Development of 18F-Labeled PET Tracer Candidates for Imaging of the Abelson Non-receptor Tyrosine Kinase in Parkinson's Disease.

Activated Abelson non-receptor tyrosine kinase (c-Abl) plays a harmful role in neurodegenerative conditions such as Parkinson's disease (PD). Inhibition of c-Abl is reported to have a neuroprotective effect and be a promising therapeutic strategy for PD. We have previously identified a series of benzo[d]thiazole derivatives as selective c-Abl inhibitors from which one compound showed high therapeutic potential. Herein, we report the development of a complementary positron emission tomography (PET) tracer. In total, three PET tracer candidates were developed and eventually radiolabeled with fluorine-18 for in vivo evaluation studies in mice. Candidate [18F]3 was identified as the most promising compound, since it showed sufficient brain uptake, good washout kinetics, and satisfactory metabolic stability. In conclusion, we believe this tracer provides a good starting point to further validate and explore c-Abl as a target for therapeutic strategies against PD supported by PET.

A Novel, Selective c-Abl Inhibitor, Compound 5, Prevents Neurodegeneration in Parkinson's Disease.

Parkinson's disease (PD) is a progressive neurodegenerative disorder that affects movement. The nonreceptor tyrosine kinase c-Abl has shown a potential role in the progression of PD. As such, c-Abl inhibition is a promising candidate for neuroprotection in PD and α-synucleinopathies. Compound 5 is a newly synthesized blood-brain barrier penetrant c-Abl inhibitor with higher efficacy than existing inhibitors. The objective of the current study was to demonstrate the neuroprotective effects of compound 5 on the α-synuclein preformed fibril (α-syn PFF) mouse model of PD. Compound 5 significantly reduced neurotoxicity, activation of c-Abl, and Lewy body pathology caused by α-syn PFF in cortical neurons. Additionally, compound 5 markedly ameliorated the loss of dopaminergic neurons, c-Abl activation, Lewy body pathology, neuroinflammatory responses, and behavioral deficits induced by α-syn PFF injection in vivo. Taken together, these results suggest that compound 5 could be a pharmaceutical agent to prevent the progression of PD and α-synucleinopathies.

Nrf2 activator via interference of Nrf2-Keap1 interaction has antioxidant and anti-inflammatory properties in Parkinson's disease animal model.

Parkinson's disease (PD) is a neurodegenerative disorder characterized by abnormal movement, including slowed movements, shuffling gait, lack of balance, and tremor. Oxidative stress has been shown to play a decisive role in dopaminergic neuronal cell death in PD. The nuclear factor E2-related factor 2 (Nrf2)-Kelch-like ECH-associated protein 1 (Keap1) signaling pathway provides the main defense system against oxidative stress by inducing the expression of antioxidant enzyme genes. Direct interference in the Keap1-Nrf2 protein-protein interaction (PPI) has emerged as an effective strategy for Nrf2 activation. Therefore, we searched for novel Nrf2 activators that can disrupt Nrf2-Keap1 interaction by using a virtual screening approach and identified a potent Nrf2 activator, KKPA4026. KKPA4026 was confirmed to induce the expression of the Nrf2-dependent antioxidant enzymes heme oxygenase-1, glutamate-cysteine ligase catalytic subunit, glutamate-cysteine ligase regulatory subunit, and NAD(P)H:quinone oxidoreductase 1 in BV-2 cells. Furthermore, KKPA4026 showed anti-inflammatory effects in an Nrf2-dependent manner. In a 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced mouse model of PD, KKPA4026 effectively attenuated PD-associated behavioral deficits and protected dopaminergic neurons. In summary, we identified KKPA4026 as a novel Nrf2 activator and suggested that Nrf2 activation through interference with the Nrf2-Keap1 interaction may be effective for PD treatment.