In Vivo Imaging and Kinetic Modeling of Novel Glycogen Synthase Kinase-3 Radiotracers [11C]OCM-44 and [18F]OCM-50 in Non-Human Primates

Abstract

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, [11C]OCM-44 and [18F]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. [11C]OCM-44 had a free fraction in the plasma of 3% at baseline and was metabolized quickly. The [11C]OCM-44 volume of distribution (VT) values in the brain increased with time; VT values from models fitted to truncated 60-min scan data were 1.4–2.9 mL/cm3 across brain regions. The plasma free fraction was 0.6% for [18F]OCM-50 and VT values (120-min) were 0.39–0.87 mL/cm3 in grey matter regions. After correcting for plasma free fraction increases during blocking scans, reductions in regional VT indicated >80% target occupancy by 0.1 mg/kg of PF-367 for both radiotracers, supporting target selectivity in vivo. [11C]OCM-44 and [18F]OCM-50 warrant further evaluation as radioligands for imaging GSK-3 in the brain, though radio-metabolite accumulation may confound image analysis.

Strategies for designing novel positron emission tomography (PET) radiotracers to cross the blood–brain barrier

“…Unfortunately, BBB-permeable radiometabolites of [ 11 C]OCM-44 were observed in NHPs and mice. 112,115 The lead 18 F-labeled analog, [ 18 F]OCM-50 (Figure 6), demonstrated peak SUV 2.0 in both Sprague-Dawley rats and NHPs. 113 Our recent F I G U R E 6 Structures of GSK-3 PET radiotracers showing improved BBB permeability with minor structural modifications.…”

“…We proceeded to develop second generation radiotracers for GSK‐3 based on PF‐367, and the highest brain uptake was observed with [ 11 C]OCM‐44 (Figure 6), which displayed a three‐fold increase in peak NHP brain uptake compared with [ 11 C]PF‐367. Unfortunately, BBB‐permeable radiometabolites of [ 11 C]OCM‐44 were observed in NHPs and mice 112,115 . The lead 18 F‐labeled analog, [ 18 F]OCM‐50 (Figure 6), demonstrated peak SUV 2.0 in both Sprague‐Dawley rats and NHPs 113 .…”

Radiolabeled imaging agents for Alzheimer's disease

“…Smart et al. recently reported a PET study using [ 11 C]OCM‐44 and [ 18 F]OCM‐50 in nonhuman primates [87]. Both radiotracers displayed good brain uptake and distribution in gray matter; however, radiometabolite accumulation may confound image analysis [87].…”

“…[ 11 C]OCM-44 was identified as a lead Glycogen synthase kinase 3 radiotracer with optimized brain uptake by PET imaging in nonhuman primates, and further assessment revealed that [ 11 C]OCM-51 is highly potent (IC 50 = 0.030 nM) and selective (over 10-fold GSK-3β/GSK-3α) for GSK-3β [86]. Both radiotracers displayed good brain uptake and distribution in gray matter; however, radiometabolite accumulation may confound image analysis [87].…”

“…Smart et al recently reported a PET study using [ 11 C] OCM-44 and [ 18F]OCM-50 in nonhuman primates[87].…”