Glycogen Synthase Kinase-3 Maleimide Inhibitors As Potential PET-Tracers for Imaging Alzheimer’s Disease: ¹¹C-Synthesis and In Vivo Proof of Concept

Abstract

Herein we present the evaluation of 11C-labeled-maleimides as radiotracers for positron emission tomography imaging of GSK-3 associated with Alzheimer′s disease (AD). 3-Acetyl-4-(1-[11C]-methyl-1H-indol-3-yl)­[1H]­pyrrole-2,5-dione ([11C]-2) was obtained by direct methylation using [11C]-CH3I and Cs2CO3 in DMF with a 31 ± 4% radiochemical yield and a radiochemical purity of 97.7 ± 0.8%. [11C]-2 was stable both in its final formulation and in human plasma for 120 min and had a plasma protein binding of 70 ± 1% and a LogD7.4 value of 1.84 ± 0.04. [11C]-2 ex vivo biodistributions in healthy animals demonstrated significant brain uptake and retention, showing its ability to penetrate the intact blood–brain barrier. In vivo PET imaging in mice bearing AD showed, with respect to normal animals, significant differences in uptake in the hypothalamus, the striatum, and the amygdala and a significant increase in amygdala uptake in later stages of the pathology. These results are very promising, and further studies are being performed for a complete validation of this compound as novel tracer for AD.

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

“…Subsequently, radiotracers based on PF-367 (including OCM-44) were applied to measure GSK-3 binding in vitro in both a preclinical model of Alzheimer’s disease and in post-mortem human brain tissue, which provides preliminary evidence of intriguing disease- and sex-related differences in binding [ 20 ] and underscores the utility of these radiotracers in brain research. Despite persistent efforts [ 12 , 13 , 14 , 15 , 21 ], it has been a challenge to develop a radioligand suitable for in vivo brain imaging of GSK-3 in clinical research. The present work is a notable step forward in these efforts, with thorough characterization in non-human primates of [ 11 C]OCM-44 and [ 18 F]OCM-50, the first GSK-3 radioligands to date demonstrated to enter the brain and show kinetics amenable to quantification.…”

Positron Emission Tomography in Animal Models of Alzheimer’s Disease Amyloidosis

“…In addition to the aforementioned targets, many emerging targets show potential as indicators for pathological alterations in AD, and are yet to be further investigated in amyloidosis animal models, such as 1) metal dysregulation and copper trafficking e.g. using [ 64 Cu]GTSM [208]; 2) reactive oxygen species [209] and pH alterations [210]; 3) microtubule using [ 11 [214][215][216]: 5) mitochondria imaging using [ 18 F]BCPP-EF [217]; and 6) Glycogen Synthase Kinase-3 imaging using [ 11 C]2, [ 11 C]OCM-44, [ 3 H]PF-367 [218,219].…”

Identifying Potential Ligand Binding Sites on Glycogen Synthase Kinase 3 Using Atomistic Cosolvent Simulations

“…Not surprisingly, abnormal activity of GSK3 is associated with a host of diseases, including cancer, non-insulin-dependent diabetes mellitus, pathological inflammation, asthma, myeloid leukemia, cardiac hypertrophy, and neurological and neurodevelopmental disorders such as bipolar disorder and Alzheimer’s disease . GSK3’s multifarious roles in many cellular events make it an important therapeutic target for the treatment of these disorders. − …”