In Vivo Imaging and Kinetic Modeling of Novel Glycogen Synthase Kinase-3 Radiotracers [C]OCM-44 and [F]OCM-50 in Non-Human Primates.

Glycogen synthase kinase 3 (GSK-3) is a potential therapeutic target for a range of neurodegenerative and psychiatric disorders. The goal of this work was to evaluate two leading GSK-3 positron emission tomography (PET) radioligands, [C]OCM-44 and [F]OCM-50, in non-human primates to assess their potential for clinical translation. A total of nine PET scans were performed with the two radiotracers using arterial blood sampling in adult rhesus macaques. Brain regional time-activity curves were extracted and fitted with one- and two-tissue compartment models using metabolite-corrected arterial input functions. Target selectivity was assessed after pre-administration of the GSK-3 inhibitor PF-04802367 (PF-367, 0.03-0.25 mg/kg). Both radiotracers showed good brain uptake and distribution throughout grey matter. [C]OCM-44 had a free fraction in the plasma of 3% at baseline and was metabolized quickly. The [C]OCM-44 volume of distribution () values in the brain increased with time; values from models fitted to truncated 60-min scan data were 1.4-2.9 mL/cm across brain regions. The plasma free fraction was 0.6% for [F]OCM-50 and values (120-min) were 0.39-0.87 mL/cm in grey matter regions. After correcting for plasma free fraction increases during blocking scans, reductions in regional indicated >80% target occupancy by 0.1 mg/kg of PF-367 for both radiotracers, supporting target selectivity in vivo. [C]OCM-44 and [F]OCM-50 warrant further evaluation as radioligands for imaging GSK-3 in the brain, though radio-metabolite accumulation may confound image analysis.