Glycogen Synthase Kinase 3β Inhibitor Scaffolds for PET Radiotracer Development

Objectives Glycogen Synthase Kinase-3β (GSK3β) dysregulation is implicated in prevalent neurodegenerative diseases, which feature neurological changes prior to the onset of clinical symptoms. As such, treatment success in GSK3β-mediated diseases using GSK3β inhibitors is predicated on early detection of enzyme dysregulation. This, in turn, necessitates the development of GSK3β-specific probes that can identify these subclinical changes. Two tracers, [¹¹C]PyrATP-1 and [¹¹C]AR-A014418, were previously evaluated for this purpose by our group (Nucl. Med. Biol. 2014) and the Vasdev group (Bioorg. Med. Chem. Lett. 2005), respectively, but neither crossed the blood brain barrier in vivo. Reflecting this, we have an agressive program to develop a PET radiotracer for GSK3β that is urgently evaluating 3 new scaffolds: [¹¹C]SB-216763 (arylindolemaleimide 1), [¹⁸F]4FPB (halomethylketone 2), and [¹⁸F]VP1.15 (iminothiadiazole 3).

Methods Precursors were synthesized in house and radiolabeled with [¹⁸F]KF or [¹¹C]MeI using standard automated synthesis modules. Preclinical evaluation was conducted using autoradiography and/or microPET imaging (rodent and/or non-human primate).

Results [¹¹C]SB-216763 (1) was synthesized in 1% RCY, and microPET imaging in rodents and non-human primates displayed good uptake in areas of the brain rich in GSK3β (SUV = 2-2.5). 4-Pinacolboraneacetophenone was fluorinated using Gouverneur's procedure (ACIE, 2014) to obtain 4-¹⁸F-acetophenone in 48% RCY, which was subsequently brominated to obtain [¹⁸F]4FPB (2) in good yield. Autoradiography / microPET experiments are in progress for this new radiotracer. Attempts to prepare VP1.15 (3) from diphenylphosphoryl and 4-nitrophenyl precursors are ongoing.

Conclusions New GSK3β inihibitor scaffolds have been radiolabeled using ¹¹C or ¹⁸F. Initial pre-clinical evaluation using autoradiography and microPET has revealed promising imaging properties, and tracers are currently being optimized and considered for translation into clinical imaging studies.

Research Support Financial support of this research by the US DOE/NIBIB (DE-SC0012484), NIH (T32-EB005172) and Alzheimer’s Association (NIRP-14-305669) is gratefully acknowledged.