Radiosynthesis and evaluation of 4-(6-[18F]Fluoro-4-(5-isopropoxy-1H-indazol-3-yl)pyridin-2-yl)morpholine as a novel radiotracer candidate targeting leucine-rich repeat kinase 2

Mutations that increase leucine-rich repeat kinase 2 (LRRK2) activity in the brain are associated with Parkinson's disease. Here, we synthesized a novel compound 4-(6-fluoro-4-(5-isopropoxy-1H-indazol-3-yl)pyridin-2-yl)morpholine (FIPM) and labeled it with fluorine-18 (F-18), to develop a positron emission tomography (PET) tracer forin vivovisualization of LRRK2 in the brain. FIPM showed highin vitrobinding affinity for LRRK2 (IC50= 8.0 nM). [F-18]FIPM was prepared in 5% radiochemical yield (n= 5), by inserting(18)F into a pyridine ring, followed by removal of the protecting group. After HPLC separation and formulation, [F-18]FIPM was acquired with >97% radiochemical purity and 103-300 GBq mu mol(-1)of molar activity at the end of radiosynthesis. Biodistribution and small-animal PET studies in mice indicated a lowin vivospecific binding of [F-18]FIPM. While [F-18]FIPM presented limited potential as anin vivoPET tracer for LRRK2, we suggested that it can be used as a lead compound for developing new radiotracers with improvedin vivobrain properties.