Ligands for the Translocator Protein (18 kDa) (TSPO)

Ref: 12003
Novel lead series of ligands for the Translocator Protein (18 kDa) for treatment of neurodegenerative disorders and neuroinflammation

Key advantages
  • Proven high affinity and selectivity for TSPO in vitro and in vivo
  • Structural diversity resulting in various functional properties
  • Small molecules with suitable physiochemical properties
  • Ongoing validation in animal models of disease

Background

Researchers at the University of Sydney have developed novel chemical entities which bind to the TSPO with high affinity and display a range of functional activity.

Functionally, the TSPO is indispensable as it plays a pivotal role in the transportation of cholesterol from the outer to inner mitochondrial membrane and is thus the rate limiting step of neurosteroid biosynthesis and an indirect modulator of neurotransmission.

TSPO agonists have been shown to increase the concentration of neurosteroids in the brain and reduce the level of microglial activation thereby providing a novel neuroprotective mechanism.

It has also been suggested that TSPO ligands may influence neuronal function and possibly participate directly in regeneration by regulating the synthesis of neurosteroids.

The invention

This technology entails the development of viable synthetic strategies for a series of pyrazolopyrimidines, oxazepines and pyridazines and their pharmacological characterisation.

Measurements of in vitro binding, intrinsic functional activity in steroidogenesis assays and in vivo binding properties in the same study that for the first time provides correlates derived between all three parameters.

For example the novel pyrazolopyrimidine N,N-diethyl-2-[2-(4-methoxy-phenyl)-5,7-dimethylpyrazolo[1,5-a]pyrimidin-3-yl]acetate (DPA-713), displayed high affinity and selectivity for the TSPO.

In an attempt to further explore the structure activity profile of DPA-713 as a lead molecule, the methoxy moiety was modified to a simple fluoro ethoxy group resulting in the formation of the new chemical entity N,N-diethyl-2-{2-[4-(2-fluoro-ethoxy)-phenyl]-5,7-dimethylpyrazolo[1,5-a] pyrimidin-3-yl] acetate (DPA-714).

This resulted in an extraordinary fluorinated analogue that
although displayed similar affinity to the parent DPA-713 molecule appeared to be one of the most potent agonist in the pregnenolone stimulation steroidogenic assay.

This class of compounds now represents one of the most exciting scaffold for the development of molecular probes for the TSPO that can be used to further elucidate the role of this enigmatic protein.

Applications

Treatment of neurodegenerative diseases such as Alzheimer's disease, Parkinson’s disease, schizophrenia, etc.; Therapeutic treatment as neuroprotective agents; Treatment of infection and inflammation; Treatment of various cancers

Principal inventors

  • Associate Professor Michael Kassiou
  • Mr Chris Luus
  • Ms Michelle James

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