Radiosynthesis and evaluation of a carbon-11 labeled PET ligand for imaging of O-GlcNAcase

O-GlcNAcase (OGA) is a key enzyme involved in regulating the dynamic cycling of O-GlcNAc modifications on intracellular proteins. OGA has emerged as a promising therapeutic target for neurodegenerative diseases, including Alzheimer's disease. In this report, we present the radiosynthesis and preclinical assessment of a novel carbon-11 labeled positron emission tomography (PET) radioligand [¹¹C]1 (codenamed OGA-2504) targeting OGA. The aminopyrimidine-based compound 1 and its corresponding desmethyl precursor were synthesized efficiently with good chemical yields. Radiosynthesis of [¹¹C]1 was accomplished <i>via</i> ¹¹C-methylation, yielding an 8% decay-corrected radiochemical yield with high purity (>98%) and high molar activity (92.5 GBq/µmol). [¹¹C]1 exhibited moderate lipophilicity (LogD = 2.11) and excellent <i>in vivo</i> stability in serum. However, preliminary PET imaging revealed low brain uptake and slow clearance of [¹¹C]1 in mice, suggesting a need for further structural optimization to enhance brain penetration.