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

Area of Science:

• Biochemistry
• Neuroscience
• Radiochemistry

Background:

• O-GlcNAcase (OGA) regulates intracellular O-GlcNAc protein modifications.
• OGA is a potential therapeutic target for neurodegenerative diseases like Alzheimer's disease.

Purpose of the Study:

• To develop and evaluate a novel carbon-11 labeled PET radioligand, [¹¹C]1 (OGA-2504), for targeting OGA.
• To assess the radiosynthesis, preclinical properties, and brain uptake of [¹¹C]1 in a mouse model.

Main Methods:

• Radiosynthesis of [¹¹C]1 via ¹¹C-methylation.
• Assessment of radiochemical yield, purity, molar activity, lipophilicity, and in vivo stability.
• Preclinical PET imaging in mice to evaluate brain uptake and clearance.

Main Results:

• Efficient synthesis of [¹¹C]1 with good yield, high purity (>98%), and high molar activity (92.5 GBq/µmol).
• [¹¹C]1 demonstrated moderate lipophilicity (LogD = 2.11) and excellent in vivo serum stability.
• Preliminary PET imaging revealed low brain uptake and slow clearance of [¹¹C]1 in mice.

Conclusions:

• The novel PET radioligand [¹¹C]1 shows promising characteristics for OGA imaging but requires further optimization.
• Structural modifications are necessary to enhance brain penetration and improve its utility for neurodegenerative disease research.