Synthesis and Initial in Vivo Studies with [¹¹C]SB-216763: The First Radiolabeled Brain Penetrative Inhibitor of GSK-3

Abstract

Quantifying glycogen synthase kinase-3 (GSK-3) activity in vivo using positron emission tomography (PET) imaging is of interest because dysregulation of GSK-3 is implicated in numerous diseases and neurological disorders for which GSK-3 inhibitors are being considered as therapeutic strategies. Previous PET radiotracers for GSK-3 have been reported, but none of the published examples cross the blood− brain barrier. Therefore, we have an ongoing interest in developing a brain penetrating radiotracer for GSK-3. To this end, we were interested in synthesis and preclinical evaluation of [ 11 C]SB-216763, a high-affinity inhibitor of GSK-3 (K i = 9 nM; IC 50 = 34 nM). Initial radiosyntheses of [ 11 C]SB-216763 proved ineffective in our hands because of competing [3 + 3] sigmatropic shifts. Therefore, we have developed a novel one-pot two-step synthesis of [ 11 C]SB-216763 from a 2,4-dimethoxybenzyl-protected maleimide precursor, which provided high specific activity [ 11 C]SB-216763 in 1% noncorrected radiochemical yield (based upon [ 11 C]CH 3 I) and 97−100% radiochemical purity (n = 7). Initial preclinical evaluation in rodent and nonhuman primate PET imaging studies revealed high initial brain uptake (peak rodent SUV = 2.5 @ 3 min postinjection; peak nonhuman primate SUV = 1.9 @ 5 min postinjection) followed by washout. Brain uptake was highest in thalamus, striatum, cortex, and cerebellum, areas known to be rich in GSK-3. These results make the arylindolemaleimide skeleton our lead scaffold for developing a PET radiotracer for quantification of GSK-3 density in vivo and ultimately translating it into clinical use.

Synthesis and Evaluation of [18F]RAGER: A First Generation Small-Molecule PET Radioligand Targeting the Receptor for Advanced Glycation Endproducts

“…To this end, our lab and others have been working extensively to develop PET probes relevant to AD outside the scope of traditional Aβ targeting, such as radioligands with affinity for metal-Aβ species, 11,12 glutaminyl-cyclase, 13 and glycogen synthase kinase-3. 14 Notably, we are increasingly interested in using PET to understand mechanisms underlying the increased accumulation of amyloid in the central nervous system (CNS) in AD. This includes potential upregulation of mediators responsible for moving amyloid across the blood-brain barrier into the CNS (e.g.…”

Radiosynthesis and in Vivo Evaluation of [11C]A1070722, a High Affinity GSK-3 PET Tracer in Primate Brain

“…26,27 [ 11 C]SB-216763 ( K i = 9 nM) penetrates the BBB in mice and baboon, but shows homogeneous distribution. 28–30 In vivo evaluation of a series of [ 11 C]labeled oxindole analogues (IC 50 = 66–35 nM) also was proven unsuccessful in normal and cold water stress (CWS)-induced tau hyperphosphorylation mice model. 31 Although 11C-radiolabeling of the nonselective CDK-GSK-3 tracer meisoindigotin has been reported, no in vivo data are available yet.…”

Discovery of a Highly Selective Glycogen Synthase Kinase‐3 Inhibitor (PF‐04802367) That Modulates Tau Phosphorylation in the Brain: Translation for PET Neuroimaging

“…[ 11 C]SB-216763 showed good brain uptake in rodents and non-human primates (NHPs) but was not selective against other structurally similar kinases. [11] [ 11 C]PyrATP-1 [12] and 11 C-oxadiazole [13] based radiotracers failed to show appreciable uptake in vivo . None of the PET radiotracers for GSK-3 has yet proven to be successful for in vivo imaging studies with specificity and/or suitable brain uptake (Figure 1).…”