Objective/Rationale:
Target engagement ligands, also known as imaging agents, are useful tools in the development of drugs and this project seeks to develop such a tool for Leucine Rich Repeat Kinase 2 (LRRK2). These can be used to gain a greater understanding as to the extent of interaction that is required between a drug and LRRK2 in order to have a therapeutically useful effect on Parkinson’s disease. A target engagement ligand will in particular be instrumental in selecting the right dose for human use.
Project Description:
At H. Lundbeck A/S we have identified small molecules that bind to the LRRK2 enzyme. These molecules or compounds, however, need optimization. Synthetic chemistry will be undertaken at our laboratories in order to prepare new compounds with improved potency against the LRRK2 enzyme as well as selectivity for LRRK2 vs other kinases. The potential for lead compounds to enter the brain will be assessed. We will also work on developing in vivo and in vitro assays that demonstrate the effects of LRRK2 inhibition. It is expected that a number of compounds will be identified that will be amenable to labeling with a radionuclide such as 11C or 18F and thus useful for imaging by positron emission tomography (PET).
Relevance to Diagnosis/Treatment of Parkinson’s Disease:
The development of a target engagement ligand will allow an improved measurement of interaction, also known as target occupancy, with LRRK2 in relation to the beneficial effects on Parkinson’s disease both pre-clinically but also in the clinic. This information will be invaluable in designing clinical trials as a therapeutic dose can be more accurately estimated. This will enable swifter and more effective evaluation of LRRK2 inhibition as a treatment for Parkinson’s disease.
Anticipated Outcome:
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 with 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.