgus monkeybrain where a high brain uptake was found (7 SUV at 4 min). A pronouncedpretreatment effect was found, indicating specific binding to OGAenzyme. Radiolabeling of [C-11]BIO-1819578 with [C-11]CO was successfully accomplished. [C-11]BIO-1819578 bindsspecifically to OGA enzyme. The results suggest that [C-11]BIO-1819578 is a potential radioligand for imaging and for measuringtarget engagement of OGA in the human brain.

Automated summary

Imaging O-GlcNAcase OGA using positron emission tomography (PET) can provide important information on neurodegenerative diseases and drug-target engagement. This study aimed to develop a method for labeling BIO-1819578 with carbon-11 using CO-C-11 and evaluate its potential for measuring OGA enzyme levels in non-human primate brains. Radiolabeling was achieved through a one-pot carbonylation reaction using C-11 carbon monoxide. PET measurements were used to evaluate the brain distribution of [C-11]BIO-1819578 in non-human primates, showing specific binding to the OGA enzyme. This suggests that [C-11]BIO-1819578 has potential as a radioligand for imaging and measuring OGA target engagement in the human brain.