Mutations in the leucine-rich repeat kinase 2 (LRRK2) gene are commonly associated with sporadic and familial cases of Parkinson’s disease (PD). The most frequent mutation, G2019S, is associated with increased kinase activity and as a result has led to a significant medicinal chemistry effort to discover selective LRRK2 inhibitors as a potential therapy for PD. The development of a LRRK2-selective PET tracer would greatly facilitate these efforts by confirming central in vivo target engagement of potential clinical candidates. This poster describes the medicinal chemistry effort to discover potent LRRK2 (WT full-length enzyme) selective inhibitor compounds 1 and 2 as tool compounds to assess the feasibility of developing a CNS LRRK2 PET tracer. Both compounds were observed to have displaceable and saturable binding of LRRK2 WT full-length enzyme: [3H]-1 and [3H]-2 bind to one site in LRRK2 WT full-length enzyme with very high affinity (Kd = 56 pM and Kd = 57 pM ). Further in vitro studies of [3H]-2 showed minimal saturable and displaceable binding in rat, rhesus, and human brain tissue (cortexand/or striatum) with a consistent low target density Bmax (0.3nM-1.4nM), which suggests a low probability of success for the development of a CNS-targeted PET tracer for LRRK2.

Discovery of highly selective LRRK2 inhibitors as tool compounds to assess CNS PET tracer feasibility

255th National Meeting (2018)

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