Promising Outcomes of Original Grant:
With our initial grant from MJFF, we focused on designing and synthesizing chemical matter with physico-chemical properties such that it could travel into the brain. Once located at the desired site, the compound would need to exhibit the requisite potency towards LRRK2 in order to engage the target with sufficient selectivity to properly image the desired brain regions. Hundreds of thousands of compounds were triaged for these attributes, resulting in several compounds being radiolabeled. These compounds were characterized in binding assays to assess their feasibility for use as PET ligands.
Objectives for Supplemental Investigation:
The current grant will allow us to continue to profile the identified compounds and to biologically characterize the target. Ideally, PET ligands have a binding potential that is greater than 10. This parameter is a ratio of the number of binding sites (number of LRRK2 targets in the brain) to the affinity of the compound for the binding site (binding dissociation constant). The initial phase of the grant will be to determine this binding potential, while, in parallel, we will continue the chemical design and synthesis of additional analogs to improve upon our compound properties. Once completed, the selected compound(s) will be radiolabeled, with an appropriate PET tracer element, and preliminary pre-clinical imaging studies will be conducted to assess the ability of the compound to image specific brain regions. This data will greatly enable us to improve the compounds and spark the planning of additional, more in-depth studies towards developing a clinical PET tracer for LRRK2 and Parkinson’s disease.
Importance of This Research for the Development of a New PD Therapy:
Three factors need to be measured in the clinic to sufficiently assess whether the therapeutic being investigated is having the desired effect on the target of interest. First, the drug needs to be present at the target site of action with sufficient exposure. Second, the therapeutic needs to bind to the target. Third, the binding of the therapeutic to the target results in the desire pharmacological effect. Since directly accessing the brain is not feasible, alternative methods are required to measure these endpoints. PET ligands are the clinically approved method for determining the second endpoint. The deliverable from this work would be a LRRK2 PET ligand that would permit ready determination of the effectiveness for any LRRK2-based therapeutic for Parkinson’s disease.