Objective/Rationale:
LRRK2 is an emerging target for discovery of a neuroprotective agent for treatment of PD. Multiple mutations within the LRRK2 gene are associated with PD and many of these have been shown to increase LRRK2 activity. To associate clinical and pre-clinical outcomes with binding of a therapeutic agent to LRRK2, a target engagement ligand useful in imaging studies is desirable.
Project Description:
We have identified multiple chemical series that inhibit LRRK2 kinase activity with some selectivity and appear to cross the blood brain barrier. Because most LRRK2 therapeutic agents are directed towards the kinase active site, we believe these series are a good starting point for development of a LRRK2 target engagement ligand. We will begin by optimizing these series further to identify lead compounds for radio-labeling and PET imaging studies. Compounds will initially be tested for selectivity in a kinase panel followed by selectivity of binding to LRRK2 in the brain using LRRK2 knock-out and normal pre-clinical models. Selectivity measurements and PET imaging experiments will be conducted in collaboration with Johns Hopkins University Medical School.
Relevance to Diagnosis/Treatment of Parkinson’s Disease:
PET imaging agents discovered through this program can be used to map LRRK2 kinase active sites in the brain. In a pre-clinical and clinical setting, such a ligand may be displaced by LRRK2-directed therapeutic agents allowing researches to determine if their drug candidate is binding to LRRK2 in the brain. This will facilitate and enhance interpretation of clinical outcome data.
Anticipated Outcome:
The ultimate outcome of this program is to produce a LRRK2 targeted PET imaging agent. The first year of the program will identify multiple lead compounds for radio-labeling.