Funded Studies
Objective/Rationale:
The exciting discovery of activating mutations in the LRRK2 kinase in familial PD patients, coupled with the emergence of kinase inhibitors as a new class of efficacious drugs, provide a realistic prospect of developing novel drugs that may ameliorate, LRRK2-driven PD. Evaluation of such compounds in pre-clinical models, and consequent clinical studies, will be facilitated by an in vivo assay of the efficiency with which LRRK2 inhibitor compounds bind to LRRK2 in the brain.
Project Description:
We have generated a proprietary small molecule inhibitor of LRRK2 that satisfies a battery of prospective criteria required of a ligand for use in positron emission tomography (PET) of brain tissue in pre-clinical models. We will determine the optimal synthetic route to radiolabel this compound and use it to quantitate the density of LRRK2 in brain tissue homogenates and brain slice autoradiography studies. We will then use radio-labeled compound in pre-clinical models to examine its suitability as a selective PET ligand to measure LRRK2 density in brain and determine the ability of non-labeled compound to inhibit the signal. Further studies will then be performed to provide a data package required to support consequent decisions to deploy this LRRK2 PET ligand in initial human studies.
Relevance to Diagnosis/Treatment of Parkinson’s Disease:
Clinical association of activating LRRK2 mutations in familial Parkinson’s patients presents a tractable opportunity to develop novel drugs to treat this condition. By funding this work we aim to deliver a tool reagent that will be valuable for evaluation of potential clinical candidate LRRK2 inhibitor compounds for their effectiveness in engaging the LRRK2 target in brain tissue in vivo – so enabling selection of compounds and dosing regimens for consequent clinical studies of LRRK2 inhibitors.
Anticipated Outcome:
By working with MJFF we will expedite evaluation of the suitability of our proprietary compound as a PET ligand. We will understand the density of LRRK2 in brain tissue and establish an assay to measure the effectiveness of small molecule inhibitors of LRRK2 kinase activity to engage the LRRK2 target in brain in pre-clinical studies. We will also generate a data package necessary for consequent potential use of this PET ligand in human clinical studies.