Radiosynthesis and evaluation of [¹¹C]CMP, a high affinity GSK3 ligand

Area of Science:

• Neuroscience
• Radiochemistry
• Pharmacology

Background:

• Glycogen synthase kinase 3 (GSK3) dysfunction is linked to brain diseases, inflammation, cardiac conditions, and cancer.
• Positron Emission Tomography (PET) imaging offers in vivo detection and quantification of GSK3, potentially guiding therapy and monitoring disease progression.

Purpose of the Study:

• To synthesize and evaluate a novel high-affinity GSK3 ligand, [11C]2-(cyclopropanecarboxamido)-N-(4-methoxypyridin-3-yl)isonicotinamide ([11C]CMP), for PET imaging applications.
• To assess the in vivo performance of [11C]CMP in terms of brain penetration and binding.

Main Methods:

• Synthesis of [11C]CMP via radiomethylation of the corresponding phenolate using [11C]CH3I.
• Evaluation of radioligand affinity (IC50) and lipophilicity (LogP).
• Assessment of [11C]CMP uptake and specific binding in U251 human glioblastoma cells and via MicroPET studies in rats, including experiments with cyclosporine administration.

Main Results:

• [11C]CMP demonstrated high affinity for GSK3 (IC50 = 3.4 nM) and a suitable LogP (1.1).
• The radioligand showed modest uptake with approximately 50% specific binding in U251 cells.
• MicroPET studies revealed negligible blood-brain barrier (BBB) penetration of [11C]CMP in rats.
• Cyclosporine pretreatment significantly enhanced brain radioactivity uptake and tracer binding, indicating P-gp efflux substrate activity.

Conclusions:

• [11C]CMP is a high-affinity GSK3 ligand with potential for PET imaging.
• Its limited BBB penetration in rats, likely due to P-gp efflux, poses challenges for routine in vivo brain PET evaluations.
• Further investigation may be needed to overcome efflux limitations for effective brain imaging of GSK3.