We found a match
Your institution may have rights to this item. Sign in to continue.
- Title
In Vivo Imaging and Kinetic Modeling of Novel Glycogen Synthase Kinase-3 Radiotracers [ 11 C]OCM-44 and [ 18 F]OCM-50 in Non-Human Primates.
- Authors
Smart, Kelly; Zheng, Ming-Qiang; Holden, Daniel; Felchner, Zachary; Zhang, Li; Han, Yanjiang; Ropchan, Jim; Carson, Richard E.; Vasdev, Neil; Huang, Yiyun
- 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.
- Subjects
GLYCOGEN synthase kinase-3; GLYCOGEN synthase kinase; RADIOACTIVE tracers; POSITRON emission tomography; PRIMATES
- Publication
Pharmaceuticals (14248247), 2023, Vol 16, Issue 2, p194
- ISSN
1424-8247
- Publication type
Article
- DOI
10.3390/ph16020194