Radiosynthesis and in Vivo Evaluation of [11C]A1070722, a High Affinity GSK-3 PET Tracer in Primate Brain.
Jaya PrabhakaranFrancesca ZanderigoKiran Kumar Solingapuram SaiHarry Rubin-FalconeMatthew J JorgensenJay R KaplanAkiva MintzJ John MannJ S Dileep KumarPublished in: ACS chemical neuroscience (2017)
Dysfunction of glycogen synthase kinase 3 (GSK-3) is implicated in the etiology of Alzheimer's disease, Parkinson's disease, diabetes, pain, and cancer. A radiotracer for functional positron emission tomography (PET) imaging could be used to study the kinase in brain disorders and to facilitate the development of small molecule inhibitors of GSK-3 for treatment. At present, there is no target-specific or validated PET tracer available for the in vivo monitoring of GSK-3. We radiolabeled the small molecule inhibitor [11C]1-(7-methoxy- quinolin-4-yl)-3-(6-(trifluoromethyl)pyridin-2-yl)urea ([11C]A1070722) with high affinity to GSK-3 (Ki = 0.6 nM) in excellent radiochemical yield. PET imaging experiments in anesthetized vervet/African green monkey exhibited that [11C]A1070722 penetrated the blood-brain barrier (BBB) and accumulated in brain regions, with highest radioactivity binding in frontal cortex followed by parietal cortex and anterior cingulate, and with the lowest bindings found in caudate, putamen, and thalamus, similarly to the known distribution of GSK-3 in human brain. Our studies suggest that [11C]A1070722 can be a potential PET radiotracer for the in vivo quantification of GSK-3 in brain.
Keyphrases
- pet imaging
- positron emission tomography
- resting state
- pi k akt
- functional connectivity
- small molecule
- signaling pathway
- computed tomography
- white matter
- cardiovascular disease
- pet ct
- blood brain barrier
- working memory
- cell proliferation
- tyrosine kinase
- neuropathic pain
- spinal cord injury
- chronic pain
- radiation therapy
- young adults
- oxidative stress
- cognitive decline
- adipose tissue
- pain management
- lymph node
- binding protein
- combination therapy
- glycemic control
- locally advanced