The overall objective of this project is to generate the data necessary to ultimately identify a small organic molecule capable of binding to a sub-domain of the LRRK2 protein with sufficient potency and specificity that it may be appropriately labeled for validation as an imaging tracer for pre-clinical/clinical testing. Positron Emission Tomography (PET) is a noninvasive tomographic method for imaging the regional distribution of radioactive tracers. PET may facilitate early diagnosis, differential diagnosis, and evaluation of drug treatment in patients with Parkinson’s disease.
The leading cause for the failure in developing PET ligands is related to the observation of high non-specific tissue binding confounding the imaging process. Pfizer has defined a set of selection criteria, based on physicochemical properties of small molecules, to minimize this non-specific binding and facilitate the rational design and prioritized synthesis of compounds with optimized properties. Iterative cycles, applying this design expertise, should narrow the list screening list of potential compounds for radiolabeling. This would have the benefit of generating fit-for-purpose ligands in a rapid fashion that could be profiled for preclinical/clinical evaluation.
Relevance to Diagnosis/Treatment of Parkinson’s Disease:
While PET tracers have been developed for the dopaminergic system, a key neurotransmitter system affected by PD, there are no currently available methods to image LRRK2. This project will provide the knowledge base for the development of a PET ligand specifically for LRRK2 with the potential broader applicability for PD.
Collaborating with the MJFF will greatly enable quantification of the biological parameters necessary for determining the protein expression profile for LRRK2. This data is required for establishing that a potential PET ligand can be developed.