This grant builds upon the research from a prior grant: LRRK2 Target Engagement Ligand
Promising Outcomes of Original Grant:
New compounds from several distinct series have been synthesized that have improved inhibition of the LRRK2 enzymatic kinase activity. We assessed their suitability as target engagement tool molecules by measuring their effects in cells, their penetration into the pre-clinical model brain, stability in the liver and the amount of compound that is freely available in plasma and brain. Front-runner compounds that showed good selectivity for LRRK2 in-vivo, as well as good exposure in the brains of models, were labeled with radioactive tritium. These did not have the right characteristics to be used as target engagement ligands (molecules that bond to atoms). Further more potent compounds are being sought for labeling.
Objectives for Supplemental Investigation:
In the proposed LRRK2 imaging project, synthetic chemistry will be undertaken for a further six months at Lundbeck. The objective will be to identify LRRK2 ligands with improved properties, including potency and selectivity for LRRK2. Although we have compounds that exhibit these features, combining these requirements into a single molecule still requires further optimization. Another requisite will be the preparation of a radiolabelled compound to allow us to determine properties of the ligand as a tracer compound.
Importance of This Research for the Development of a New PD Therapy:
The development of a target engagement ligand for a kinase, such as LRRK2, in the central nervous system is a relatively unexplored area of research, and it is expected that this project will deliver with one or more ligands. The project will contribute a greater understanding of the challenges and opportunities in this area as well as the extent to which the LRRK2 protein needs to be inhibited in order to demonstrate a therapeutically useful benefit.