Towards Imaging Tau Hyperphosphorylation: Is DYRK1A a Potential Target for Imaging Hyperphosphorylation of Tau? Molecular Modeling Assessment and Synthesis of [125I]Radioiodinated DYRK1A Inhibitor

Dual specificity tyrosine-phosphorylation regulated kinase 1A (DYRK1A), a phosphorylation kinase, is localized within the central nervous system and is linked to hyperphosphorylation of Tau. Imaging of DYRK1A may provide an earlier biomarker for Tauopathies, including Alzheimer&rsquo:s disease (AD). We have used Chimera-Autodock to evaluate potential molecules for binding to the binding site of DYRK1A. Five molecules, 10-bromo-2-iodo-11H-indolo[3,2-c]quinoline-6-carboxylic acid (4E3), 10-iodo-11H-indolo[3,2-c]quinoline-6-carboxylic acid (KuFal184), harmine, 6-(fluoro-3-(1H-pyrrolo[2,3-c]pyridin-1-yl)isoquinolin-5-amine (MK-6240), and 6-iodo-3-(1H-pyrrolo[2,3-c]pyridine-1-yl)isoquinoline (IPPI), were found to have binding energies of &minus:10.4, &minus:10.1, &minus:9.0, &minus:9.1, and &minus:9.4 kcal/mole, respectively. Two molecules, 4E3 and KuFal184, were selective for DYRK1A, while harmine also had a monoamine oxidase A affinity, and MK-6240 and IPPI had affinity for Tau. Tau present in the brain slices of AD subject were labeled with [125I]IPPI. KuFal184 had no effect on the binding of [125I]IPPI, suggesting the absence of binding overlap of the two molecules. MK-6240, a known Tau agent was, however, able to compete with [125I]IPPI. The binding energies of harmine, MK-6240, and IPPI for the DYRK1A site suggest affinities of approximately 80&ndash:100 nM, which is insufficient to serve as an imaging agent. The higher affinity of KuFal184 (6 nM for DYRK1A) suggested that [125I]KuFal184 may be a potential imaging agent. Electrophilic radioiodination was used to synthesize [125I]KuFal184 in modest yields (25%) and high radiochemical purity (&gt:95%). Preliminary binding studies with [125I]KuFal184 in AD brain slices showed some selectivity for cortical grey matter regions containing Tau.