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  • 2021-01
  • br Acknowledgments br Casein kinases CK are


    Casein kinases (CK) are serine/threonine-specific enzymes and can be divided two subtypes: casein kinase 1 (CK1) and casein kinase 2 (CK2). CK1 contains at least seven isoforms (α, β, γ1, γ2, γ3, δ and ε) expressed in eukaryotic organisms, CK1 is involved in various cellular processes including membrane trafficking, circadian rhythm, Phos-tag Biotin BTL-104 progression, chromosome segregation, apoptosis and cellular differentiation, and deregulation of CK1 activity is linked to several pathological disorders and diseases like cancer, neurodegenerative diseases such as Alzheimer’s disease (AD), Parkinson’s disease (PD) and amyotrophic lateral sclerosis (ALS), and inflammatory disorders., The overexpression of CK1 has been described in the human AD brain, since CK1 leads to an increase in amyloid-β (Aβ) peptide production, and also participates in the tau fibrillization reaction pathway through phosphorylation of tau., CK1 has become an interesting therapeutic target for AD where an urgent need for effective treatment exists, because it opens the door for the use of CK1 inhibitors as novel therapeutic approaches for AD. CK1 inhibitors can prevent Aβ formation and reverse tau hyperphosphorylation in AD, and have been used to treat neurodegenerative disorders including AD., , Recently a new series of difluoro-dioxolo-benzoimidazol-benzamides have been developed as potent CK1 inhibitors with nanomolar inhibitory activity, these compounds exhibited significant inhibitory effects on several tumor cell lines, and their biological data suggested they can be as therapeutics for AD as well. AD is a complicated neurodegenerative disease in the central nervous system (CNS), the cause of AD remains unclear, and so far no any effective treatment strategy is approved for preventing, curing and slowing the progress of AD. To discover more effective treatments, more accurate diagnostic tools are crucial to reveal new therapeutic targets. New noninvasive diagnostic imaging modalities for AD are really needed, both to detect and monitor the evolution of this disease, and to evaluate the efficacy of treatments. Advanced biomedical imaging technique positron emission tomography (PET) is one of the most widespread imaging techniques for AD, and significant progress has been made to develop PET agents for two key neuropathological substrates of AD: Aβ plaques and tau neurofibrillary tangles (NFTs)., The representative PET Aβ and tau tracers [C]PIB and [F]Amyvid ([F]AV-45);, [C]PBB3 and [F]T807 ([F]AV-1451), are listed in . The development of PET imaging probes for detection of Alzheimer’s brains is critical for early and accurate diagnosis and for the successful discovery of AD therapies. The success and limitations of Aβ imaging and tau imaging have spurred efforts worldwide to develop new selective PET tracers for different imaging targets. CK1 has emerged as a new molecular imaging target of AD, but so far no any carbon-11 or fluorine-18 labeled CK1 inhibitors as PET radiotracers for imaging of CK1 were reported. We are interested in the development of new PET AD imaging agents, and a series of enzyme- or receptor-based PET agents have been developed in this laboratory. In our previous work, we have targeted the enzyme glycogen synthase kinase-3 (GSK-3) and developed carbon-11-labeled GSK-3 inhibitors;, and we have also targeted serotonin (5-hydroxytryptamine) 6 receptor (5-HTR) and developed carbon-11-labeled 5-HTR antagonists, as PET radiotracers for AD imaging (). In this ongoing study, we first target CK1, which is a novel and attractive molecular target for treatment and PET imaging of AD. Here, we report the design, synthesis and labeling of carbon-11-labeled CK1 inhibitors, [C]methyl 3-((2,2-difluoro-5-[1,3]dioxolo[4′,5′:4,5]benzo[1,2-]imidazol-6-yl)carbamoyl)benzoate ([C]) and -(2,2-difluoro-5-[1,3]dioxolo[4′,5′:4,5]benzo[1,2-]imidazol-6-yl)-3-[C]methoxybenzamide ([C]), as new potential PET radiotracers for imaging of AD, for the first time. The basic evaluations of the radiotracers including lipophilicity and stability are presented as well.